Tecentriq Hybreza Drug Information
Generic name: ATEZOLIZUMAB AND HYALURONIDASE-TQJS
Programmed Death Receptor-1 Blocking Antibody [EPC] Endoglycosidase [EPC]
Uses of Tecentriq Hybreza
Non-Small Cell Lung Cancer TECENTRIQ
HYBREZA, as monotherapy, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage II to IIIA non-small cell lung cancer (NSCLC) whose tumors have PD-L1 expression on ≥ 1% of tumor cells, as determined by an FDA- authorized test. TECENTRIQ HYBREZA, as monotherapy, is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression (PD-L1 stained ≥ 50% of tumor cells or PD-L1 stained tumor-infiltrating immune cells covering ≥ 10% of the tumor area ), as determined by an FDA- authorized test, with no EGFR or ALK genomic tumor aberrations. TECENTRIQ HYBREZA, in combination with bevacizumab, paclitaxel, and carboplatin, is indicated for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations.
TECENTRIQ HYBREZA, as monotherapy, is indicated for the treatment of adult patients with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for NSCLC harboring these aberrations prior to receiving TECENTRIQ HYBREZA.
Small Cell Lung Cancer TECENTRIQ HYBREZA, in combination with carboplatin and etoposide, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). TECENTRIQ HYBREZA, in combination with lurbinectedin, is indicated for the maintenance treatment of adult patients with ES-SCLC whose disease has not progressed after first-line induction therapy with TECENTRIQ HYBREZA or intravenous atezolizumab, carboplatin and etoposide.
Hepatocellular Carcinoma TECENTRIQ HYBREZA, in combination with bevacizumab, is indicated for the treatment of adult patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy.
Melanoma TECENTRIQ HYBREZA, in combination with cobimetinib and vemurafenib, is indicated for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma as determined by an FDA-approved test.
Alveolar Soft Part Sarcoma TECENTRIQ
HYBREZA, as monotherapy, is indicated for the treatment of adult patients and pediatric patients (12 years of age and older who weigh 40 kg or greater) with unresectable or metastatic alveolar soft part sarcoma (ASPS).
Muscle Invasive Bladder Cancer TECENTRIQ
HYBREZA, as monotherapy, is indicated as adjuvant treatment of adult patients with muscle invasive bladder cancer (MIBC) after cystectomy who have circulating tumor DNA molecular residual disease (ctDNA MRD) as determined by an FDA-authorized test.
Dosage & Administration of Tecentriq Hybreza
Patient Selection for Treatment of Non-Small Cell Lung Cancer, Melanoma and Muscle Invasive Bladder Cancer Select adult patients with: Stage II to IIIA NSCLC for adjuvant treatment with TECENTRIQ HYBREZA as a monotherapy (following tumor resection and platinum-based chemotherapy) based on PD-L1 expression on tumor cells. Metastatic NSCLC for first-line treatment with TECENTRIQ HYBREZA as monotherapy based on the PD-L1 expression on tumor cells or on tumor-infiltrating immune cells. Unresectable or metastatic melanoma for treatment with TECENTRIQ HYBREZA in combination with cobimetinib and vemurafenib after confirming the presence of a BRAF V600 mutation.
MIBC for treatment with TECENTRIQ HYBREZA, as a monotherapy based on detection of ctDNA MRD in plasma via serial testing between six weeks and one year after cystectomy. Information on FDA-authorized tests for the determination of PD-L1 expression in metastatic NSCLC, for detection of BRAF V600 mutations in melanoma, or for the determination of ctDNA MRD status in MIBC is available at: http://www.fda.gov/CompanionDiagnostics.
Important Dosage and Administration Information TECENTRIQ HYBREZA has different recommended dosage and administration than intravenous atezolizumab products. To reduce the risk of medication errors, prior to administration, check the vial labels to ensure that the drug being prepared is subcutaneously administered TECENTRIQ HYBREZA and not intravenously administered atezolizumab. Do not substitute TECENTRIQ HYBREZA for or with intravenous atezolizumab products because they have different recommended dosages.
Adult patients who are treated with intravenous atezolizumab can switch to subcutaneous TECENTRIQ HYBREZA at their next scheduled dose. TECENTRIQ HYBREZA is for subcutaneous use in the thigh only. Administer over approximately 7 minutes.
Inject in healthy skin and never into areas where the skin is red, bruised, tender, or hard. When possible, alternate injections between the left and right thigh. Ensure the injection site is at least 2.5 cm from the previous site.
Do not administer TECENTRIQ HYBREZA intravenously. TECENTRIQ HYBREZA must be administered by a healthcare professional. Do not administer the remaining volume in the tubing to the patient.
If using concomitant subcutaneous drugs, administer at sites other than the thighs.
Recommended Dosage and Administration Instructions
The recommended dosage of TECENTRIQ HYBREZA in adult patients and pediatric patients (12 years of age and older who weigh 40 kg or greater) is one 15 mL injection (containing 1,875 mg of atezolizumab and 30,000 units of hyaluronidase, referred to as TECENTRIQ HYBREZA) administered subcutaneously in the thigh over approximately 7 minutes every 3 weeks. The recommended dosage for pediatric patients 12 years of age and older who weigh less than 40 kg has not been established. Administration instructions for TECENTRIQ HYBREZA as monotherapy and in combination with other therapeutic agents are presented in Table 1.
For the recommended dosage of each therapeutic agent administered in combination with TECENTRIQ HYBREZA refer to the product's respective Prescribing Information. Table 1: TECENTRIQ HYBREZA Administration Instructions and s No dose reduction for TECENTRIQ HYBREZA is recommended. In general, withhold TECENTRIQ HYBREZA for severe (Grade 3) immune-mediated adverse reactions.
Permanently discontinue TECENTRIQ HYBREZA for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce the daily corticosteroid dosage to 10 mg or less of prednisone or equivalent corticosteroid dosage within 12 weeks of initiating corticosteroids. Dosage modifications for TECENTRIQ HYBREZA for adverse reactions that require management different from these general guidelines are summarized in Table 2. Table 2: Recommended
Preparation Instructions TECENTRIQ
HYBREZA does not contain any antimicrobial preservative. If the TECENTRIQ HYBREZA dose is not administered immediately, refer to "Storage Instructions". Remove the vial from the refrigerator and allow the solution to acclimate to room temperature.
Visually inspect for particulate matter and discoloration prior to administration. Discard the vial if the solution is cloudy, discolored, or visible particles are observed. Do not shake, freeze, or dilute.
The unpunctured vial may be stored at room temperature in ambient light for a maximum of 4 hours prior to the preparation for administration. Use an 18-gauge transfer needle and syringe to withdraw the entire contents of the TECENTRIQ HYBREZA solution from the vial. Discard the vial and any residual drug remaining.
TECENTRIQ HYBREZA is compatible with stainless steel transfer and injection needles, and polypropylene, polycarbonate, polyvinyl chloride, and polyurethane syringe material and subcutaneous administration sets. Remove the transfer needle from the syringe and replace it with a subcutaneous administration set (e.g. winged/butterfly) containing 23-gauge, 24-gauge, or 25-gauge hypodermic needle and with a priming volume that does not exceed 0.5 mL for administration. Prime the subcutaneous administration line with TECENTRIQ HYBREZA to eliminate the air in the line and stop when the fluid reaches the needle.
Ensure the syringe contains exactly 15 mL of TECENTRIQ HYBREZA after priming the administration line by expelling any excess volume from the syringe. Administer immediately to avoid needle clogging. Discard any unused portion remaining.
Storage Instructions
Do not store the prepared syringe that has been attached to the already-primed subcutaneous administration set. If the prepared syringe containing TECENTRIQ HYBREZA is not for immediate use, do not attach a subcutaneous administration set. The capped syringe may be stored at room temperature in ambient room lighting for up to 8 hours and in the refrigerator for up to 72 hours.
If the prepared syringe is stored at 2°C to 8°C (36°F to 46°F), allow the syringe to acclimate to room temperature prior to administration.
| Indication | Administration Instructions for TECENTRIQ HYBREZA | Duration of Therapy |
|---|---|---|
| Adjuvant Treatment of Non-Small Cell Lung Cancer | Administer TECENTRIQ HYBREZA as monotherapy | Up to one year, unless there is disease recurrence or unacceptable toxicity |
| Metastatic Non-Small Cell Lung Cancer | Until disease progression or unacceptable toxicity | |
| Non-Small Cell Lung Cancer | Administer TECENTRIQ HYBREZA prior to chemotherapy and bevacizumab when given on the same day. | Until disease progression or unacceptable toxicity |
| Small Cell Lung Cancer | Administer TECENTRIQ HYBREZA prior to chemotherapy when given on the same day. | |
| Hepatocellular Carcinoma | Administer TECENTRIQ HYBREZA prior to bevacizumab when given on the same day. Bevacizumab is administered intravenously at 15 mg/kg every 3 weeks. | |
| Melanoma | Prior to initiating TECENTRIQ HYBREZA, patients should receive the following 28-day treatment cycle of cobimetinib and vemurafenib: Days 1 to 21: cobimetinib 60 mg orally once daily in combination with 960 mg of oral vemurafenib twice daily Days 22 to 28: withhold cobimetinib and administer vemurafenib 720 mg orally twice daily | |
| Alveolar Soft Part Sarcoma | Administer TECENTRIQ HYBREZA as monotherapy | Until disease progression or unacceptable toxicity |
| Muscle Invasive Bladder Cancer | Administer TECENTRIQ HYBREZA as monotherapy | Up to one year, unless there is disease recurrence or unacceptable toxicity |
| Adverse Reaction | Severity Based on Common Terminology Criteria for Adverse Events (CTCAE), version 5 | Dosage Modification |
|---|---|---|
| ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson syndrome, TEN = toxic epidermal necrolysis | ||
| Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) ] | ||
| Pneumonitis | Grade 2 | Withhold Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids |
| Grades 3 or 4 | Permanently discontinue | |
| Colitis | Grades 2 or 3 | Withhold |
| Grade 4 | Permanently discontinue | |
| Hepatitis with no tumor involvement of the liver | AST or ALT increases to more than 3 and up to 8 times ULN or Total bilirubin increases to more than 1.5 and up to 3 times ULN | Withhold |
| AST or ALT increases to more than 8 times ULN or Total bilirubin increases to more than 3 times ULN | Permanently discontinue | |
| Hepatitis with tumor involvement of the liver If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue TECENTRIQ HYBREZA based on recommendations for hepatitis with no liver involvement | Baseline AST or ALT is more than 1 and up to 3 times ULN and increases to more than 5 and up to 10 times ULN or Baseline AST or ALT is more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULN | Withhold |
| AST or ALT increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULN | Permanently discontinue | |
| Endocrinopathies | Grades 3 or 4 | Withhold until clinically stable or permanently discontinue depending on severity |
| Nephritis with Renal Dysfunction | Grades 2 or 3 increased blood creatinine | Withhold |
| Grade 4 increased blood creatinine | Permanently discontinue | |
| Exfoliative Dermatologic Conditions | Suspected SJS, TEN, or DRESS | Withhold |
| Confirmed SJS, TEN, or DRESS | Permanently discontinue | |
| Myocarditis or pericarditis | Grades 2, 3, or 4 | Permanently discontinue |
| Neurological Toxicities | Grade 2 | Withhold |
| Grades 3 or 4 | Permanently discontinue | |
| Other Adverse Reactions | ||
| Infusion-Related Reactions [see Warnings and Precautions (5.2) ] | Grades 1 or 2 | Pause or slow the rate of injection Premedication with antipyretic and antihistamines may be considered for subsequent doses. |
| Grades 3 or 4 | Permanently discontinue | |
Side Effects of Tecentriq Hybreza
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions of TECENTRIQ HYBREZA in Adult Patients with NSCLC The safety of TECENTRIQ HYBREZA was evaluated in IMscin001, open-label, multi-center, international, randomized trial for patients with locally advanced or metastatic NSCLC who have not been exposed to cancer immunotherapy and who have had disease progression on prior platinum-based therapy. Patients with previously treated metastatic non-small cell lung cancer (NSCLC) either received TECENTRIQ HYBREZA (containing 1,875 mg of atezolizumab and 30,000 units of hyaluronidase) administered subcutaneously into the thigh over approximately 7 minutes every 3 weeks or intravenous atezolizumab every 3 weeks until disease progression or unacceptable toxicity.
Serious adverse reactions occurred in 19% of patients who received TECENTRIQ HYBREZA. Serious adverse reactions (> 1%) included pneumonia, myocardial infarction, and pleural effusion. Fatal adverse reactions occurred in 6% of patients who received TECENTRIQ HYBREZA, including pneumonia ( %).
Permanent discontinuation of TECENTRIQ HYBREZA due to an adverse reaction occurred in 3.6% of patients. Adverse reactions which resulted in permanent discontinuation of TECENTRIQ HYBREZA in > 1% of patients included pneumonia (2%). Dosage interruptions of TECENTRIQ HYBREZA due to an adverse reaction occurred in 32% of patients.
Adverse reactions which required dosage interruption in > 1% of patients were COVID-19 (4.9%), increased aspartate aminotransferase ( %), and viral respiratory tract infection (1.2%). The most common adverse reactions of any grade (occurring in ≥ %). Tables 3 and 4 summarize adverse reactions and selected laboratory abnormalities, respectively in TECENTRIQ HYBREZA-treated patients in IMscin001.
Table 4: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Adult Patients with Advanced or Metastatic NSCLC Who Received TECENTRIQ HYBREZA in IMscin001 s in Adult Patients with NSCLC Treated with Intravenous Atezolizumab The safety of TECENTRIQ HYBREZA for its approved NSCLC indications has been established in adequate and well-controlled studies of intravenous atezolizumab for the: adjuvant treatment (following tumor resection and platinum-based chemotherapy) in adult patients with stage II to IIIA NSCLC whose tumors have PD-L1 expression on ≥ 1% of tumor cells (IMpower010 study). first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression (PD-L1 stained ≥ 50% of tumor cells or PD-L1 stained tumor-infiltrating immune cells covering ≥ 10% of the tumor area ), with no EGFR or ALK genomic tumor aberrations (IMpower110 study). first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (IMpower150 study). first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (IMpower130 study). first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression, with no EGFR or ALK genomic tumor aberrations (OAK study). Below is a description of adverse reactions of intravenous atezolizumab in these adequate and well-controlled NSCLC studies. Non-Small Cell Lung Cancer (NSCLC) Adjuvant Treatment of Early-stage NSCLC IMpower010 The safety of intravenous atezolizumab was evaluated in IMpower010, a multicenter, open-label, randomized trial for the adjuvant treatment of patients with stage IB (tumors ≥ 4 cm) -IIIA NSCLC who had complete tumor resection and received up to 4 cycles of cisplatin-based adjuvant chemotherapy.
