Lumakras Drug Information
Generic name: SOTORASIB
Uses of Lumakras
KRAS G12C-mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)
LUMAKRAS as a single agent is indicated for the treatment of adult patients with KRAS G12C -mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test , who have received at least one prior systemic therapy. This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR) . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
KRAS G12C-mutated Metastatic Colorectal Cancer (mCRC)
LUMAKRAS, in combination with panitumumab, is indicated for the treatment of adult patients with KRAS G12C -mutated metastatic colorectal cancer (mCRC), as determined by an FDA-approved test, who have received prior fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy .
Dosage & Administration of Lumakras
| 480 mg (two 240 mg or four 120 mg tablets) once daily | |
| 240 mg (one 240 mg or two 120 mg tablets) once daily |
Side Effects of Lumakras
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. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to LUMAKRAS as a single agent at 960 mg orally once daily until disease progression or unacceptable toxicity in 549 patients with NSCLC with KRAS G12C mutation in the following trials: CodeBreaK 200 (NCT04303780), CodeBreaK 100 (NCT03600883), CodeBreaK 101 (NCT04185883) and CodeBreaK 105 (NCT04380753). Among these 549 patients who received LUMAKRAS, 44% were exposed for 6 months or longer and 21% were exposed for greater than one year. The pooled safety population described in WARNINGS AND PRECAUTIONS also reflects exposure to LUMAKRAS 960 mg once daily in combination with panitumumab in 126 patients who received LUMAKRAS in combination with panitumumab for mCRC in CodeBreaK 300 (NCT05198934) and CodeBreaK 101 (NCT04185883). Among the 126 patients who received LUMAKRAS 960 mg in combination with panitumumab, 40% were exposed for 6 months or longer and 10% were exposed for greater than one year.
Metastatic Non-Small Cell Lung Cancer The safety of LUMAKRAS was evaluated in a subset of patients with KRAS G12C -mutated locally advanced or metastatic NSCLC in CodeBreaK 100 . Patients received LUMAKRAS 960 mg orally once daily until disease progression or unacceptable toxicity (n = 204). Among patients who received LUMAKRAS, 39% were exposed for 6 months or longer and 3% were exposed for greater than one year. The median age of patients who received LUMAKRAS was 66 years (range: 37 to 86); 55% female; 80% White, 15% Asian, and 3% Black. Serious adverse reactions occurred in 50% of patients treated with LUMAKRAS. Serious adverse reactions in ≥ 2% of patients were pneumonia (8%), hepatotoxicity (3.4%), and diarrhea (2%). Fatal adverse reactions occurred in 3.4% of patients who received LUMAKRAS due to respiratory failure (0.8%), pneumonitis (0.4%), cardiac arrest (0.4%), cardiac failure (0.4%), gastric ulcer (0.4%), and pneumonia (0.4%). Permanent discontinuation of LUMAKRAS due to an adverse reaction occurred in 9% of patients.
Adverse reactions resulting in permanent discontinuation of LUMAKRAS in ≥ 2% of patients included hepatotoxicity (4.9%). Dosage interruptions of LUMAKRAS due to an adverse reaction occurred in 34% of patients. Adverse reactions which required dosage interruption in ≥ 2% of patients were hepatotoxicity (11%), diarrhea (8%), musculoskeletal pain (3.9%), nausea (2.9%), and pneumonia (2.5%). Dose reductions of LUMAKRAS due to an adverse reaction occurred in 5% of patients. Adverse reactions which required dose reductions in ≥ 2% of patients included increased ALT (2.9%) and increased AST (2.5%). The most common adverse reactions (≥ 20%) were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough.