The median number of cycles received was 16 (range: 1, 16). Fatal adverse reactions occurred in 1.8% of patients receiving intravenous atezolizumab; these included multiple organ dysfunction syndrome, pneumothorax, interstitial lung disease, arrhythmia, acute cardiac failure, myocarditis, cerebrovascular accident, death of unknown cause, and acute myeloid leukemia (1 patient each). Serious adverse reactions occurred in 18% of patients receiving intravenous atezolizumab.
Adverse reactions leading to interruption of intravenous atezolizumab occurred in 29% of patients; the most common (> 1%) were rash (3.0%), hyperthyroidism ( %). Tables 5 and 6 summarize adverse reactions and selected laboratory abnormalities in patients receiving intravenous atezolizumab in IMpower010. Table 5: Adverse Reactions Occurring in ≥ 10% of Patients with Early-Stage NSCLC Receiving 6 0 Table 6: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients with Early-Stage NSCLC Receiving Metastatic Chemotherapy-Naïve NSCLC IMpower110 The safety of intravenous atezolizumab was evaluated in IMpower110, a multicenter, international, randomized, open-label study in 549 chemotherapy-naïve patients with stage IV NSCLC, including those with EGFR or ALK genomic tumor aberrations.
Patients received intravenous atezolizumab 1200 mg every 3 weeks (n = 286) or platinum-based chemotherapy consisting of carboplatin or cisplatin with either pemetrexed or gemcitabine (n = 263) until disease progression or unacceptable toxicity. IMpower110 enrolled patients whose tumors express PD-L1 (PD-L1 stained ≥ 1% of tumor cells or PD-L1 stained tumor-infiltrating immune cells covering ≥ 1% of the tumor area). The median duration of exposure to intravenous atezolizumab was 5.3 months (0 to 33 months).
Fatal adverse reactions occurred in 3.8% of patients receiving intravenous atezolizumab; these included death (reported as unexplained death and death of unknown cause), aspiration, chronic obstructive pulmonary disease, pulmonary embolism, acute myocardial infarction, cardiac arrest, mechanical ileus, sepsis, cerebral infarction, and device occlusion (1 patient each). Intravenous atezolizumab was discontinued due to adverse reactions in 6% of patients; the most common adverse reactions (≥ 2 patients) leading to intravenous atezolizumab discontinuation were peripheral neuropathy and pneumonitis. The median duration of exposure to intravenous atezolizumab was 8.3 months in patients receiving intravenous atezolizumab with bevacizumab, paclitaxel, and carboplatin.
Fatal adverse reactions occurred in 6% of patients receiving intravenous atezolizumab; these included hemoptysis, febrile neutropenia, pulmonary embolism, pulmonary hemorrhage, death, cardiac arrest, cerebrovascular accident, pneumonia, aspiration pneumonia, chronic obstructive pulmonary disease, intracranial hemorrhage, intestinal angina, intestinal ischemia, intestinal obstruction and aortic dissection. Serious adverse reactions occurred in 44%. The most frequent serious adverse reactions (> 2%) were febrile neutropenia, pneumonia, diarrhea, and hemoptysis.
Intravenous atezolizumab was discontinued due to adverse reactions in 15% of patients; the most common adverse reaction leading to discontinuation was pneumonitis (1.8%). Adverse reactions leading to interruption of intravenous atezolizumab occurred in 48%; the most common (> 1%) were neutropenia, thrombocytopenia, fatigue/asthenia, diarrhea, hypothyroidism, anemia, pneumonia, pyrexia, hyperthyroidism, febrile neutropenia, increased ALT, dyspnea, dehydration and proteinuria. Among patients receiving intravenous atezolizumab, 55% were exposed for 6 months or longer and 3.5% were exposed for greater than one year.
Intravenous atezolizumab was discontinued due to adverse reactions in 13% of patients; the most common adverse reactions leading to discontinuation were pneumonia ( %). Adverse reactions leading to interruption of intravenous atezolizumab occurred in 62% of patients; the most common (> 1%) were neutropenia, thrombocytopenia, anemia, diarrhea, fatigue/asthenia, pneumonia, dyspnea, pneumonitis, pyrexia, nausea, acute kidney injury, vomiting, pulmonary embolism, arthralgia, infusion-related reaction, abdominal pain, chronic obstructive pulmonary disease exacerbation, dehydration, and hypokalemia. Tables 11 and 12 summarize adverse reactions and laboratory abnormalities in patients receiving intravenous atezolizumab with paclitaxel protein-bound and carboplatin in IMpower: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ Previously Treated Metastatic NSCLC OAK The safety of intravenous atezolizumab was evaluated in OAK, a multicenter, international, randomized, open-label trial in patients with metastatic NSCLC who progressed during or following a platinum-containing regimen, regardless of PD-L1 expression.
The study excluded patients with active or prior autoimmune disease or with medical conditions that required systemic corticosteroids. The study population characteristics were: median age of % had Eastern Cooperative Oncology Group (ECOG) performance status of 1. Fatal adverse reactions occurred in 1.6% of patients; these included pneumonia, sepsis, septic shock, dyspnea, pulmonary hemorrhage, sudden death, myocardial ischemia or renal failure.
Serious adverse reactions occurred in 33.5% of patients. The most frequent serious adverse reactions (> 1%) were pneumonia, sepsis, dyspnea, pleural effusion, pulmonary embolism, pyrexia and respiratory tract infection. The most common adverse reactions leading to intravenous atezolizumab discontinuation were fatigue, infections and dyspnea.
Adverse reactions leading to interruption of intravenous atezolizumab occurred in 25% of patients; the most common (> 1%) were pneumonia, liver function test abnormality, dyspnea, fatigue, pyrexia, and back pain. Tables 13 and 14 summarize adverse reactions and laboratory abnormalities, respectively, in OAK. Table: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ s in Adult Patients with Small Cell Lung Cancer The safety of TECENTRIQ HYBREZA for its approved Small Cell Lung Cancer (SCLC) indications has been established in adequate and well-controlled studies of intravenous atezolizumab for SCLC (IMpower133 and IMforte studies).
These included pneumonia, respiratory failure, neutropenia, and death (1 patient each). The most frequent adverse reaction requiring permanent discontinuation in > 2% of patients was infusion-related reactions (2.5%). Tables 15 and 16 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received intravenous atezolizumab with carboplatin and etoposide in IMpower: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ IMforte The safety of intravenous atezolizumab in combination with lurbinectedin was evaluated in IMforte.
Primary prophylaxis of G-CSF was administered to 84% of patients. Permanent discontinuation of intravenous atezolizumab due to an adverse reaction occurred in 2.5% of patients. The adverse reactions requiring permanent discontinuation in ≥ 1% of patients who received intravenous atezolizumab were immune-mediated nephritis, peripheral neuropathy, nephropathy, pneumonitis, anemia, neutropenia, and thrombocytopenia.
Dosage interruptions of intravenous atezolizumab due to an adverse reaction occurred in 29% of patients. Adverse reactions which required dosage interruption in ≥ 2% of patients included anemia, fatigue, decreased neutrophil count, pneumonitis, and decreased platelet count. Tables 17 and 18 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received intravenous atezolizumab with lurbinectedin in IMforte.
Table 17: Adverse Reactions (≥10%) in Patients with ES-SCLC Who Received 2 Clinically relevant adverse reactions in < 10% of patients who received intravenous atezolizumab in combination with lurbinectedin included pneumonia, phlebitis, extravasation resulting in skin necrosis, hypersensitivity and increased creatine phosphokinase. Table 18: Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with ES-SCLC Who Received Intravenous Atezolizumab in Combination with Lurbinectedin in IMforte s in Adult Patients with Hepatocellular Carcinoma The safety of TECENTRIQ HYBREZA for its approved indication hepatocellular carcinoma has been established in adequate and well-controlled studies of intravenous atezolizumab for hepatocellular carcinoma (IMbrave150 study). Hepatocellular Carcinoma IMbrave150 The safety of intravenous atezolizumab in combination with bevacizumab was evaluated in IMbrave150, a multicenter, international, randomized, open-label trial in patients with locally advanced or metastatic or unresectable hepatocellular carcinoma who have not received prior systemic treatment.
Fatal adverse reactions occurred in 4.6% of patients in the intravenous atezolizumab and bevacizumab arm. The most common adverse reactions leading to death were gastrointestinal and esophageal varices hemorrhage (1.2%) and infections (1.2%). Serious adverse reactions occurred in 38% of patients in the intravenous atezolizumab and bevacizumab arm.
Adverse reactions leading to discontinuation of intravenous atezolizumab occurred in 9% of patients in the intravenous atezolizumab and bevacizumab arm. Immune-related adverse reactions requiring systemic corticosteroid therapy occurred in 12% of patients in the intravenous atezolizumab and bevacizumab arm. Tables 19 and 20 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received intravenous atezolizumab and bevacizumab in IMbrave: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ s in Adult Patients with Melanoma The safety of TECENTRIQ HYBREZA for its approved melanoma indication has been established in adequate and well-controlled studies of intravenous atezolizumab for melanoma (IMspire150 study).
Metastatic Melanoma IMspire150 The safety of intravenous atezolizumab, administered with cobimetinib and vemurafenib, was evaluated in IMspire150, a double-blind, randomized (1:1), placebo-controlled study conducted in patients with previously untreated BRAF V600 mutation-positive metastatic or unresectable melanoma. Patients received intravenous atezolizumab with cobimetinib and vemurafenib (n = 230) or placebo with cobimetinib and vemurafenib (n = 281). Fatal adverse reactions occurred in 3% of patients in the intravenous atezolizumab plus cobimetinib and vemurafenib arm.
Adverse reactions leading to death were hepatic failure, fulminant hepatitis, sepsis, septic shock, pneumonia, and cardiac arrest. Serious adverse reactions occurred in 45% of patients in the intravenous atezolizumab plus cobimetinib and vemurafenib arm. Adverse reactions leading to discontinuation of intravenous atezolizumab occurred in 21% of patients in the intravenous atezolizumab plus cobimetinib and vemurafenib arm.
The most frequent (≥ 2%) adverse reactions leading to intravenous atezolizumab discontinuation were increased ALT (2.2%) and pneumonitis (2.6%). Adverse reactions leading to interruption of intravenous atezolizumab occurred in 68% of patients in the intravenous atezolizumab plus cobimetinib and vemurafenib arm. Table 21: Adverse Reactions Occurring in ≥ 10% of Patients on the Intravenous Atezolizumab plus Cobimetinib and Vemurafenib Arm or the Placebo plus Cobimetinib and Vemurafenib Arm and at a Higher Incidence Between Arm Difference of ≥ 5% All Grades or ≥ 2% Grades 3-4 7 Clinically important adverse reactions in < 10% of patients who received intravenous atezolizumab plus cobimetinib and vemurafenib were: Cardiac Disorders: Arrhythmias, ejection fraction decreased, electrocardiogram QT prolonged Eye Disorders: Uveitis Gastrointestinal disorders: Pancreatitis Infections and infestations: Pneumonia, urinary tract infection Metabolism and nutrition disorders: Hyperglycemia Nervous system Disorders: Dizziness, dysgeusia, syncope: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients Receiving Intravenous Atezolizumab Plus Cobimetinib and Vemurafenib Arm or the Placebo Plus Cobimetinib and Vemurafenib Arm and at a Higher Incidence (Between Arm Difference of ≥ 5% All Grades or ≥ 2% Grades 3–4) in IMspire s in Adults with Alveolar Soft Part Sarcoma The safety of TECENTRIQ HYBREZA for its approved alveolar soft part sarcoma (ASPS) indication has been established in adequate and well-controlled studies of intravenous atezolizumab for ASPS (ML39345 study).
Alveolar Soft Part Sarcoma ML39345 Study The safety of intravenous atezolizumab was evaluated in 47 adult and 2 pediatric patients enrolled in Study ML39345. The median duration of exposure to intravenous atezolizumab was 8.9 months (1 to 40 months). The most frequent serious adverse reactions (> 2%) were fatigue, pain in extremity, pulmonary hemorrhage, and pneumonia (4.1% each).
The most common adverse reactions (≥ 3%) leading to dose interruptions were pneumonitis and pain in extremity (4.1% each). Tables 23 and 24 summarize adverse reactions and laboratory abnormalities in Study ML: Laboratory Abnormalities Worsening from Baseline Occurring in ≥ s in Adult Patients with Muscle Invasive Bladder Cancer The safety of TECENTRIQ HYBREZA for its approved muscle invasive bladder cancer (MIBC) indication has been established in an adequate and well-controlled study of intravenous atezolizumab for MIBC (IMvigor011 study). Muscle Invasive Bladder Cancer IMvigor011 The safety of intravenous atezolizumab was evaluated in IMvigor011, a multi-center, randomized, double-blind, placebo-controlled trial in 248 patients with MIBC after cystectomy who had circulating tumor DNA molecular residual disease (ctDNA MRD).
The median duration of exposure to intravenous atezolizumab was 6.5 months (0 to 11.8 months). Serious adverse reactions occurred in 27% of patients who received intravenous atezolizumab. Serious adverse reactions in ≥ 2% of patients included urinary tract infection (9%), and acute kidney injury (2.4%).
Fatal adverse reactions occurred in 3% of patients who received intravenous atezolizumab including septic shock, skin infection, death of unknown cause, interstitial lung disease, and congestive cardiac failure (1 patient each). Permanent discontinuation of intravenous atezolizumab due to adverse reactions occurred in 9% of patients. Adverse reactions which resulted in permanent discontinuation of intravenous atezolizumab in ≥1% of patients included pneumonitis (1.8%).
Dosage interruptions of intravenous atezolizumab due to adverse reactions occurred in 24% of patients. Tables 25 and 26 summarize the adverse reactions and laboratory abnormalities in patients receiving intravenous atezolizumab in IMvigor0 Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 0
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of intravenous atezolizumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac: pericarditis, pericardial effusion, cardiac tamponade Musculoskeletal and Connective Tissue: tenosynovitis
| Adverse Reaction Graded per NCI CTCAE v5.0 | TECENTRIQ HYBREZA n = 247 | Intravenous Atezolizumab n = 124 | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| General Disorder and Administration Site Conditions | ||||
| Fatigue Composite term includes fatigue, asthenia | 19 | 0.8 | 18 | 0 |
| Musculoskeletal and Connective Tissue disorders | ||||
| Musculoskeletal Pain Composite term includes back pain, myalgia, bone pain, musculoskeletal chest pain, neck pain, spinal pain, non-cardiac chest pain | 15 | 0.4 | 13 | 3.2 |
| Respiratory, Thoracic and Mediastinal | ||||
| Cough Composite term includes cough, productive cough | 13 | 0 | 7 | 0 |
| Dyspnea Composite term includes dyspnea, dyspnea at rest, dyspnea exertional | 12 | 1.2 | 15 | 1.6 |
| Metabolism and Nutrition Disorders | ||||
| Decreased appetite | 11 | 0 | 11 | 0 |
| Laboratory Abnormality Graded per NCI CTCAE v5.0 | TECENTRIQ HYBREZA (n = 247) | Intravenous Atezolizumab (n = 124) | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TECENTRIQ HYBREZA (48-233) and intravenous atezolizumab (19-117) | ||||
| Hematology | ||||
| Decreased Hemoglobin | 67 | 6 | 63 | 5 |
| Decreased lymphocytes | 37 | 9 | 45 | 15 |
| Chemistry | ||||
| Decreased Sodium | 46 | 3.9 | 47 | 5 |
| Decreased Albumin | 34 | 2.2 | 27 | 0 |
| Increased Alkaline Phosphatase | 33 | 1.3 | 27 | 0 |
| Increased AST | 28 | 2.6 | 32 | 2.6 |
| Increased ALT | 28 | 2.6 | 23 | 1.7 |
| Decreased calcium | 22 | 2.6 | 23 | 0.9 |
| Increased calcium | 20 | 2.6 | 24 | 1.7 |
| Increased potassium | 21 | 1.7 | 22 | 1.7 |
| Increased INR | 20 | 2 | 23 | 0 |
| Increased Creatinine | 19 | 1.7 | 26 | 0.9 |
| Adverse Reaction Graded per NCI CTCAE v4.0 | Intravenous Atezolizumab N = 495 | Best Supportive Care N = 495 | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| Skin and Subcutaneous Tissue | ||||
| Rash Includes rash, dermatitis, genital rash, skin exfoliation, rash maculo-papular, rash erythematous, rash papular, lichen planus, eczema asteatotic, dermatitis exfoliative, palmar-plantar erythrodysaesthesia syndrome, dyshidrotic eczema, eczema, drug eruption, rash pruritic, toxic skin eruption, dermatitis acneiform | 17 | 1.2 | 1.4 | 0 |
| Pruritus | 10 | 0 | 0.6 | 0 |
| Endocrine Disorders | ||||
| Hypothyroidism Includes hypothyroidism, autoimmune hypothyroidism, primary hypothyroidism, blood thyroid stimulating hormone increased | 14 | 0 | 0.6 | 0 |
| Respiratory, Thoracic and Mediastinal | ||||
| Cough Productive cough, upper airway cough syndrome, cough | 16 | 0 | 11 | 0 |
| General | ||||
| Pyrexia Includes pyrexia, body temperature increased, hyperthermia | 14 | 0.8 | 2.2 | 0.2 |
| Fatigue Includes fatigue, asthenia | 14 | 0.6 | 5 | 0.2 |
| Nervous System Disorders | ||||
| Peripheral neuropathy Includes paraesthesia, neuropathy peripheral, peripheral sensory neuropathy, hypoaesthesia, polyneuropathy, dysaesthesia, neuralgia, axonal neuropathy | 12 | 0.4 | 7 | 0.2 |
| Musculoskeletal and Connective Tissue | ||||
| Musculoskeletal pain Includes myalgia, bone pain, back pain, spinal pain, musculoskeletal chest pain, pain in extremity, neck pain, non-cardiac chest pain, musculoskeletal discomfort, musculoskeletal stiffness, musculoskeletal pain | 14 | 0.8 | 9 | 0.2 |
| Arthralgia Includes arthralgia, arthritis | 11 | 0.6 | 6 | 0 |
| Laboratory Abnormality Graded per NCI CTCAE v4.0, except for increased creatinine which only includes patients with creatinine increase based on upper limit of normal definition for Grade 1 events (NCI CTCAE v5.0). | Intravenous Atezolizumab The denominators used to calculate the rate varied from 78–480 for BSC arm and 483 for intravenous atezolizumab are for all tests of interest based on the number of patients with a baseline value and at least one post-treatment value. | Best Supportive Care | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| Chemistry | ||||
| Increased aspartate aminotransferase | 34 | 2.5 | 18 | 0 |
| Increased alanine aminotransferase | 30 | 3.3 | 19 | 0.4 |
| Hyperkalemia | 24 | 3.5 | 15 | 2.5 |
| Increased blood creatinine | 31 | 0.2 | 23 | 0.2 |
| Adverse Reaction | Intravenous Atezolizumab N = 286 | Platinum-Based Chemotherapy N = 263 | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| Graded per NCI CTCAE v4.0 | ||||
| Gastrointestinal | ||||
| Nausea | 14 | 0.3 | 34 | 1.9 |
| Constipation | 12 | 1.0 | 22 | 0.8 |
| Diarrhea | 11 | 0 | 12 | 0.8 |
| General | ||||
| Fatigue/Asthenia | 25 | 1.4 | 34 | 4.2 |
| Pyrexia | 14 | 0 | 9 | 0.4 |
| Metabolism and Nutrition | ||||
| Decreased appetite | 15 | 0.7 | 19 | 0 |
| Respiratory, Thoracic and Mediastinal | ||||
| Dyspnea | 14 | 0.7 | 10 | 0 |
| Cough | 12 | 0.3 | 10 | 0 |
| Laboratory Abnormality | Intravenous Atezolizumab | Platinum-Based Chemotherapy | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| Each test incidence is based on the number of patients who had at least one on-study laboratory measurement available: intravenous atezolizumab (range: 278–281); platinum-based chemotherapy (range: 256–260). Graded per NCI CTCAE v4.0. Increased blood creatinine only includes patients with test results above the normal range. | ||||
| Hematology | ||||
| Anemia | 69 | 1.8 | 94 | 20 |
| Lymphopenia | 47 | 9 | 59 | 17 |
| Chemistry | ||||
| Hypoalbuminemia | 48 | 0.4 | 39 | 2 |
| Increased alkaline phosphatase | 46 | 2.5 | 42 | 1.2 |
| Hyponatremia | 44 | 9 | 36 | 7 |
| Increased ALT | 38 | 3.2 | 32 | 0.8 |
| Increased AST | 36 | 3.2 | 32 | 0.8 |
| Hyperkalemia | 29 | 3.9 | 36 | 2.7 |
| Hypocalcemia | 24 | 1.4 | 24 | 2.7 |
| Increased blood creatinine | 24 | 0.7 | 33 | 1.5 |
| Hypophosphatemia | 23 | 3.6 | 21 | 2 |
| Adverse Reaction | Intravenous Atezolizumab with Bevacizumab, Paclitaxel, and Carboplatin N = 393 | Bevacizumab, Paclitaxel and Carboplatin N = 394 | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| Graded per NCI CTCAE v4.0 | ||||
| Nervous System | ||||
| Neuropathy Includes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy | 56 | 3 | 47 | 3 |
| Headache | 16 | 0.8 | 13 | 0 |
| General | ||||
| Fatigue/Asthenia | 50 | 6 | 46 | 6 |
| Pyrexia | 19 | 0.3 | 9 | 0.5 |
| Skin and Subcutaneous Tissue | ||||
| Alopecia | 48 | 0 | 46 | 0 |
| Rash Includes rash, rash maculo-papular, drug eruption, eczema, eczema asteatotic, dermatitis, contact dermatitis, rash erythematous, rash macular, pruritic rash, seborrheic dermatitis, dermatitis psoriasiform | 23 | 2 | 10 | 0.3 |
| Musculoskeletal and Connective Tissue | ||||
| Myalgia/Pain Includes pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain, back pain, myalgia, and bone pain | 42 | 3 | 34 | 2 |
| Arthralgia | 26 | 1 | 22 | 1 |
| Gastrointestinal | ||||
| Nausea | 39 | 4 | 32 | 2 |
| Diarrhea Includes diarrhea, gastroenteritis, colitis, enterocolitis | 33 | 6 | 25 | 0.5 |
| Constipation | 30 | 0.3 | 23 | 0.3 |
| Vomiting | 19 | 2 | 18 | 1 |
| Metabolism and Nutrition | ||||
| Decreased appetite | 29 | 4 | 21 | 0.8 |
| Vascular | ||||
| Hypertension | 25 | 9 | 22 | 8 |
| Respiratory | ||||
| Cough | 20 | 0.8 | 19 | 0.3 |
| Epistaxis | 17 | 1 | 22 | 0.3 |
| Renal | ||||
| Proteinuria Based on adverse reaction terms since laboratory data for proteinuria was not systematically collected | 16 | 3 | 15 | 3 |
| Laboratory Abnormality | Intravenous Atezolizumab with Bevacizumab, Paclitaxel, and Carboplatin | Bevacizumab, Paclitaxel and Carboplatin | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Intravenous Atezolizumab with bevacizumab, paclitaxel, and carboplatin range: (337–380); bevacizumab, paclitaxel, and carboplatin (range: 337–382). Graded per NCI CTCAE v4.0 | ||||
| Hematology | ||||
| Anemia | 83 | 10 | 83 | 9 |
| Neutropenia | 52 | 31 | 45 | 26 |
| Lymphopenia | 48 | 17 | 38 | 13 |
| Chemistry | ||||
| Hyperglycemia | 61 | 0 | 60 | 0 |
| Increased BUN | 52 | NA NA = Not applicable. NCI CTCAE does not provide a Grades 3–4 definition for these laboratory abnormalities | 44 | NA |
| Hypomagnesemia | 42 | 2 | 36 | 1 |
| Hypoalbuminemia | 40 | 3 | 31 | 2 |
| Increased AST | 40 | 4 | 28 | 0.8 |
| Hyponatremia | 38 | 10 | 36 | 9 |
| Increased Alkaline Phosphatase | 37 | 2 | 32 | 1 |
| Increased ALT | 37 | 6 | 28 | 0.5 |
| Increased TSH | 30 | NA | 20 | NA |
| Hyperkalemia | 28 | 3 | 25 | 2 |
| Increased Creatinine | 28 | 1 | 19 | 2 |
| Hypocalcemia | 26 | 3 | 21 | 3 |
| Hypophosphatemia | 25 | 4 | 18 | 4 |
| Hypokalemia | 23 | 7 | 14 | 4 |
| Hyperphosphatemia | 25 | NA | 19 | NA |
| Adverse Reaction | Intravenous Atezolizumab with Paclitaxel Protein-Bound and Carboplatin N = 473 | Paclitaxel Protein-Bound and Carboplatin N = 232 | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| Graded per NCI CTCAE v4.0 | ||||
| General | ||||
| Fatigue/Asthenia | 61 | 11 | 60 | 8 |
| Gastrointestinal | ||||
| Nausea | 50 | 3.4 | 46 | 2.2 |
| Diarrhea Includes diarrhea, colitis, and gastroenteritis | 43 | 6 | 32 | 6 |
| Constipation | 36 | 1.1 | 31 | 0 |
| Vomiting | 27 | 2.7 | 19 | 2.2 |
| Musculoskeletal and Connective Tissue | ||||
| Myalgia/Pain Includes back pain, pain in extremity, myalgia, musculoskeletal chest pain, bone pain, neck pain and musculoskeletal discomfort | 38 | 3 | 22 | 0.4 |
| Nervous System | ||||
| Neuropathy Includes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy | 33 | 2.5 | 28 | 2.2 |
| Respiratory, Thoracic and Mediastinal | ||||
| Dyspnea Includes dyspnea, dyspnea exertional and wheezing | 32 | 4.9 | 25 | 1.3 |
| Cough | 27 | 0.6 | 17 | 0 |
| Skin and Subcutaneous Tissue | ||||
| Alopecia | 32 | 0 | 27 | 0 |
| Rash Includes rash, rash maculo-papular, eczema, rash pruritic, rash erythematous, dermatitis, dermatitis contact, drug eruption, seborrheic dermatitis and rash macular | 20 | 0.6 | 11 | 0.9 |
| Metabolism and Nutrition | ||||
| Decreased appetite | 30 | 2.1 | 26 | 2.2 |
| Laboratory Abnormality | Intravenous Atezolizumab with Paclitaxel Protein-Bound and Carboplatin N = 473 | Paclitaxel Protein-Bound and Carboplatin N = 232 | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous atezolizumab with paclitaxel protein-bound and carboplatin (range: 423–467); paclitaxel protein-bound and carboplatin (range: 218–229). Graded per NCI CTCAE v4.0. | ||||
| Hematology | ||||
| Anemia | 92 | 33 | 87 | 25 |
| Neutropenia | 75 | 50 | 67 | 39 |
| Thrombocytopenia | 73 | 19 | 59 | 13 |
| Lymphopenia | 71 | 23 | 61 | 16 |
| Chemistry | ||||
| Hyperglycemia | 75 | 8 | 66 | 8 |
| Hypomagnesemia | 50 | 3.4 | 42 | 3.2 |
| Hyponatremia | 37 | 9 | 28 | 7 |
| Hypoalbuminemia | 35 | 1.3 | 31 | 0 |
| Increased ALT | 31 | 2.8 | 24 | 3.9 |
| Hypocalcemia | 31 | 2.6 | 27 | 1.8 |
| Hypophosphatemia | 29 | 6 | 20 | 3.2 |
| Increased AST | 28 | 2.2 | 24 | 1.8 |
| Increased TSH | 26 | NA NA = Not applicable. NCI CTCAE does not provide a Grades 3–4 definition for these laboratory abnormalities | 5 | NA |
| Hypokalemia | 26 | 6 | 24 | 4.4 |
| Increased Alkaline Phosphatase | 25 | 2.6 | 22 | 1.3 |
| Increased Blood Creatinine | 23 | 2.8 | 16 | 0.4 |
| Hyperphosphatemia | 21 | NA | 13 | NA |
| Adverse Reaction | Intravenous Atezolizumab N = 609 | Docetaxel N = 578 | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| Graded per NCI CTCAE v4.0 | ||||
| General | ||||
| Fatigue/Asthenia Includes fatigue and asthenia | 44 | 4 | 53 | 6 |
| Pyrexia | 18 | < 1 | 13 | < 1 |
| Respiratory | ||||
| Cough Includes cough and exertional cough | 26 | < 1 | 21 | < 1 |
| Dyspnea | 22 | 2.8 | 21 | 2.6 |
| Metabolism and Nutrition | ||||
| Decreased appetite | 23 | < 1 | 24 | 1.6 |
| Musculoskeletal | ||||
| Myalgia/Pain Includes musculoskeletal pain, musculoskeletal stiffness, musculoskeletal chest pain, myalgia | 20 | 1.3 | 20 | < 1 |
| Arthralgia | 12 | 0.5 | 10 | 0.2 |
| Gastrointestinal | ||||
| Nausea | 18 | < 1 | 23 | < 1 |
| Constipation | 18 | < 1 | 14 | < 1 |
| Diarrhea | 16 | < 1 | 24 | 2 |
| Skin | ||||
| Rash Includes rash, erythematous rash, generalized rash, maculopapular rash, papular rash, pruritic rash, pustular rash, pemphigoid | 12 | < 1 | 10 | 0 |