The most common laboratory abnormalities (≥ 25%) were decreased lymphocytes, decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, decreased calcium, increased alkaline phosphatase, increased urine protein, and decreased sodium. Table 3 summarizes the common adverse reactions observed in CodeBreaK 100. Table 3. Adverse Reactions (≥ 10%) of Patients with KRAS G12C-Mutated NSCLC who Received LUMAKRAS in CodeBreaK 100 Grading defined by NCI CTCAE version 5.0. Adverse Reaction LUMAKRAS N = 204 All Grades (%) Grades 3 to 4 (%) Gastrointestinal disorders Diarrhea 42 5 Nausea 26 1 Vomiting 17
Constipation 16 0.5 Abdominal pain Abdominal pain includes abdominal pain, abdominal pain
upper, and abdominal pain lower. 15
Hepatobiliary disorders Hepatotoxicity Hepatotoxicity includes alanine aminotransferase increased, aspartate aminotransferase increased, blood
bilirubin increased, drug-induced liver injury, hepatitis, hepatotoxicity, liver function test increased, and transaminases increased. 25 12 Respiratory, thoracic, and mediastinal disorders Cough Cough includes cough, productive cough, and upper-airway cough syndrome. 20
Dyspnea Dyspnea includes dyspnea and dyspnea exertional. 16 2.9 Musculoskeletal and connective
tissue disorders Musculoskeletal pain Musculoskeletal pain includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, and pain in extremity. 35 8 Arthralgia 12
General disorders and administration site conditions Fatigue Fatigue includes fatigue and asthenia.
26
Edema Edema includes generalized edema, localized edema, edema, edema peripheral, periorbital edema
and testicular edema. 15 0 Metabolism and nutrition disorders Decreased appetite 13
Infections and infestations Pneumonia Pneumonia includes pneumonia, pneumonia aspiration, pneumonia bacterial, and
pneumonia staphylococcal. 12 7 Skin and subcutaneous tissue disorders Rash Rash includes dermatitis, dermatitis acneiform, rash, rash-maculopapular, and rash pustular. 12 0 Table 4 summarizes the selected laboratory adverse reactions observed in CodeBreaK 100. Table 4. Select Laboratory Abnormalities (≥ 20%) that Worsened from Baseline in Patients with KRAS G12C-Mutated NSCLC who Received LUMAKRAS in CodeBreaK 100 Laboratory Abnormalities LUMAKRAS N = 204 N = number of patients who had at least one on-study assessment for the parameter of interest. Grades 1 to 4 (%) Grades 3 to 4 (%) Chemistry Increased aspartate aminotransferase 39 9 Increased alanine aminotransferase 38 11 Decreased calcium 35 0 Increased alkaline phosphatase 33
Hematology Decreased lymphocytes 48 2 Decreased hemoglobin 43 0.5 Increased activated partial
thromboplastin time 23
Metastatic Colorectal Cancer
The safety of LUMAKRAS in combination with panitumumab was evaluated in the CodeBreaK 300 study . Patients with KRAS G12C-mutated mCRC received LUMAKRAS 960 mg orally once daily in combination with panitumumab 6 mg/kg intravenously (IV) once every 2 weeks (N = 47), LUMAKRAS 240 mg orally once daily in combination with panitumumab 6 mg/kg IV once every 2 weeks (N = 50), or the investigator's choice of standard of care (SOC) trifluridine/ tipiracil or regorafenib (N = 50). Among patients who received LUMAKRAS 960 mg orally once daily in combination with panitumumab, 36% were exposed to LUMAKRAS for greater than 6 months and 6% were exposed for greater than 12 months. The median age of patients who received LUMAKRAS 960 mg in combination with panitumumab arm was 63 years (range: 37-79 years); 38% were age 65 years or older; 49% were female; 79% were White and 13% were Asian. Serious adverse reactions occurred in 26% of patients receiving LUMAKRAS 960 mg in combination with panitumumab.