| Laboratory Abnormality | Intravenous Atezolizumab | Docetaxel | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous atezolizumab (range: 546–585) and docetaxel (range: 532–560). Graded according to NCI CTCAE version 4.0 | ||||
| Hematology | ||||
| Anemia | 67 | 3 | 82 | 7 |
| Lymphocytopenia | 49 | 14 | 60 | 21 |
| Chemistry | ||||
| Hypoalbuminemia | 48 | 4 | 50 | 3 |
| Hyponatremia | 42 | 7 | 31 | 6 |
| Increased Alkaline Phosphatase | 39 | 2 | 25 | 1 |
| Increased AST | 31 | 3 | 16 | 0.5 |
| Increased ALT | 27 | 3 | 14 | 0.5 |
| Hypophosphatemia | 27 | 5 | 23 | 4 |
| Hypomagnesemia | 26 | 1 | 21 | 1 |
| Increased Creatinine | 23 | 2 | 16 | 1 |
| Adverse Reaction | Intravenous Atezolizumab with Carboplatin and Etoposide N = 198 | Placebo with Carboplatin and Etoposide N = 196 | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| Graded per NCI CTCAE v4.0 | ||||
| General | ||||
| Fatigue/Asthenia | 39 | 5 | 33 | 3 |
| Gastrointestinal | ||||
| Nausea | 38 | 1 | 33 | 1 |
| Constipation | 26 | 1 | 30 | 1 |
| Vomiting | 20 | 2 | 17 | 3 |
| Skin and Subcutaneous Tissue | ||||
| Alopecia | 37 | 0 | 35 | 0 |
| Metabolism and Nutrition | ||||
| Decreased appetite | 27 | 1 | 18 | 0 |
| Laboratory Abnormality | Intravenous Atezolizumab with Carboplatin and Etoposide | Placebo with Carboplatin and Etoposide | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Intravenous Atezolizumab (range: 181–193); Placebo (range: 181–196). Graded per NCI CTCAE v4.0 | ||||
| Hematology | ||||
| Anemia | 94 | 17 | 93 | 19 |
| Neutropenia | 73 | 45 | 76 | 48 |
| Thrombocytopenia | 58 | 20 | 53 | 17 |
| Lymphopenia | 46 | 14 | 38 | 11 |
| Chemistry | ||||
| Hyperglycemia | 67 | 10 | 65 | 8 |
| Increased Alkaline Phosphatase | 38 | 1 | 35 | 2 |
| Hyponatremia | 34 | 15 | 33 | 11 |
| Hypoalbuminemia | 32 | 1 | 30 | 0 |
| Decreased TSH TSH = thyroid-stimulating hormone. NCI CTCAE v4.0 does not include these laboratories. | 28 | NA NA = Not applicable | 15 | NA |
| Hypomagnesemia | 31 | 5 | 35 | 6 |
| Hypocalcemia | 26 | 3 | 28 | 5 |
| Increased ALT | 26 | 3 | 31 | 1 |
| Increased AST | 22 | 1 | 21 | 2 |
| Increased Blood Creatinine | 22 | 4 | 15 | 1 |
| Hyperphosphatemia | 21 | NA | 23 | NA |
| Increased TSH | 21 | NA | 7 | NA |
| Adverse Reaction | Intravenous Atezolizumab with Lurbinectedin N = 242 | Intravenous Atezolizumab N = 240 | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3 or 4 (%) | All Grades (%) | Grades 3 or 4 (%) | |
| Graded per NCI CTCAE v5.0 | ||||
| Gastrointestinal | ||||
| Nausea | 36 | 3 | 4 | 1 |
| Diarrhea Includes diarrhea and colitis. | 15 | 0 | 8 | 0 |
| Vomiting | 14 | 1 | 3 | 0 |
| Constipation | 12 | 0 | 6 | 1 |
| General disorders and administration site conditions | ||||
| Fatigue Includes fatigue and asthenia. | 32 | 5 | 13 | 2 |
| Musculoskeletal and connective tissue disorders | ||||
| Musculoskeletal Pain Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, and pain in extremity. | 19 | 2 | 16 | 1 |
| Metabolism and Nutrition | ||||
| Decreased appetite | 17 | 0 | 7 | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough Includes cough, productive cough, and upper-airway cough syndrome. | 12 | 0 | 8 | 0 |
| Dyspnea Includes dyspnea and dyspnea exertional. | 11 | 2 | 10 | 2 |
| Laboratory Abnormality | Intravenous Atezolizumab with Lurbinectedin N = 242 | Intravenous Atezolizumab N = 240 | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| Graded per NCI CTCAE v5.0 | ||||
| Hematology | ||||
| Lymphopenia | 55 | 17 | 31 | 11 |
| Thrombocytopenia | 54 | 15 | 15 | 3 |
| Anemia | 51 | 13 | 12 | 3 |
| Neutropenia | 36 | 18 | 7 | 4 |
| Chemistry | ||||
| Increased alkaline phosphatase | 29 | 1 | 14 | 0 |
| Decreased sodium | 27 | 4 | 30 | 5 |
| Increased ALT | 25 | 3 | 18 | 2 |
| Increased AST | 24 | 3 | 22 | 1 |
| Decreased calcium | 24 | 3 | 8 | 1 |
| Increased creatinine | 21 | 3 | 14 | 0 |
| Adverse Reaction | Intravenous Atezolizumab in combination with Bevacizumab (n = 329) | Sorafenib (n = 156) | ||
|---|---|---|---|---|
| All Grades Graded per NCI CTCAE v4.0 (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| Vascular Disorders | ||||
| Hypertension | 30 | 15 | 24 | 12 |
| General Disorders and Administration Site Conditions | ||||
| Fatigue/Asthenia Includes fatigue and asthenia | 26 | 2 | 32 | 6 |
| Pyrexia | 18 | 0 | 10 | 0 |
| Renal and Urinary Disorders | ||||
| Proteinuria | 20 | 3 | 7 | 0.6 |
| Investigations | ||||
| Weight Decreased | 11 | 0 | 10 | 0 |
| Skin and Subcutaneous Tissue Disorders | ||||
| Pruritus | 19 | 0 | 10 | 0 |
| Rash | 12 | 0 | 17 | 2.6 |
| Gastrointestinal Disorders | ||||
| Diarrhea | 19 | 1.8 | 49 | 5 |
| Constipation | 13 | 0 | 14 | 0 |
| Abdominal Pain | 12 | 0 | 17 | 0 |
| Nausea | 12 | 0 | 16 | 0 |
| Vomiting | 10 | 0 | 8 | 0 |
| Metabolism and Nutrition Disorders | ||||
| Decreased Appetite | 18 | 1.2 | 24 | 3.8 |
| Respiratory, Thoracic and Mediastinal Disorders | ||||
| Cough | 12 | 0 | 10 | 0 |
| Epistaxis | 10 | 0 | 4.5 | 0 |
| Injury, Poisoning and Procedural Complications | ||||
| Infusion-Related Reaction | 11 | 2.4 | 0 | 0 |
| Laboratory Abnormality | Intravenous Atezolizumab in combination with Bevacizumab (n = 329) | Sorafenib (n = 156) | ||
|---|---|---|---|---|
| All Grades Graded per NCI CTCAE v4.0 (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous atezolizumab plus bevacizumab (222-323) and sorafenib (90-153) | ||||
| Chemistry | ||||
| Increased AST | 86 | 16 | 90 | 16 |
| Increased Alkaline Phosphatase | 70 | 4 | 76 | 4.6 |
| Increased ALT | 62 | 8 | 70 | 4.6 |
| Decreased Albumin | 60 | 1.5 | 54 | 0.7 |
| Decreased Sodium | 54 | 13 | 49 | 9 |
| Increased Glucose | 48 | 9 | 43 | 4.6 |
| Decreased Calcium | 30 | 0.3 | 35 | 1.3 |
| Decreased Phosphorus | 26 | 4.7 | 58 | 16 |
| Increased Potassium | 23 | 1.9 | 16 | 2 |
| Hypomagnesemia | 22 | 0 | 22 | 0 |
| Hematology | ||||
| Decreased Platelet | 68 | 7 | 63 | 4.6 |
| Decreased Lymphocytes | 62 | 13 | 58 | 11 |
| Decreased Hemoglobin | 58 | 3.1 | 62 | 3.9 |
| Increased Bilirubin | 57 | 8 | 59 | 14 |
| Decreased Leukocyte | 32 | 3.4 | 29 | 1.3 |
| Decreased Neutrophil | 23 | 2.3 | 16 | 1.1 |
| Adverse Reaction | Intravenous Atezolizumab in combination with Cobimetinib and Vemurafenib (n=230) | Placebo with Cobimetinib and Vemurafenib (n=281) | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| Skin and Subcutaneous Tissue Disorders | ||||
| Rash Includes rash, rash maculo-papular, dermatitis acneiform, rash macular, rash erythematous, eczema, skin exfoliation, rash papular, rash pustular, palmar-plantar erythrodysesthesia syndrome, dermatitis, dermatitis contact, erythema multiforme, rash pruritic, drug eruption, nodular rash, dermatitis allergic, exfoliative rash, dermatitis exfoliative generalized and rash morbilliform | 75 | 27 | 72 | 23 |
| Pruritus | 26 | < 1 | 17 | < 1 |
| Photosensitivity reaction | 21 | < 1 | 25 | 3.2 |
| General Disorders and Administration Site Conditions | ||||
| Fatigue Includes fatigue, asthenia and malaise | 51 | 3 | 45 | 1.8 |
| Pyrexia Includes pyrexia and hyperpyrexia | 49 | 1.7 | 35 | 2.1 |
| Edema Includes edema peripheral, lymphoedema, edema, face edema, eyelid edema, periorbital edema, lip edema and generalized edema | 26 | < 1 | 21 | 0 |
| Gastrointestinal Disorders | ||||
| Hepatotoxicity Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, transaminases increased, hepatitis, hepatic enzyme increased, hepatotoxicity, hypertransaminasemia, bilirubin conjugated increased, hepatocellular injury, hyperbilirubinemia, liver function test increased, hepatic failure, hepatitis fulminant and liver function test abnormal | 50 | 21 | 36 | 13 |
| Nausea | 30 | < 1 | 32 | 2.5 |
| Stomatitis Includes stomatitis, mucosal inflammation, aphthous ulcer, mouth ulceration, cheilitis and glossitis | 23 | 1.3 | 15 | < 1 |
| Musculoskeletal and Connective Tissue Disorders | ||||
| Musculoskeletal pain Includes arthralgia, myalgia, pain in extremity, back pain, musculoskeletal pain, arthritis, neck pain, musculoskeletal chest pain, musculoskeletal stiffness, bone pain, spinal pain, immune-mediated arthritis, joint stiffness and non-cardiac chest pain | 62 | 4.3 | 48 | 3.2 |
| Endocrine Disorders | ||||
| Hypothyroidism Includes hypothyroidism and blood thyroid stimulating hormone increased | 22 | 0 | 10 | 0 |
| Hyperthyroidism | 18 | < 1 | 8 | 0 |
| Injury, Poisoning and Procedural Complications | ||||
| Infusion-related reaction Includes infusion related reaction and hypersensitivity | 10 | 2.6 | 8 | < 1 |
| Respiratory, Thoracic and Mediastinal Disorders | ||||
| Pneumonitis Includes pneumonitis and interstitial lung disease | 12 | 1.3 | 6 | < 1 |
| Vascular Disorders | ||||
| Hypertension Includes hypertension, blood pressure increased, hypertensive crisis | 17 | 10 | 18 | 7 |
| Laboratory Abnormality | Intravenous Atezolizumab in combination with Cobimetinib and Vemurafenib (n=230) | Placebo with Cobimetinib and Vemurafenib (n=281) | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| Graded per NCI CTCAE v4.0. Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous atezolizumab plus cobimetinib and vemurafenib (28-277), placebo plus cobimetinib and vemurafenib arm (25-230). | ||||
| Hematology | ||||
| Decreased Lymphocytes | 80 | 24 | 72 | 17 |
| Decreased Hemoglobin | 77 | 2.6 | 72 | 2.2 |
| Decreased Platelet | 34 | 1.3 | 24 | 0.4 |
| Decreased Neutrophils | 26 | 2.2 | 19 | 1.5 |
| Chemistry | ||||
| Increased Creatine Kinase | 88 | 22 | 81 | 18 |
| Increased AST | 80 | 13 | 68 | 6 |
| Increased ALT | 79 | 18 | 62 | 12 |
| Increased Triacylglycerol Lipase | 75 | 46 | 62 | 35 |
| Increased Alkaline Phosphatase | 73 | 6 | 63 | 2.9 |
| Decreased Phosphorus | 67 | 22 | 64 | 14 |
| Increased Amylase | 51 | 13 | 45 | 13 |
| Increased Blood Urea Nitrogen | 47 | NA NA = Not applicable. NCI CTCAE v4.0 does not include these laboratories | 37 | NA |
| Decreased Albumin | 43 | 0.9 | 34 | 1.5 |
| Increased Bilirubin | 42 | 3.1 | 33 | 0.7 |
| Decreased Calcium | 41 | 1.3 | 28 | 0 |
| Decreased Sodium | 40 | 5 | 34 | 7 |
| Decreased Thyroid-Stimulating Hormone | 38 | NA | 23 | NA |
| Increased Thyroid-Stimulating Hormone Increased Thyroid Stimulating Hormone has a difference < 5% (All Grades) between arms and is included for clinical completeness | 37 | NA | 33 | NA |
| Decreased Potassium | 36 | 5 | 22 | 4.3 |
| Increased Triiodothyronine | 33 | NA | 18 | NA |
| Increased Free Thyroxine | 32 | NA | 21 | NA |
| Decreased Total Triiodothyronine | 32 | NA | 8 | NA |
| Increased Potassium | 29 | 1.3 | 19 | 1.4 |
| Decreased Triiodothyronine | 27 | NA | 21 | NA |
| Increased Sodium | 20 | 0 | 13 | 0.4 |
| Adverse Reaction | Intravenous Atezolizumab N = 49 | |
|---|---|---|
| All Grades (%) | Grades 3–4 (%) | |
| Graded per NCI CTCAE v4.0 | ||
| General disorders and administration site conditions | ||
| Fatigue | 55 | 2 |
| Pyrexia | 25 | 2 |
| Influenza like illness | 18 | 0 |
| Gastrointestinal disorders | ||
| Nausea | 43 | 0 |
| Vomiting | 37 | 0 |
| Constipation | 33 | 0 |
| Diarrhea | 27 | 2 |
| Abdominal pain Includes abdominal pain and abdominal pain upper | 25 | 0 |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 22 | 2 |
| Respiratory, Thoracic and Mediastinal | ||
| Cough Includes cough, upper-airway cough syndrome, and productive cough | 45 | 0 |
| Dyspnea | 33 | 0 |
| Rhinitis allergic | 16 | 0 |
| Musculoskeletal and connective tissue disorders | ||
| Musculoskeletal pain Includes arthralgia, pain in extremity, myalgia, non-cardiac chest pain, neck pain, musculoskeletal chest pain, and back pain | 67 | 8 |
| Skin and subcutaneous tissue disorders | ||
| Rash Includes rash maculo-papular, rash, dermatitis acneiform, eczema, skin exfoliation, and drug eruption | 47 | 2 |
| Nervous system disorders | ||
| Headache | 43 | 4 |
| Dizziness Includes vertigo and dizziness | 29 | 4 |
| Vascular disorders | ||
| Hypertension | 43 | 6 |
| Hemorrhage Includes pulmonary hemorrhage, hemoptysis, conjunctival hemorrhage, epistaxis, hematuria, rectal hemorrhage, and laryngeal hemorrhage | 29 | 2 |
| Psychiatric disorders | ||
| Insomnia | 27 | 0 |
| Anxiety | 25 | 0 |
| Cardiac Disorders | ||
| Arrhythmia Includes atrial fibrillation, sinus bradycardia, ventricular tachycardia, and sinus tachycardia | 22 | 2 |
| Endocrine disorders | ||
| Hypothyroidism Includes hypothyroidism and blood thyroid stimulating hormone increased | 25 | 0 |
| Investigations | ||
| Weight decreased | 18 | 0 |
| Weight increased | 16 | 6 |
| Laboratory Abnormality Laboratory tests which do not have NCI CTCAE grading criteria are also included for All Grade assessments, which were performed by comparing to respective lab normal ranges | Intravenous Atezolizumab The denominators used to calculate the rate varied from 4–49 for all tests of interest based on the number of patients with a baseline value and at least one on-study laboratory measurement available | |
|---|---|---|
| All Grades (%) | Grades 3–4 (%) | |
| Hematology | ||
| Decreased Hemoglobin | 63 | 0 |
| Decreased Platelets | 27 | 0 |
| Increased Platelets | 29 | 0 |
| Chemistry | ||
| Increased Alkaline Phosphatase | 29 | 0 |
| Decreased Amylase | 40 | 0 |
| Increased Amylase | 20 | 20 |
| Decreased Bilirubin | 49 | 0 |
| Decreased Calcium | 47 | 0 |
| Increased Calcium | 25 | 14 |
| Decreased Glucose | 33 | 0 |
| Increased Glucose | 78 | 0 |
| Decreased Glucose (fasting) | 25 | 0 |
| Decreased Magnesium | 21 | 0 |
| Increased Magnesium | 26 | 26 |
| Increased AST | 39 | 2 |
| Increased ALT | 33 | 2 |
| Decreased Sodium | 43 | 0 |
| Increased Lipase | 25 | 25 |
| Adverse Reaction Graded per NCI-CTCAE v5.0 | Intravenous Atezolizumab N = 165 | Placebo N=83 | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| Renal and Urinary Disorders | ||||
| Urinary tract infection Includes multiple related terms | 22 | 8.5 | 18 | 4.8 |
| Skin and Subcutaneous Tissue | ||||
| Pruritus | 18 | 0 | 11 | 0 |
| Rash | 13 | 0.6 | 3.6 | 0 |
| Endocrine Disorders | ||||
| Hypothyroidism | 13 | 0 | 4.8 | 0 |
| Gastrointestinal | ||||
| Constipation | 11 | 0 | 7 | 0 |
| Laboratory Abnormality | Intravenous Atezolizumab N=165 | Placebo N=83 | ||
|---|---|---|---|---|
| All Grades (%) | Grades 3–4 (%) | All Grades (%) | Grades 3–4 (%) | |
| Graded per NCI-CTCAE v5.0 Denominator is based on patients with at least one post-baseline assessment. For each parameter, the denominator includes patients with baseline Grade 0-2 in the specified direction of abnormality or patients with missing baseline values | ||||
| Hematology | ||||
| Decreased hemoglobin | 30 | 1.8 | 24 | 0 |
| Decreased lymphocytes | 26 | 3.1 | 15 | 0 |
| Chemistry | ||||
| Increased alanine aminotransferase | 23 | 2.5 | 10 | 0 |
| Increased alkaline phosphatase | 23 | 1.2 | 15 | 0 |
Warnings & Cautions for Tecentriq Hybreza
Severe and Fatal Immune-Mediated Adverse Reactions TECENTRIQ HYBREZA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue.
Immune-mediated adverse reactions can occur at any time after starting a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies.
Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection.
Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue TECENTRIQ HYBREZA depending on severity. In general, if TECENTRIQ HYBREZA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less.
Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.
Immune-Mediated Pneumonitis TECENTRIQ HYBREZA can cause immune-mediated pneumonitis, including fatal adverse reactions. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Pneumonitis led to the withholding of TECENTRIQ HYBREZA in one patient.
Systemic corticosteroids were required in 40% (2/5) patients with pneumonitis who received TECENTRIQ HYBREZA as monotherapy. Pneumonitis resolved in both patients. The single patient in whom TECENTRIQ HYBREZA was withheld for pneumonitis reinitiated TECENTRIQ HYBREZA after symptom improvement.
Pneumonitis led to permanent discontinuation of intravenous atezolizumab in 2.6% of patients and withholding of intravenous atezolizumab in 7.4% of patients. Systemic corticosteroids were required in 55% (16/29) of patients with pneumonitis. Pneumonitis resolved in 97% of the 29 patients.
Of the 17 patients in whom intravenous atezolizumab was withheld for pneumonitis, 10 reinitiated intravenous atezolizumab after symptom improvement; of these, 50% had recurrence of pneumonitis. Immune-Mediated Colitis TECENTRIQ HYBREZA can cause immune-mediated colitis, including Grade 3 adverse reactions. Colitis can present with diarrhea, abdominal pain, and lower gastrointestinal bleeding.
Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Hepatitis led to the withholding of TECENTRIQ HYBREZA in 0.4% of patients.
Systemic corticosteroids were required in 67% (2/3) of patients with hepatitis who received TECENTRIQ HYBREZA as monotherapy. Hepatitis resolved in 1 of the 3 patients. Hepatitis led to permanent discontinuation of intravenous atezolizumab in 2.2% and withholding of intravenous atezolizumab in 1.7% of patients.
Systemic corticosteroids were required in 50% (7/14) of patients with hepatitis. Hepatitis resolved in 93% of the 14 patients. Of the 4 patients in whom intravenous atezolizumab was withheld for hepatitis, 3 reinitiated intravenous atezolizumab after symptom improvement; of these, 33% had recurrence of hepatitis.
For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Adrenal insufficiency led to the withholding of TECENTRIQ HYBREZA in both patients. Systemic corticosteroids were required in 50% (1/2) of patients with adrenal insufficiency who received TECENTRIQ HYBREZA as monotherapy; this single patient remained on systemic corticosteroids.
Hypophysitis: TECENTRIQ HYBREZA can cause immune-mediated hypophysitis, including Grade 2 adverse reactions. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism.
Initiate hormone replacement as clinically indicated. Hypophysitis led to the withholding of TECENTRIQ HYBREZA in this patient. Thyroid Disorders: TECENTRIQ HYBREZA can cause immune-mediated thyroid disorders.
Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or medical management for hyperthyroidism as clinically indicated.
Thyroiditis resolved in 50% of patients. Hyperthyroidism led to withholding of TECENTRIQ HYBREZA in 0.8% of patients. Anti-thyroid therapy was required in 40% (2/5) of patients with hyperthyroidism who received TECENTRIQ HYBREZA as monotherapy.
Of these 2 patients, one remained on anti-thyroid treatment. Of the 2 patients in whom TECENTRIQ HYBREZA was withheld for hyperthyroidism, 1 patient reinitiated TECENTRIQ HYBREZA; this patient did not have recurrence of hyperthyroidism. Hyperthyroidism led to permanent discontinuation of intravenous atezolizumab in 0.4% and withholding of intravenous atezolizumab in 10% of patients.
Antithyroid therapy was required in 53% (23/43) of patients with hyperthyroidism. Of these 23 patients, the majority remained on antithyroid treatment. Of the 24 patients in whom intravenous atezolizumab was withheld for hyperthyroidism, 18 patients reinitiated intravenous atezolizumab; of these, 28% had recurrence of hyperthyroidism.
Hypothyroidism: TECENTRIQ HYBREZA can cause immune-mediated hypothyroidism, including Grade 4 adverse reactions. Immune-mediated hypothyroidism occurred in 10% (25/247) of patients with locally advanced or metastatic NSCLC who received TECENTRIQ HYBREZA as monotherapy in the IMscin001 trial. Hormone replacement was required in 68% (17/25) of patients with hypothyroidism who received TECENTRIQ HYBREZA as monotherapy.
Two patients with hypothyroidism remained on thyroid hormone replacement. Hypothyroidism led to permanent discontinuation of intravenous atezolizumab in 0.1% and withholding of intravenous atezolizumab in 1.6% of patients. Hormone replacement therapy was required in 71% (198/277) of patients with hypothyroidism.
The majority of patients with hypothyroidism remained on thyroid hormone replacement. Of the 39 patients in whom intravenous atezolizumab was withheld for hypothyroidism, 9 reinitiated intravenous atezolizumab after symptom improvement. Intravenous Atezolizumab in Combination with Cobimetinib and Vemurafenib: Hypothyroidism occurred in 26% (60/230) of patients receiving intravenous atezolizumab in combination with cobimetinib and vemurafenib in the IMspire150 trial, including Grade 2 (9.1%) adverse reactions.
Hormone replacement therapy was required in 52% (31/60) of patients with hypothyroidism. Of the 6 patients in whom intravenous atezolizumab was withheld for hypothyroidism, 4 reinitiated intravenous atezolizumab after symptom improvement. The majority of patients with hypothyroidism required long term thyroid replacement.
Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis: TECENTRIQ HYBREZA can cause type 1 diabetes mellitus, including Grade 3 adverse reactions and diabetic ketoacidosis. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated.
Intravenous Atezolizumab in Combination with Cobimetinib and Vemurafenib: Immune-mediated nephritis with renal dysfunction occurred in 1.3% (3/230) of patients receiving intravenous atezolizumab in combination with cobimetinib and vemurafenib in the IMspire150 trial, including Grade 2 (1.3%) adverse reactions. Nephritis led to permanent discontinuation of intravenous atezolizumab in 0.4% and withholding of intravenous atezolizumab in 0.9% of patients. Nephritis resolved in all 3 of these patients.
Of the 2 patients in whom intravenous atezolizumab was withheld for nephritis, both reinitiated intravenous atezolizumab after symptom improvement and neither had recurrence of nephritis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes.
One fatal case of an immune-mediated dermatologic adverse reaction, due to TEN, occurred (0.4%, 1/247) in patients with locally advanced or metastatic NSCLC receiving TECENTRIQ HYBREZA as monotherapy in the IMscin001 trial. Other Immune-Mediated Adverse Reactions The following clinically significant immune-mediated adverse reactions occurred at an incidence of < 1% (unless otherwise noted) in patients receiving intravenous atezolizumab or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.
Cardiac/Vascular: Myocarditis, pericarditis, vasculitis. Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy. Ocular: Uveitis, iritis, and other ocular inflammatory toxicities occurred.
Some cases were associated with retinal detachment. Various grades of visual impairment, including blindness, occurred. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.
Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis. Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic. Endocrine: Hypoparathyroidism.
Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection. Other: Myocarditis-Myositis-Myasthenia Gravis (or Myasthenia-Like) Overlap Syndrome, reported as the co-occurrence of either two or all three adverse reactions.
Infusion-Related Reactions TECENTRIQ HYBREZA can cause severe or life-threatening infusion-related reactions, including Grade 3 adverse reactions and anaphylaxis. Monitor for signs and symptoms of infusion-related reactions. Pause, slow the rate of, or permanently discontinue TECENTRIQ HYBREZA based on the severity.
For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses.
Complications of Allogeneic
HSCT after PD-1/PD-L1 Inhibitors Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockage and allogeneic HSCT.
Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefits versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.
Embryo-Fetal Toxicity Based on its mechanism of action, TECENTRIQ HYBREZA can cause fetal harm when administered to a pregnant woman. There are no available data on the use of TECENTRIQ HYBREZA in pregnant women. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal death.
Verify pregnancy status of females of reproductive potential prior to initiating TECENTRIQ HYBREZA. Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TECENTRIQ HYBREZA and for 5 months after the last dose.
Pregnancy Safety for Tecentriq Hybreza
Pregnancy Risk Summary Based on its mechanism of action, TECENTRIQ HYBREZA can cause fetal harm when administered to a pregnant woman. There are no available data on the use of TECENTRIQ HYBREZA in pregnant women. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal death (see Data ).
Advise females of reproductive potential of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Animal Data: TECENTRIQ HYBREZA for subcutaneous injection contains atezolizumab and hyaluronidase.
Atezolizumab: Animal reproduction studies have not been conducted with atezolizumab to evaluate its effect on reproduction and fetal development. A literature-based assessment of the effects on reproduction demonstrated that a central function of the PD-L1/PD-1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to a fetus. Blockage of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to a fetus and to result in an increase in fetal loss; therefore, potential risks of administering atezolizumab during pregnancy include increased rates of abortion or stillbirth.