Serious adverse reactions in ≥ 2 patients receiving LUMAKRAS 960 mg in combination with panitumumab were sepsis (6%) and intestinal obstruction (4.3%). Fatal adverse reactions occurred in 2 patients (4.3%) receiving LUMAKRAS 960 mg in combination with panitumumab, consisting of cardiac arrest and sepsis (1 patient each). Permanent discontinuation of LUMAKRAS due to an adverse reaction occurred in 1 patient for decreased corrected calcium. Dosage interruptions of LUMAKRAS due to an adverse reaction occurred in 26% of patients. Adverse reactions which required dosage interruption in ≥ 2 patients were rash, hepatotoxicity and intestinal obstruction.
A dose reduction of LUMAKRAS due to an adverse reaction occurred in 1 patient for nausea. The most common adverse reactions (≥ 20%) in patients receiving LUMAKRAS 960 mg in combination with panitumumab were rash, dry skin, diarrhea, stomatitis, fatigue and musculoskeletal pain. The most common Grade 3-4 laboratory abnormalities in ≥ 2 patients (4.3%) were decreased magnesium, decreased potassium, decreased corrected calcium, and increased potassium.
Table 5 and Table 6 summarize the adverse reactions and laboratory abnormalities, respectively, identified in CodeBreaK 300. Table 5. Adverse Reactions (≥ 10%) in Patients with KRAS G12C-Mutated mCRC who Received LUMAKRAS 960 mg in Combination with Panitumumab in CodeBreaK 300 Adverse Reaction LUMAKRAS 960 mg in combination with panitumumab N = 47 Trifluridine/tipiracil or regorafenib N = 50 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Skin and subcutaneous tissue disorders Rash Rash includes dermatitis acneiform, dermatosis, drug eruption, eczema, erythema, hand dermatitis, rash, rash erythematous, rash maculo-papular, rash papular, rash pruritic, rash pustular, and skin toxicity. 87 26 8 2 Dry skin Dry skin includes dry skin, xerosis, and xeroderma. 28 0 2 0 Pruritis 17 0 4 0 Nail Disorder Nail disorders includes nail avulsion, nail cuticle fissure, nail disorder, nail toxicity, and paronychia. 17 0 0 0 Skin fissure 13 0 0 0 Palmar-plantar erythrodysesthesia syndrome 13 0 10 4 Gastrointestinal disorders Diarrhea Diarrhea includes diarrhea, gastroenteritis, and diarrhea hemorrhagic. 28 6 26 0 Stomatitis Stomatitis includes mucosal inflammation, stomatitis, mouth ulceration, angular cheilitis, and cheilitis. 26 0 14 0 Nausea 17 2.1 36 4 Constipation 15 2.1 10 0 Abdominal pain Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, and hepatic pain. 15 0 18 2 Vomiting 13 2.1 10 2 General disorders Fatigue Fatigue includes asthenia and fatigue. 21 0 34 2 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes arthralgia, back pain, myalgia, musculoskeletal chest pain, bone pain, and pain in extremity. 21 2.1 14 2 Hematological disorders Hemorrhage Hemorrhage includes epistaxis, gastrointestinal hemorrhage, vaginal hemorrhage, rectal hemorrhage, hematochezia, hemorrhage, hemorrhage urinary tract, hematospermia, and hematuria. 13 2.1 2 0 Eye disorders Conjunctivitis Conjunctivitis includes conjunctival hyperemia, conjunctivitis, and conjunctivitis allergic. 11 0 2 0 Table 6. Select Laboratory Abnormalities (≥ 20%) that Worsened from Baseline in Patients with KRAS G12C-Mutated mCRC who Received LUMAKRAS 960 mg in combination with panitumumab in CodeBreaK 300 The denominator used to calculate the rate varied from 44 to 46 in the LUMAKRAS + panitumumab arm and 18 to 50 in the trifluridine/tipiracil or regorafenib arm based on the number of patients with a baseline value and at least one post-treatment value. Laboratory Abnormalities LUMAKRAS 960 mg in combination with panitumumab Trifluridine/tipiracil or Regorafenib All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Chemistry Magnesium decreased 76 24 8 0 Calcium (corrected) decreased 74 4.3 46 0 Aspartate aminotransferase increased 39 0 22 2 Alkaline Phosphatase increased 33 2.2 33 0 Creatine kinase increased 30 2.3 7 0 Alanine Aminotransferase increased 28 0 16 2 Potassium decreased 26 7 12 0 Albumin decreased 26 2.2 22 0 Urine protein increased 23 0 22 6 Potassium increased 22 4.3 6 0 Glucose decreased 22 0 2 0 Hematology Hemoglobin decreased 30 0 58 6 Lymphocytes decreased 26 2.2 56 8 White blood cells decreased 24 0 48 14