As reported in the literature, there were no malformations related to the blockade of PD-L1/PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to atezolizumab may increase the risk of developing immune-mediated disorders or altering the normal immune response. Hyaluronidase: In an embryo-fetal study, mice were dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase (recombinant human) at dose levels up to 2,200,000 U/kg, which is > 2,400 times higher than the human dose.
The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at a daily dose of 360,000 U/kg, which is > 400 times higher than the human dose. In a peri-and post-natal reproduction study, mice have been dosed daily by subcutaneous injection, with hyaluronidase (recombinant human) from implantation through lactation and weaning at dose levels up to 1,100,000 U/kg, which is > 1,200 times higher than the human dose.
The study found no adverse effects on sexual maturation, learning and memory or fertility of the offspring.
Pediatric Use of Tecentriq Hybreza
Pediatric Use Alveolar Soft Part Sarcoma The safety and effectiveness of TECENTRIQ HYBREZA as monotherapy for the treatment of pediatric patients (12 years of age and older who weigh 40 kg or greater) with unresectable or metastatic alveolar soft part sarcoma (ASPS) has been established. Use of TECENTRIQ HYBREZA for this pediatric indication is supported by evidence from adequate and well controlled studies of intravenous atezolizumab in adults, and additional pharmacokinetic and safety data for intravenous atezolizumab in pediatric patients 12 years and older. Atezolizumab exposures following subcutaneous administration of TECENTRIQ HYBREZA (containing 1,875 mg of atezolizumab) every 3 weeks in pediatric patients 12 years of age and older who weigh 40 kg or greater are predicted to be within the range of those observed in adults at the same dosage.
The safety and effectiveness of TECENTRIQ HYBREZA have not been established in pediatric patients <12 years of age with unresectable or metastatic ASPS. Solid Tumors and Lymphomas The safety and effectiveness of TECENTRIQ HYBREZA in pediatric patients have not been established for other approved indications.
Contraindications for Tecentriq Hybreza
TECENTRIQ HYBREZA is contraindicated in patients with known hypersensitivity to hyaluronidase or to any of its excipients.
Clinical Studies of Tecentriq Hybreza
Non-Small Cell Lung Cancer NSCLC - TECENTRIQ HYBREZA IMscin001 (NCT03735121) was an open-label, multi-center, international, randomized study conducted in adult patients with locally advanced or metastatic NSCLC who were not exposed to cancer immunotherapy and who have disease progression following platinum-based chemotherapy. Patients were excluded if they had a history of autoimmune disease; active or corticosteroid-dependent brain metastases; received a live, attenuated vaccine within 4 weeks prior to randomization; or received systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive drugs within 2 weeks prior to randomization. The primary outcome measure was atezolizumab exposure (C trough and AUC 0-21days ) of subcutaneous TECENTRIQ HYBREZA as compared to intravenous atezolizumab.
Additional descriptive efficacy outcome measures were overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Eighty percent of patients had received only one prior therapeutic regimen for NSCLC. At the primary analysis, the confirmed ORR was in the subcutaneous TECENTRIQ HYBREZA arm and in the intravenous atezolizumab arm.
After further follow up, no notable differences in PFS and OS were observed between patients who received subcutaneous TECENTRIQ HYBREZA and patients who received intravenous atezolizumab. NSCLC Trials - Intravenous Atezolizumab The effectiveness of TECENTRIQ HYBREZA has been established for: adjuvant treatment (following tumor resection and platinum-based chemotherapy) in adult patients with stage II to IIIA NSCLC whose tumors have PD-L1 expression on ≥ 1% of tumor cells (IMpower010 study). first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression (PD-L1 stained ≥ 50% of tumor cells or PD-L1 stained tumor-infiltrating immune cells covering ≥ 10% of the tumor area ), with no EGFR or ALK genomic tumor aberrations (IMpower110 study). first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (IMpower150 study). first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations (IMpower130 study). first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression, with no EGFR or ALK genomic tumor aberrations (OAK study). Use of TECENTRIQ HYBREZA for these NSCLC indications is supported by evidence from the adequate and well-controlled studies conducted with intravenous atezolizumab in these NSCLC populations and pharmacokinetics data that demonstrated comparable exposures to atezolizumab between TECENTRIQ HYBREZA and intravenous atezolizumab in the IMscin001 trial.
Below is a description of the efficacy results of these adequate and well-controlled studies of intravenous atezolizumab in these NSCLC populations. Adjuvant Treatment of Early-stage NSCLC IMpower010 The efficacy of intravenous atezolizumab was evaluated in IMpower010 (NCT02486718), a multi-center, randomized, open-label trial for the adjuvant treatment of patients with NSCLC who had complete tumor resection and were eligible to receive cisplatin-based adjuvant chemotherapy. Eligible patients were required to have Stage IB (tumors ≥ 4 cm) – Stage IIIA NSCLC per the Union for International Cancer Control/American Joint Committee on Cancer staging system, 7th edition.
Patients were excluded if they had a history of autoimmune disease; a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis; administration of a live, attenuated vaccine within 28 days prior to randomization; administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomization. A total of 1005 patients who had complete tumor resection and received cisplatin-based adjuvant chemotherapy were randomized (1:1) to receive intravenous atezolizumab 1200 mg intravenous infusion every 3 weeks for 16 cycles, unless disease recurrence or unacceptable toxicity occurred, or best supportive care (BSC). Randomization was stratified by sex, stage of disease, histology, and PD-L1 expression.
Tumor assessments were conducted at baseline of the randomization phase and every 4 months for the first year following Cycle 1, Day 1 and then every 6 months until year five, then annually thereafter. The majority of patients were White (73%) and Asian (24%). Most patients were current or previous smokers (78%) and baseline Eastern Cooperative Oncology Group (ECOG) performance status in patients was Overall, 12% of patients had Stage IB, 47% had Stage II and 41% had Stage IIIA disease.
The primary efficacy outcome measure was disease-free survival (DFS) as assessed by the investigator. The primary efficacy analysis population (n = 476) was patients with Stage II – IIIA NSCLC with PD-L1 expression on ≥ 1% of tumor cells (PD-L1 ≥ 1% TC). DFS was defined as the time from the date of randomization to the date of occurrence of any of the following: first documented recurrence of disease, new primary NSCLC, or death due to any cause, whichever occurred first.
A key secondary efficacy outcome measure was overall survival (OS) in the intent-to-treat population. At the time of the interim DFS analysis, the study demonstrated a statistically significant improvement in DFS in the PD-L1 ≥ 1% TC, Stage II – IIIA patient population. Efficacy results are presented in Table 27 and Figure 1.
Table 27: Efficacy Results from IMpower010 in Patients with Stage II - IIIA NSCLC with PD-L1 expression ≥ 1% TC In a pre-specified secondary subgroup analysis of patients with PD-L1 TC ≥ 50% Stage II – IIIA NSCLC (n = 229), the median DFS was not reached (95% CI: 42.3 months, NE) for patients in the intravenous atezolizumab arm and was 35.7 months (95% CI: 29.7, NE) for patients in the best supportive care arm, with a HR of Figure 1: Kaplan-Meier Plot of Disease-Free Survival in IMpower010 in Patients with Stage II – IIIA NSCLC with PD-L1 expression ≥ 1% TC At the time of the DFS interim analysis, 19% of patients in the PD-L1 ≥1% TC Stage II – IIIA patient population had died. An exploratory analysis of OS in this population resulted in a stratified HR of Metastatic Chemotherapy-Naïve NSCLC IMpower110 The efficacy of intravenous atezolizumab was evaluated in IMpower110 (NCT02409342), a multicenter, international, randomized, open-label trial in patients with stage IV NSCLC whose tumors express PD-L1 (PD-L1 stained ≥ 1% of tumor cells or PD-L1 stained tumor-infiltrating immune cells covering ≥ 1% of the tumor area ), who had received no prior chemotherapy for metastatic disease. PD-L1 tumor status was determined based on immunohistochemistry (IHC) testing using the VENTANA PD-L1 (SP142) Assay.
The evaluation of efficacy is based on the subgroup of patients with high PD-L1 expression (TC ≥ 50% or IC ≥ 10%), excluding those with EGFR or ALK genomic tumor aberrations. The trial excluded patients with a history of autoimmune disease, administration of a live attenuated vaccine within 28 days prior to randomization, active or untreated CNS metastases, administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomization. Randomization was stratified by sex, ECOG performance status, histology (non-squamous vs. squamous) and PD-L1 expression TC ≥ 1% and any IC vs.
TC < 1% and IC ≥ 1%. Administration of intravenous atezolizumab was permitted beyond RECIST-defined disease progression. Tumor specimens were evaluated prospectively using the VENTANA PD-L1 (SP142) Assay at a central laboratory and the results were used to define subgroups for pre-specified analyses.
The majority of patients were White (82%) and Asian (17%). Baseline ECOG performance status was were current or previous smokers; and 76% of patients had non-squamous disease while 24% of patients had squamous disease. The trial demonstrated a statistically significant improvement in OS for patients with high PD-L1 expression (TC ≥ 50% or IC ≥ 10%) at the time of the OS interim analysis.
There was no statistically significant difference in OS for the other two PD-L1 subgroups (TC ≥ 5% or IC ≥ 5%; and TC ≥ 1% or IC ≥ 1%) at the interim or final analyses. Efficacy results for patients with NSCLC with high PD-L1 expression are presented in Table 28 and Figure 2. The investigator-assessed confirmed ORR was in the intravenous atezolizumab arm and in the platinum-based chemotherapy arm.
First-Line Metastatic Non-squamous NSCLC IMpower150 The efficacy of intravenous atezolizumab with bevacizumab, paclitaxel, and carboplatin was evaluated in IMpower150 (NCT02366143), a multicenter, international, randomized (1:1:1), open-label trial in patients with metastatic non-squamous NSCLC. Patients with stage IV non-squamous NSCLC who had received no prior chemotherapy for metastatic disease but could have received prior EGFR or ALK kinase inhibitor if appropriate, regardless of PD-L1 or T-effector gene (tGE) status and ECOG performance status 0 or 1 were eligible. Randomization was stratified by sex, presence of liver metastases, and PD-L1 expression status on tumor cells (TC) and tumor-infiltrating immune cells (IC) as follows: TC3 and any IC vs.
TC0/1/2 and IC2/3 vs. TC0/1/2 and IC0/1. Tumor specimens were evaluated prior to randomization for PD-L1 tumor expression using the VENTANA PD-L1 (SP142) assay at a central laboratory.
Tumor tissue was collected at baseline for expression of tGE signature and evaluation was performed using a clinical trial assay in a central laboratory prior to the analysis of efficacy outcome measures. Major efficacy outcome measures for comparison of Arms B and C were progression free survival (PFS) by RECIST v1.1 in the tGE-WT (patients with high expression of T-effector gene signature, excluding those with EGFR- and ALK-positive NSCLC ) and in the ITT-WT subpopulations and overall survival (OS) in the ITT-WT subpopulation. Additional efficacy outcome measures for comparison of Arms B and C or Arms A and C were PFS and OS in the ITT population, OS in the tGE-WT subpopulation, and ORR/DoR in the tGE-WT and ITT-WT subpopulations.
A total of 1202 patients were enrolled across the three arms of whom 1045 were in the ITT-WT subpopulation and 447 were in the tGE-WT subpopulation. The demographic information is limited to the 800 patients enrolled in Arms B and C where efficacy has been demonstrated. Approximately 14% of patients had liver metastases at baseline, and most patients were current or previous smokers (80%).
Baseline ECOG performance status was PD-L1 was TC3 and any IC in 12%, TC0/1/2 and IC2/3 in 13%, and TC0/1/2 and IC0/1 in 75%. The demographics for the 696 patients in the ITT-WT subpopulation were similar to the ITT population except for the absence of patients with EGFR- or ALK-positive NSCLC. The trial demonstrated a statistically significant improvement in PFS between Arms B and C in both the tGE-WT and ITT-WT subpopulations, but did not demonstrate a significant difference for either subpopulation between Arms A and C based on the final PFS analyses.
In the interim analysis of OS, a statistically significant improvement was observed for Arm B compared to Arm C, but not for Arm A compared to Arm C. Efficacy results for the ITT-WT subpopulation are presented in Table 29 and Figure 3. Table 29: Efficacy Results in ITT-WT Population in IMpower150 in ITT-WT Population in IMpower150 Exploratory analyses showed that the subset of patients in the four drug regimen arm who were ADA positive by week 4 (30%) appeared to have similar efficacy (effect on overall survival) as compared to patients who tested negative for treatment-emergent ADA by week 4 (70%).
In an exploratory analysis, propensity score matching was conducted to compare ADA positive patients in the intravenous atezolizumab, bevacizumab, paclitaxel, and carboplatin arm with a matched population in the bevacizumab, paclitaxel, and carboplatin arm. Similarly, ADA negative patients in the intravenous atezolizumab, bevacizumab, paclitaxel, and carboplatin arm were compared with a matched population in the bevacizumab, paclitaxel, and carboplatin arm. Propensity score matching factors were: baseline sum of longest tumor size (BSLD), baseline ECOG, baseline albumin, baseline LDH, sex, tobacco history, metastatic site, TC level, and IC level.
The hazard ratio comparing the ADA-positive subgroup with its matched control was The hazard ratio comparing the ADA-negative subgroup with its matched control was IMpower130 The efficacy of intravenous atezolizumab with paclitaxel protein-bound and carboplatin was evaluated in IMpower130 (NCT02367781), a multicenter, randomized (2:1), open-label trial in patients with stage IV non-squamous NSCLC. Randomization was stratified by sex, presence of liver metastases, and PD-L1 tumor expression according to the VENTANA PD-L1 (SP142) assay as follows: TC3 and any IC vs. Tumor assessments were conducted every 6 weeks for the first 48 weeks, then every 9 weeks thereafter.
Major efficacy outcome measures were PFS by RECIST v1.1 and OS in the subpopulation of patients evaluated for and documented to have no EGFR or ALK genomic tumor aberrations (ITT-WT). A total of 724 patients were enrolled; of these, 681 (94%) were in the ITT-WT population. PD-L1 tumor expression was TC0/1/2 and IC0/1 in 73%; TC3 and any IC in 14%; and TC0/1/2 and IC2/3 in 13%.
Efficacy results for the ITT-WT population are presented in Table 30 and Figure 4. Table 30: Efficacy Results from IMpower130 in IMpower130 Previously Treated Metastatic NSCLC OAK The efficacy of intravenous atezolizumab was evaluated in a multicenter, international, randomized (1:1), open-label study (OAK; NCT02008227) conducted in patients with locally advanced or metastatic NSCLC whose disease progressed during or following a platinum-containing regimen. Patients with a history of autoimmune disease, symptomatic or corticosteroid-dependent brain metastases, or requiring systemic immunosuppression within 2 weeks prior to enrollment were ineligible.