Warnings & Cautions for Lumakras
Hepatotoxicity
LUMAKRAS can cause hepatotoxicity and increased alanine aminotransferase (ALT) or increased aspartate aminotransferase (AST) which may lead to drug-induced liver injury and hepatitis. In the pooled safety population of patients with NSCLC who received single agent LUMAKRAS 960 mg , hepatotoxicity occurred in 27% of patients, of which 16% were Grade ≥ 3. Among patients with hepatotoxicity who required dosage modifications, 64% required treatment with corticosteroids. In this pooled safety population of patients with NSCLC who received single agent LUMAKRAS 960 mg, 17% of patients who received LUMAKRAS had increased ALT/increased AST; of which 9% were Grade ≥ 3. The median time to first onset of increased ALT/AST was 6.3 weeks (range: 0.4 to 42). Increased ALT/AST leading to dose interruption or reduction occurred in 9% of patients treated with LUMAKRAS. LUMAKRAS was permanently discontinued due to increased ALT/AST in 2.7% of patients.
Drug-induced liver injury occurred in 1.6% (all grades) including 1.3% (Grade ≥ 3). In this pooled safety population of patients with NSCLC who received single agent LUMAKRAS 960 mg, a total of 40% patients with recent (≤ 3 months) immunotherapy prior to starting LUMAKRAS had an event of hepatotoxicity. An event of hepatotoxicity was observed in 18% of patients who started LUMAKRAS more than 3 months after last dose of immunotherapy and in 17% of those who never received immunotherapy. Regardless of time from prior immunotherapy, 94% of hepatotoxicity events improved or resolved with dosage modification of LUMAKRAS, with or without corticosteroid treatment.
In the pooled safety population of patients with CRC who received LUMAKRAS 960 mg in combination with panitumumab , hepatotoxicity occurred in 15% of patients, of which 4.8% were Grade 3. A total of 7% of patients who received LUMAKRAS had increased ALT or increased AST, of which 0.8% were Grade 3. The median time to first onset of increased ALT or increased AST was 10 weeks (range: 2 to 22). Increased ALT or increased AST leading to dose interruption occurred in 2.4% of patients. A total of 3.2% of patients who received LUMAKRAS had hyperbilirubinemia, of which 2.4% were Grade 3. The median time to first onset of hyperbilirubinemia was 12 weeks (range: 0, 29). Hyperbilirubinemia leading to dose interruption occurred in 1.6% of patients. Among patients with hepatotoxicity, 21% received corticosteroids.
Monitor liver function tests (ALT, AST, alkaline phosphatase and total bilirubin) prior to the start of LUMAKRAS, every 3 weeks for the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop transaminase and/or bilirubin elevations. Withhold, reduce the dose or permanently discontinue LUMAKRAS based on severity of the adverse reaction. Consider administering systemic corticosteroids for the management of hepatotoxicity.
Interstitial Lung Disease (ILD)/Pneumonitis
LUMAKRAS can cause ILD/pneumonitis that can be fatal. In the pooled safety population of patients with NSCLC who received single agent LUMAKRAS 960 mg , ILD/pneumonitis occurred in 2.2% of patients, of which 1.1% were Grade ≥ 3, and 1 case was fatal. The median time to first onset for ILD/pneumonitis was 8.6 weeks (range: 2.1 to 36.7 weeks). LUMAKRAS was permanently discontinued due to ILD/pneumonitis in 1.3% of LUMAKRAS-treated patients.
Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold LUMAKRAS in patients with suspected ILD/pneumonitis and permanently discontinue LUMAKRAS if no other potential causes of ILD/pneumonitis are identified . In the pooled safety population of patients with CRC who received LUMAKRAS 960 mg in combination with panitumumab, 1 patient experienced a Grade 1 event of ILD/pneumonitis .
Drug Interactions with Lumakras
Effects of Other Drugs on
LUMAKRAS Acid-Reducing Agents The solubility of sotorasib is pH-dependent. Coadministration of LUMAKRAS with gastric acid-reducing agents decreased sotorasib concentrations , which may reduce the efficacy of sotorasib. Avoid coadministration of LUMAKRAS with proton pump inhibitors (PPIs), H 2 receptor antagonists, and locally acting antacids.
If coadministration with an acid-reducing agent cannot be avoided, administer LUMAKRAS 4 hours before or 10 hours after administration of a locally acting antacid . Strong CYP3A4 Inducers Sotorasib is a CYP3A4 substrate. Coadministration of LUMAKRAS with a strong CYP3A4 inducer decreased sotorasib concentrations , which may reduce the efficacy of sotorasib. Avoid coadministration of LUMAKRAS with strong CYP3A4 inducers.
Effects of
LUMAKRAS on Other Drugs CYP3A4 Substrates Sotorasib is a CYP3A4 inducer. Coadministration of LUMAKRAS with a CYP3A4 substrate decreased its plasma concentrations , which may reduce the efficacy of the substrate. Avoid coadministration of LUMAKRAS with CYP3A4 sensitive substrates, for which minimal concentration changes may lead to therapeutic failures of the substrate.
If coadministration cannot be avoided, increase the sensitive CYP3A4 substrate dosage in accordance with its Prescribing Information. P-glycoprotein (P-gp) Substrates Sotorasib is a P-gp inhibitor. Coadministration of LUMAKRAS with a P-gp substrate increased its plasma concentrations , which may increase the adverse reactions of the substrate.
Avoid coadministration of LUMAKRAS with P-gp substrates, for which minimal concentration changes may lead to serious toxicities. If coadministration cannot be avoided, decrease the P-gp substrate dosage in accordance with its Prescribing Information. Breast Cancer Resistance Protein (BCRP) Substrates Sotorasib is a BCRP-inhibitor.
Coadministration of LUMAKRAS with a BCRP substrate increased its plasma concentrations , which may increase the risk of adverse reactions of the substrate. When coadministered with LUMAKRAS, monitor for adverse reactions of the BCRP substrate and decrease the BCRP substrate dosage in accordance with its Prescribing Information.
Pregnancy Safety for Lumakras
Pregnancy Risk Summary There are no available data on LUMAKRAS use in pregnant women. In rat and rabbit embryo-fetal development studies, oral sotorasib did not cause adverse developmental effects or embryo-lethality at exposures up to 4.6 times the human exposure at the 960 mg clinical dose (see Data ). Refer to the Full Prescribing Information of panitumumab for pregnancy risk information and contraception recommendations when LUMAKRAS is administered in combination with panitumumab. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data Animal Data In a rat embryo-fetal development study, once daily oral administration of sotorasib to pregnant rats during the period of organogenesis resulted in maternal toxicity at the 540 mg/kg dose level (approximately 4.6 times the human exposure based on area under the curve (AUC) at the clinical dose of 960 mg). Sotorasib did not cause adverse developmental effects and did not affect embryo-fetal survival at doses up to 540 mg/kg. In a rabbit embryo-fetal development study, once daily oral administration of sotorasib during the period of organogenesis resulted in lower fetal body weights and a reduction in the number of ossified metacarpals in fetuses at the 100 mg/kg dose level (approximately 2.6 times the human exposure based on AUC at the clinical dose of 960 mg), which was associated with maternal toxicity including decreased body weight gain and food consumption during the dosing phase. Sotorasib did not cause adverse developmental effects and did not affect embryo-fetal survival at doses up to 100 mg/kg.