Randomization was stratified by PD-L1 expression tumor-infiltrating immune cells (IC), the number of prior chemotherapy regimens (1 vs. 2), and histology (squamous vs. non-squamous). Tumor assessments were conducted every 6 weeks for the first 36 weeks and every 9 weeks thereafter. Major efficacy outcome measure was overall survival (OS) in the first 850 randomized patients and OS in the subgroup of patients with PD-L1-expressing tumors (defined as ≥ 1% PD-L1 expression on tumor cells or immune cells ).
Additional efficacy outcome measures were OS in all randomized patients (n = 1225), OS in subgroups based on PD-L1 expression, overall response rate (ORR), and progression free survival as assessed by the investigator per RECIST v.1.1. In an exploratory efficacy subgroup analysis of OS based on PD-L1 expression, the hazard ratio was in the high PD-L1 expression subgroup and in patients who did not have high PD-L1 expression. ADA positive patients by week 4 appeared to have similar OS compared to docetaxel-treated patients.
The hazard ratio comparing the ADA positive subgroup with its matched control was The hazard ratio comparing the ADA negative subgroup with its matched control was Below is a description of the efficacy results of these adequate and well-controlled studies of intravenous atezolizumab in combination with chemotherapy in ES-SCLC (IMpower133 and IMforte studies). Small Cell Lung Cancer (SCLC) IMpower133 The efficacy of intravenous atezolizumab with carboplatin and etoposide was investigated in IMpower133 (NCT02763579), a randomized (1:1), multicenter, double-blind, placebo-controlled trial in 403 patients with ES-SCLC. IMpower133 enrolled patients with ES-SCLC who had received no prior chemotherapy for extensive stage disease and ECOG performance status 0 or 1.
Randomization was stratified by sex, ECOG performance status, and presence of brain metastases. Patients treated beyond disease progression had tumor assessment conducted every 6 weeks until treatment discontinuation. Major efficacy outcome measures were OS and PFS as assessed by investigator per RECIST v1.1 in the intent-to-treat population.
Additional efficacy outcome measures included ORR and DoR as assessed by investigator per RECIST v1.1. A total of 403 patients were randomized, including 201 to the intravenous atezolizumab arm and 202 to the chemotherapy alone arm. Baseline ECOG performance status was of patients had a history of brain metastases, and 97% were current or previous smokers.
Efficacy results are presented in Table 32 and Figure 6. Table 32: Efficacy Results from IMpower133 in IMpower133 Figure 6 IMforte The efficacy of intravenous atezolizumab in combination with lurbinectedin as maintenance treatment was evaluated in IMforte (NCT05091567), a randomized, multicenter, open-label study in patients with ES-SCLC. Patients were eligible if their disease had not progressed after completion of four cycles of intravenous atezolizumab, carboplatin and etoposide (induction treatment) and they had an ECOG performance status of 0 or 1.
The trial excluded patients with CNS metastases, history of autoimmune disease, or administration of systemic immunosuppressive medications within 1 week prior to enrollment. Unless contraindicated, primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) was mandated for patients assigned to the intravenous atezolizumab with lurbinectedin arm. The trial randomized 483 patients who had not experienced disease progression following the completion of four cycles of intravenous atezolizumab with carboplatin and etoposide to one of the following two treatment arms: Intravenous atezolizumab 1200 mg IV in combination with lurbinectedin 3.2 mg/m 2 IV once every 3 weeks until disease progression or unacceptable toxicity, or Intravenous atezolizumab 1200 mg IV once every 3 weeks until disease progression or unacceptable toxicity Randomization was stratified by ECOG performance status prior to randomization (0 vs. 1), lactate dehydrogenase (LDH) (≤ ULN vs. > ULN) prior to randomization, presence of liver metastases prior to initial study enrollment (yes vs. no), and prior receipt of prophylactic cranial irradiation (yes vs. no).
The major efficacy outcome measures were OS and PFS by Independent Review Facility per RECIST v1.1. A total of 483 patients were randomized, including 242 to the intravenous atezolizumab with lurbinectedin arm and 241 to the intravenous atezolizumab arm. Baseline ECOG performance status was Efficacy results are presented in Table 33 and Figures 7 and 8.
Table 33: Efficacy Results from IMforte Figure 7: Kaplan-Meier Plot of IRF-assessed Progression-Free Survival in IMforte Figure 8: Kaplan-Meier Plot of Overall Survival in IMforte Figure 7 Figure 8
Hepatocellular Carcinoma
The efficacy of TECENTRIQ HYBREZA in combination with bevacizumab for the treatment of adult patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy has been established in adequate and well-controlled studies of intravenous atezolizumab in combination with bevacizumab for HCC. Below is a description of the efficacy results of intravenous atezolizumab in combination with bevacizumab in this adequate and well-controlled HCC trial. Hepatocellular Carcinoma IMbrave150 The efficacy of intravenous atezolizumab in combination with bevacizumab was investigated in IMbrave150 (NCT03434379), a multicenter, international, open-label, randomized trial in patients with locally advanced unresectable and/or metastatic hepatocellular carcinoma who have not received prior systemic therapy.
Randomization was stratified by geographic region (Asia excluding Japan vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), baseline AFP (< 400 vs. ≥ 400 ng/mL), and by ECOG performance status (0 vs. 1). Patients could discontinue either intravenous atezolizumab or bevacizumab (e.g., due to adverse events) and continue on monotherapy until disease progression or unacceptable toxicity associated with the monotherapy. The study enrolled patients who were ECOG performance score 0 or 1 and who had not received prior systemic treatment.
Patients were required to be evaluated for the presence of varices within 6 months prior to treatment, and were excluded if they had variceal bleeding within 6 months prior to treatment, untreated or incompletely treated varices with bleeding, or high risk of bleeding. Patients with Child-Pugh B or C cirrhosis, moderate or severe ascites; history of hepatic encephalopathy; a history of autoimmune disease; administration of a live, attenuated vaccine within 4 weeks prior to randomization; administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomization; or untreated or corticosteroid-dependent brain metastases were excluded. Tumor assessments were performed every 6 weeks for the first 54 weeks and every 9 weeks thereafter.
The demographics and baseline disease characteristics of the study population were balanced between the treatment arms. The majority of patients were Asian (57%) or White (35%); 40% were from Asia (excluding Japan). Approximately 75% of patients presented with macrovascular invasion and/or extrahepatic spread and 37% had a baseline AFP ≥ 400 ng/mL.
Baseline ECOG performance status was HCC risk factors were Hepatitis B in 48% of patients, Hepatitis C in 22%, and 31% of patients had non-viral liver disease. The majority of patients had BCLC stage C (82%) disease at baseline, while 16% had stage B, and 3% had stage A. Additional efficacy outcome measures were IRF-assessed overall response rate (ORR) per RECIST and mRECIST.
Efficacy results are presented in Table 34 and Figure 9. Table 34: Efficacy Results from IMbrave150 in IMbrave150 Exploratory analyses showed that the subset of patients (20%) who were ADA-positive by week 6 appeared to have reduced efficacy (effect on OS) as compared to patients (80%) who tested negative for treatment-emergent ADA by week 6. ADA-positive patients by week 6 appeared to have similar overall survival compared to sorafenib-treated patients.
In an exploratory analysis, inverse probability weighting was conducted to compare ADA-positive patients and ADA-negative patients in the intravenous atezolizumab and bevacizumab arm to the sorafenib arm. Inverse probability weighting factors were: baseline sum of longest tumor size (BSLD), baseline ECOG, baseline albumin, baseline LDH, sex, age, race, geographic region, weight, neutrophil-to-lymphocyte ratio, AFP (< 400 ng/mL vs ≥ 400 ng/mL), number of metastatic sites, MVI and/or EHS present at study entry, etiology (HBV vs. HCV vs. non-viral) and Child-Pugh Score A5 vs.
A6. The OS hazard ratio comparing the ADA-positive subgroup of the intravenous atezolizumab and bevacizumab arm to sorafenib was The OS hazard ratio comparing the ADA-negative subgroup to sorafenib was Figure 9
Melanoma
The efficacy of TECENTRIQ HYBREZA in combination with cobimetinib and vemurafenib for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma has been established in adequate and well-controlled studies of intravenous atezolizumab in combination with bevacizumab for BRAF V600 mutation-positive unresectable or metastatic melanoma. Metastatic Melanoma IMspire150 The efficacy of intravenous atezolizumab in combination with cobimetinib and vemurafenib was evaluated in a double-blind, randomized (1:1), placebo-controlled, multicenter trial (IMspire150; NCT02908672) conducted in 514 patients. Randomization was stratified by geographic location North America vs.
Europe vs. Australia, New Zealand, and others and baseline lactate dehydrogenase (LDH). Eligible patients were required to have previously untreated unresectable or metastatic BRAF V600 mutation-positive melanoma as detected by a locally available test and centrally confirmed with the FoundationOne™ assay.
Treatment continued until disease progression or unacceptable toxicity. There was no crossover at the time of disease progression. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS) per RECIST v1.1.
Additional efficacy outcomes included PFS assessed by an independent central review, investigator-assessed ORR, OS, and DOR. Based on central testing, 74% were identified as having a V600E mutation, 11% as having V600K mutation, and 1% as having V600D or V600R mutations. Efficacy results are summarized in Table 35 and Figure 10.
Patients had a median survival follow up time of 18.9 months. Table 35: Efficacy Results from IMspire150 in IMspire150 At a pre-specified analysis at the time of the primary analysis of PFS, the OS data were not mature. The hazard ratio for OS was and the p-value was 0.2310.
Figure 10
Alveolar Soft Part Sarcoma
The efficacy of TECENTRIQ HYBREZA as monotherapy for the treatment of adult patients and pediatric patients 12 years of age or older with unresectable or metastatic alveolar soft part sarcoma (ASPS) has been established in adequate and well-controlled studies of intravenous atezolizumab for ASPS. The efficacy of intravenous atezolizumab was evaluated in study ML39345 (NCT03141684), an open-label, single-arm study, in 49 adult and pediatric patients aged 2 years and older with unresectable or metastatic ASPS. Eligible patients were required to have histologically or cytologically confirmed ASPS that was not curable by surgery, and an ECOG performance status of ≤ 2.
Patients were excluded if they had known primary central nervous system (CNS) malignancy or symptomatic CNS metastases, known clinically significant liver disease, or history of idiopathic pulmonary fibrosis, pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. The major efficacy outcomes were Overall Response Rate (ORR) and Duration of Response (DOR) by Independent Review Committee according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. A total of 49 patients were enrolled.
All patients had prior surgery for ASPS and 55% received at least one prior line of treatment for ASPS; 55% received radiotherapy and 53% received chemotherapy. Of the patients who reported staging at initial diagnosis, all were Stage IV. Efficacy results of this study are summarized in Table 36.
Table 36: Efficacy Results from Study ML39345
Muscle Invasive Bladder Cancer
The efficacy of TECENTRIQ HYBREZA as an adjuvant treatment for adult patients with MIBC after cystectomy who have ctDNA MRD has been established in an adequate and well-controlled study of intravenous atezolizumab for MIBC. Muscle Invasive Bladder Cancer IMvigor011 The efficacy of intravenous atezolizumab was evaluated in IMvigor011 (NCT04660344), a multi-center, randomized, double-blind, placebo-controlled trial for the adjuvant treatment of patients with MIBC after cystectomy who had circulating tumor DNA molecular residual disease (ctDNA MRD). The trial enrolled patients with histologically confirmed MIBC who underwent radical cystectomy with lymph node dissection.
Eligible patients had pathologic tumor staging of pT2-4a and/or positive lymph nodes following cystectomy, with no evidence of residual disease or metastasis on imaging, confirmed within 28 days before randomization. Patients were eligible regardless of whether they had received prior neoadjuvant chemotherapy (NAC) or not. Patients were excluded if they had received any anti-cancer therapy within 3 weeks prior to trial enrollment or had a history of autoimmune disease.
Serial ctDNA MRD testing was performed every 6 weeks for 9 months starting at least 6 weeks after cystectomy with a final test at one year. Patients who did not develop ctDNA MRD within the testing period were monitored without study treatment, while those who had ctDNA MRD were screened for the treatment phase by confirming that they remained free of radiographic disease. The ctDNA MRD status was determined using either a Signatera™ clinical trial assay (whole exome-based tumor NGS sequencing and 16-plex NGS-based plasma sequencing) or a clinical trial assay performed locally in China.
Randomization was stratified by nodal status (positive vs. negative), tumor stage (≤(y)pT2 vs. (y)pT3/pT4), PD-L1 immunohistochemistry (IHC) (IC <5% vs. IC ≥5%), and time from cystectomy to first ctDNA MRD positive sample (≤20 weeks vs. >20 weeks). Arm B: Placebo intravenously every 4 weeks on Day 1 of each 28-day cycle Treatment continued for up to 12 cycles or 1 year (whichever occurred first) unless there was disease recurrence, or unacceptable toxicity.
A total of 48% of patients in the TECENTRIQ arm received prior platinum containing neoadjuvant chemotherapy. Overall Survival (OS) was an additional efficacy measure. The study demonstrated statistically significant improvements in DFS and OS for patients randomized to the intravenous atezolizumab arm compared with placebo.