Pediatric Use of Lumakras
Pediatric Use The safety and effectiveness of LUMAKRAS have not been established in pediatric patients.
Clinical Studies of Lumakras
KRAS G12C-mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer
The efficacy of LUMAKRAS was demonstrated in a subset of patients enrolled in a single-arm, open-label, multicenter trial (CodeBreaK 100 ). Eligible patients were required to have locally advanced or metastatic KRAS G12C -mutated NSCLC with disease progression after receiving an immune checkpoint inhibitor and/or platinum-based chemotherapy, an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1, and at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1). All patients were required to have prospectively identified KRAS G12C -mutated NSCLC in tumor tissue samples by using the QIAGEN therascreen ® KRAS RGQ PCR Kit performed in a central laboratory. Of 126 total enrolled subjects, 2 (2%) were unevaluable for efficacy analysis due to the absence of radiographically measurable lesions at baseline. Of the 124 patients with KRAS G12C mutations confirmed in tumor tissue, plasma samples from 112 patients were tested retrospectively using the Guardant360 ® CDx. 78/112 patients (70%) had KRAS G12C mutation identified in plasma specimen, 31/112 patients (28%) did not have KRAS G12C mutation identified in plasma specimen and 3/112 (2%) were unevaluable due to Guardant360 ® CDx test failure.
A total of 124 patients had at least one measurable lesion at baseline assessed by Blinded Independent Central Review (BICR) according to RECIST v1.1 and were treated with LUMAKRAS 960 mg once daily until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR), and duration of response (DOR) as evaluated by BICR according to RECIST v1.1. The baseline demographic and disease characteristics of the study population were: median age 64 years (range: 37 to 80) with 48% ≥ 65 years and 8% ≥ 75 years; 50% Female; 82% White, 15% Asian, 2% Black; 70% ECOG PS 1; 96% had stage IV disease; 99% with non-squamous histology; 81% former smokers, 12% current smokers, 5% never smokers. All patients received at least 1 prior line of systemic therapy for metastatic NSCLC; 43% received only 1 prior line of therapy, 35% received 2 prior lines of therapy, 23% received 3 prior lines of therapy; 91% received prior anti-PD-1/PD-L1 immunotherapy, 90% received prior platinum-based chemotherapy, 81% received both platinum-based chemotherapy and anti-PD-1/PD-L1. The sites of known extra-thoracic metastasis included 48% bone, 21% brain, and 21% liver.
Efficacy results are summarized in Table 7. Table 7. Efficacy Results for Patients with KRAS G12C-mutated NSCLC who Received LUMAKRAS in CodeBreaK 100 Efficacy Parameter LUMAKRAS N = 124 CI = confidence interval Objective Response Rate (95% CI) Assessed by Blinded Independent Central Review (BICR). 36 Complete response rate, % 2 Partial response rate, % 35 Duration of Response Median Estimate using Kaplan-Meier method., months (range) 10 (1.3+, 11.1) Patients with duration ≥ 6 months Observed proportion of patients with duration of response beyond landmark time., % 58%
KRAS G12C-mutated Metastatic Colorectal Cancer
The efficacy of LUMAKRAS in combination with panitumumab was evaluated in CodeBreaK 300, a multicenter, randomized, open-label, active-controlled study conducted in previously treated patients with KRAS G12C -mutated mCRC. Key eligibility criteria included patients 18 years of age or older, who had received at least one prior line of therapy for mCRC, and who had received fluoropyrimidine, oxaliplatin, and irinotecan for metastatic disease unless there was a medical contraindication. All patients were also required to have prospectively identified KRAS G12C- mutated mCRC in tumor tissue samples by using the QIAGEN therascreen ® KRAS RGQ PCR Kit performed in a central laboratory. Other eligibility criteria included an ECOG PS of ≤ 2 and at least one measurable lesion as defined by RECIST v1.1. A total of 160 patients with previously treated mCRC with the KRAS G12C mutation were randomized 1:1:1 to receive either LUMAKRAS 960 mg orally once daily and panitumumab 6 mg/kg IV every 2 weeks (N = 53), or LUMAKRAS 240 mg orally once daily and panitumumab 6 mg/kg IV every 2 weeks (N = 53), or investigator's choice of SOC trifluridine/tipiracil or regorafenib (N = 54). Randomization was stratified by prior anti-angiogenic therapy (yes or no), time from initial diagnosis of metastatic disease to randomization (≥ 18 months; < 18 months), and ECOG status (0 or 1 versus 2). Patients received treatment until disease progression, lack of clinical benefit or intolerance to treatment.
LUMAKRAS discontinuation required panitumumab discontinuation, however, patients could continue to receive LUMAKRAS if panitumumab was discontinued. Four patients randomized to LUMAKRAS 960 mg in combination with panitumumab continued LUMAKRAS single agent therapy after discontinuing panitumumab. The major efficacy outcome measure was progression-free survival (PFS) as evaluated by BICR according to RECIST 1.1. Additional efficacy outcome measures included overall survival (OS), overall response rate (ORR), and duration of response (DOR). Only the results of the approved dosing regimen LUMAKRAS 960 mg in combination with panitumumab are described below.
Of the 107 patients randomized to either LUMAKRAS 960 mg once daily in combination with panitumumab or the control arms, the median age was 64 years (range: 34-81 years); 46% were age 65 years or older; 50% were female; 74% were White; 17% were Asian and 97% of the patients had ECOG PS 0 or 1. The primary site of disease was colon (69%) or rectum (31%). The median number of prior lines of therapy for metastatic disease was 2. Among the 107 patients, 100% received prior fluoropyrimidine, 99% received prior oxaliplatin, 93% received prior irinotecan and 18% of patients had received prior trifluridine and tipiracil, or regorafenib. The trial demonstrated a statistically significant improvement in PFS for patients randomized to LUMAKRAS 960 mg in combination with panitumumab compared to the investigator's choice SOC. The final analysis of OS was not statistically significant. The final analysis of PFS for patients randomized to LUMAKRAS 240 mg in combination with panitumumab compared to investigator's choice of SOC was not statistically significant.
The efficacy results from CodeBreaK 300 are summarized in Table 8 and Figure 1. Table 8. Efficacy Results for Patients with KRAS G12C-mutated mCRC in CodeBreaK 300 Efficacy Parameters Sotorasib 960 mg QD + Panitumumab (N = 53) SOC (trifluridine/tipiracil or regorafenib) (N = 54) N = Number of randomized subjects, NR = Not Reached, QD = once daily, SOC = standard of care, CR = complete response, PR = partial response, BICR = Blinded Independent Central Review Committee, CI = Confidence Interval Progression-Free Survival (PFS) per BICR Number of Events (%) 32 35 Median in months (95% CI) 5.6 2 Hazard ratio (95% CI) Hazard ratios and 95% CIs were estimated using a stratified Cox proportional hazards model. 0.48 p -value (2-sided) p-value was calculated using a stratified log-rank test. 0.005 Overall Survival (OS) OS analysis was based on 6-month additional follow-up data from the time of PFS primary analysis. Deaths (%) 24 30 Median in months (95% CI) NR (8.6, NR) 10.3 (7, NR) Hazard ratio (95% CI)
Overall Response Rate (ORR) per
BICR ORR, % (95% CI) 95% CIs were estimated using the Clopper-Pearson method. 26 0 CR, n (%) 1 0 PR, n (%) 13 0 Duration of Response (DOR) Median in months, (range) For DOR + indicates censored subjects. 4.4 (1.9+, 6+) - Figure 1. Kaplan-Meier Curve for Progression-Free Survival in CodeBreaK 300 Figure 1
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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