Efficacy results are presented in Table 37 and Figures 11 and 12. The unstratified HR for OS was median OS was not reached in either arm (95% CI: 21.1 months, not reached in the intravenous atezolizumab arm and 18.4 months, not reached in the placebo arm). Figure 11 Figure 12
Patient Experience The IMscin002 study (NCT03735121) was a randomized, multi-center, open-label cross-over trial conducted in 179 patients with either PD-L1-positive early-stage NSCLC receiving adjuvant treatment or were chemotherapy-naïve with high PD-L1 stage IV NSCLC. Eighty-seven of 123 patients (71%) reported preferring subcutaneous administration of TECENTRIQ HYBREZA over intravenous atezolizumab and the most common reason was that administration required less time in the clinic; 26 out of 123 patients (21%) reported preferring intravenous atezolizumab over TECENTRIQ HYBREZA and the most common reason was that it felt more comfortable during administration; and 10 out of 123 patients (8%) had no preference for the route of administration. Patients in both arms could continue to receive treatment after the crossover period for up to 16 cycles (patients with early-stage NSCLC) or until disease progression or unacceptable toxicity (patients with stage IV NSCLC).
| Arm A: Intravenous Atezolizumab N = 248 | Arm B: Best Supportive Care N = 228 | |
|---|---|---|
| CI = Confidence interval, NE = Not estimable, NR = Not reached | ||
| Disease-Free Survival | ||
| Number of events (%) | 88 (35) | 105 (46) |
| Median, months | NR | 35.3 |
| (95% CI) | (36.1, NE) | (29.0, NE) |
| Hazard ratio Stratified by stage, sex, and histology (95% CI) | 0.66 (0.50, 0.88) | |
| p-value | 0.004 | |
| Arm A: Intravenous Atezolizumab | Arm B: Platinum-Based Chemotherapy | |
|---|---|---|
| N = 107 | N = 98 | |
| CI = confidence interval; NE = not estimable | ||
| Overall Survival Based on OS interim analysis. The median survival follow-up time in patients was 15.7 months | ||
| Deaths (%) | 44 (41%) | 57 (58%) |
| Median, months | 20.2 | 13.1 |
| (95% CI) | (16.5, NE) | (7.4, 16.5) |
| Hazard ratio Stratified by sex and ECOG performance status (95% CI) | 0.59 (0.40, 0.89) | |
| p-value Based on the stratified log-rank test compared to Arm A | 0.0106 Compared to the allocated alpha of 0.0413 (two-sided) for this interim analysis | |
| Arm C: Bevacizumab, Paclitaxel and Carboplatin | Arm B: Intravenous Atezolizumab with Bevacizumab, Paclitaxel, and Carboplatin | Arm A: Intravenous Atezolizumab with Paclitaxel, and Carboplatin | |
|---|---|---|---|
| N = 337 | N = 359 | N = 349 | |
| CI = confidence interval | |||
| Overall Survival Based on OS interim analysis | |||
| Deaths (%) | 197 (59%) | 179 (50%) | 179 (51%) |
| Median, months | 14.7 | 19.2 | 19.4 |
| (95% CI) | (13.3, 16.9) | (17.0, 23.8) | (15.7, 21.3) |
| Hazard ratio Stratified by sex, presence of liver metastases, and PD-L1 expression status on TC and IC (95% CI) | --- | 0.78 (0.64, 0.96) | 0.84 (0.72, 1.08) |
| p-value Based on the stratified log-rank test compared to Arm C | --- | 0.016 Compared to the allocated α=0.0174 (two sided) for this interim analysis | 0.204 Compared to the allocated α=0.0128 (two sided) for this interim analysis |
| Progression-Free Survival As determined by independent review facility (IRF) per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1) | |||
| Number of events (%) | 247 (73%) | 247 (69%) | 245 (70%) |
| Median, months | 7.0 | 8.5 | 6.7 |
| (95% CI) | (6.3, 7.9) | (7.3, 9.7) | (5.6, 6.9) |
| Hazard ratio (95% CI) | --- | 0.71 (0.59, 0.85) | 0.94 (0.79, 1.13) |
| p-value | --- | 0.0002 Compared to the allocated α=0.006 (two sided) for the final PFS analysis | 0.5219 |
| Objective Response Rate | |||
| Number of responders (%) | 142 (42%) | 196 (55%) | 150 (43%) |
| (95% CI) | (37, 48) | (49, 60) | (38, 48) |
| Complete Response | 3 (1%) | 14 (4%) | 9 (3%) |
| Partial Response | 139 (41%) | 182 (51%) | 141 (40%) |
| Duration of Response | n = 142 | n = 196 | n = 150 |
| Median, months | 6.5 | 10.8 | 9.5 |
| (95% CI) | (5.6, 7.6) | (8.4, 13.9) | (7.0, 13.0) |
| Intravenous Atezolizumab with Paclitaxel Protein-Bound and Carboplatin | Paclitaxel Protein-Bound and Carboplatin | |
|---|---|---|
| CI = confidence interval | ||
| Overall Survival Based on OS interim analysis | n = 453 | n = 228 |
| Deaths (%) | 228 (50%) | 131 (57%) |
| Median, months | 18.6 | 13.9 |
| (95% CI) | (15.7, 21.1) | (12.0, 18.7) |
| Hazard ratio Stratified by sex and PD-L1 tumor expression on tumor cells (TC) and tumor infiltrating cells (IC) (95% CI) | 0.80 (0.64, 0.99) | |
| p-value Based on the stratified log-rank test | 0.0384 Compared to the allocated α=0.0428 (two sided) for this interim analysis | |
| Progression-Free Survival As determined by independent review facility (IRF) per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1) | n = 453 | n = 228 |
| Number of events (%) | 330 (73%) | 177 (78%) |
| Median, months | 7.2 | 6.5 |
| (95% CI) | (6.7, 8.3) | (5.6, 7.4) |
| Hazard ratio (95% CI) | 0.75 (0.63, 0.91) | |
| p-value | 0.0024 Compared to the allocated α=0.006 (two sided) for the final PFS analysis | |
| Overall Response Rate, Confirmed response | n = 453 | n = 228 |
| Number of responders (%) | 207 (46%) | 74 (32%) |
| (95% CI) | (41, 50) | (26, 39) |
| Complete Response | 22 (5%) | 2 (1%) |
| Partial Response | 185 (41%) | 72 (32%) |
| Duration of Response, | n = 207 | n = 74 |
| Median, months | 10.8 | 7.8 |
| (95% CI) | (9.0, 14.4) | (6.8, 10.9) |
| Intravenous Atezolizumab | Docetaxel | |
|---|---|---|
| CI = confidence interval; NE = not estimable | ||
| Overall Survival in first 850 patients | ||
| Number of patients | N = 425 | N = 425 |
| Deaths (%) | 271 (64%) | 298 (70%) |
| Median, months | 13.8 | 9.6 |
| (95% CI) | (11.8, 15.7) | (8.6, 11.2) |
| Hazard ratio Stratified by PD-L1 expression in tumor infiltrating immune cells, the number of prior chemotherapy regimens, and histology (95% CI) | 0.74 (0.63, 0.87) | |
| p-value Based on the stratified log-rank test | 0.0004 Compared to the pre-specified allocated α of 0.03 for this analysis | |
| Progression-Free Survival | ||
| Number of Patients | N = 425 | N = 425 |
| Events (%) | 380 (89%) | 375 (88%) |
| Progression (%) | 332 (78%) | 290 (68%) |
| Deaths (%) | 48 (11%) | 85 (20%) |
| Median, months | 2.8 | 4.0 |
| (95% CI) | (2.6, 3.0) | (3.3, 4.2) |
| Hazard ratio (95% CI) | 0.95 (0.82, 1.10) | |
| Overall Response Rate Per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1) | ||
| Number of Patients | N = 425 | N = 425 |
| ORR, n (%) | 58 (14%) | 57 (13%) |
| (95% CI) | (11%, 17%) | (10%, 17%) |
| Complete Response | 6 (1%) | 1 (0.2%) |
| Partial Response | 52 (12%) | 56 (13%) |
| Duration of Response | N = 58 | N = 57 |
| Median, months | 16.3 | 6.2 |
| (95% CI) | (10.0, NE) | (4.9, 7.6) |
| Overall Survival in all 1225 patients | ||
| Number of patients | N = 613 | N = 612 |
| Deaths (%) | 384 (63%) | 409 (67%) |
| Median, months | 13.3 | 9.8 |
| (95% CI) | (11.3, 14.9) | (8.9, 11.3) |
| Hazard ratio (95% CI) | 0.79 (0.69, 0.91) | |
| p-value | 0.0013 Compared to the allocated α of 0.0177 for this interim analysis based on 86% information using O'Brien-Fleming boundary | |
| Intravenous Atezolizumab with Carboplatin and Etoposide | Placebo with Carboplatin and Etoposide | |
|---|---|---|
| CI = confidence interval | ||
| Overall Survival | N = 201 | N = 202 |
| Deaths (%) | 104 (52%) | 134 (66%) |
| Median, months | 12.3 | 10.3 |
| (95% CI) | (10.8, 15.9) | (9.3, 11.3) |
| Hazard ratio Stratified by sex and ECOG performance status (95% CI) | 0.70 (0.54, 0.91) | |
| p-value Based on the stratified log-rank test, Compared to the allocated α of 0.0193 for this interim analysis based on 78% information using O'Brien-Fleming boundary | 0.0069 | |
| Progression-Free Survival As determined by investigator assessment, per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1) | N = 201 | N = 202 |
| Number of events (%) | 171 (85%) | 189 (94%) |
| Median, months | 5.2 | 4.3 |
| (95% CI) | (4.4, 5.6) | (4.2, 4.5) |
| Hazard ratio (95% CI) | 0.77 (0.62, 0.96) | |
| p-value, Compared to the allocated α of 0.05 for this analysis | 0.0170 | |
| Objective Response Rate,, Confirmed response | N = 201 | N = 202 |
| Number of responders (%) | 121 (60%) | 130 (64%) |
| (95% CI) | (53, 67) | (57, 71) |
| Complete Response (%) | 5 (2%) | 2 (1%) |
| Partial Response (%) | 116 (58%) | 128 (63%) |
| Duration of Response,, | N = 121 | N = 130 |
| Median, months | 4.2 | 3.9 |
| (95% CI) | (4.1, 4.5) | (3.1, 4.2) |
| Intravenous Atezolizumab in combination with Bevacizumab (N= 336) | Sorafenib (N=165) | |
|---|---|---|
| + Denotes a censored value CI = confidence interval; HCC mRECIST = Modified RECIST Assessment for Hepatocellular Carcinoma; NE = not estimable; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors v1.1 | ||
| Overall Survival | ||
| Number of deaths (%) | 96 (29) | 65 (39) |
| Median OS in months | NE | 13.2 |
| (95% CI) | (NE, NE) | (10.4, NE) |
| Hazard ratio Stratified by geographic region (Asia excluding Japan vs. rest of world), macrovascular invasion and/or extrahepatic spread (presence vs. absence), and baseline AFP (< 400 vs. ≥ 400 ng/mL) (95% CI) | 0.58 (0.42, 0.79) | |
| p-value Based on two-sided stratified log-rank test; as compared to significance level 0.004 (2-sided) based on 161/312=52% information using the OBF method | 0.0006 | |
| Progression-Free Survival Per independent radiology review | ||
| Number of events (%) | 197 (59) | 109 (66) |
| Median PFS in months (95% CI) | 6.8 (5.8, 8.3) | 4.3 (4.0, 5.6) |
| Hazard ratio (95% CI) | 0.59 (0.47, 0.76) | |
| p-value | < 0.0001 | |
| Overall Response Rate, Confirmed responses (ORR), RECIST 1.1 | ||
| Number of responders (%) | 93 (28) | 19 (12) |
| (95% CI) | (23, 33) | (7,17) |
| p-value Based on two-sided Cochran-Mantel-Haesnszel test | < 0.0001 | |
| Complete responses, n (%) | 22 (7) | 0 |
| Partial responses, n (%) | 71 (21) | 19 (12) |
| Duration of Response, (DOR) RECIST 1.1 | ||
| (n=93) | (n=19) | |
| Median DOR in months | NE | 6.3 |
| (95% CI) | (NE, NE) | (4.7, NE) |
| Range (months) | (1.3+, 13.4+) | (1.4+, 9.1+) |
| Overall Response Rate, (ORR), HCC mRECIST | ||
| Number of responders (%) | 112 (33) | 21 (13) |
| (95% CI) | (28, 39) | (8, 19) |
| p-value | < 0.0001 | |
| Complete responses, n (%) | 37 (11) | 3 (1.8) |
| Partial responses, n (%) | 75 (22) | 18 (11) |
| Duration of Response, (DOR) HCC mRECIST | ||
| (n=112) | (n=21) | |
| Median DOR in months | NE | 6.3 |
| (95% CI) | (NE, NE) | (4.9, NE) |
| Range (months) | (1.3+, 13.4+) | (1.4+, 9.1+) |
| Intravenous Atezolizumab + Cobimetinib + Vemurafenib N = 256 | Placebo + Cobimetinib + Vemurafenib N = 258 | |
|---|---|---|
| Progression-Free Survival As determined by investigator assessment with Response Evaluation Criteria in Solid Tumors v1.1.; CI = confidence interval | ||
| Number of events (%) | 148 (58) | 179 (69) |
| Median, months | 15.1 | 10.6 |
| (95% CI) | (11.4, 18.4) | (9.3, 12.7) |
| Hazard ratio Stratified by baseline LDH (95% CI) | 0.78 (0.63, 0.97) | |
| p-value Based on the stratified log-rank test | 0.0249 | |
| Overall Response Rate, Confirmed responses | ||
| Number of responders (%) | 170 (66) | 168 (65) |
| (95% CI) | (60, 72) | (59, 71) |
| Complete responses, n (%) | 41 (16) | 46 (18) |
| Partial response, n (%) | 129 (50) | 122 (47) |
| Duration of Response, | n = 170 | n = 168 |
| Median, months | 20.4 | 12.5 |
| (95% CI) | (15.1, NE) | (10.7, 16.6) |
| Endpoint | All Patients (N=49) |
|---|---|
| CI: confidence interval; N: number of patients; +: Censored | |
| Overall Response Rate (95% CI) 95% CI based on Clopper-Pearson exact method. | 24% (13, 39) |
| Complete responses, n | 0 |
| Partial responses, n (%) | 12 (24) |
| Duration of Response | |
| Median, month | NE |
| (95% CI) | (17.0, NE) |
| Range | 1+, 41+ |
| Durability of response | |
| ≥ 6 months, n (%) | 8 (67%) |
| ≥ 12 months, n (%) | 5 (42%) |
| Intravenous Atezolizumab N=167 | Placebo N=83 | |
|---|---|---|
| CI=confidence interval; NE=not estimable | ||
| Investigator - assessed DFS | ||
| Number of events (%) | 112 (67%) | 66 (80%) |
| Median Based on Kaplan-Meier estimates, months | 9.9 | 4.8 |
| (95% CI) | (7.2, 12.7) | (4.1, 8.3) |
| Hazard ratio Based on stratified Cox proportional hazards model, Stratified by programmed death-ligand 1 (PD-L1) status, nodal status, tumor stage after cystectomy (95% CI) | 0.64 (0.47, 0.87) | |
| p-value, Based on stratified log-rank test | 0.0047 | |
| Overall survival | ||
| Number of deaths (%) | 60 (36%) | 36 (43%) |
| Median, months | 32.8 | 21.1 |
| (95% CI) | (27.7, NE) | (14.7, NE) |
| Hazard ratio, (95% CI) | 0.59 (0.39, 0.90) | |
| p-value, | 0.0131 | |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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