Alecensa Drug Information
Generic name: ALECTINIB HYDROCHLORIDE
Uses of Alecensa
Adjuvant Treatment of Resected
ALK-Positive Non-Small Cell Lung Cancer (NSCLC) ALECENSA is indicated as adjuvant treatment in adult patients following tumor resection of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) (tumors ≥ 4 cm or node positive), as detected by an FDA-approved test.
Treatment of Metastatic
ALK-Positive NSCLC ALECENSA is indicated for the treatment of adult patients with ALK-positive metastatic NSCLC as detected by an FDA-approved test .
Dosage & Administration of Alecensa
| Adjuvant treatment of resected NSCLC | 600 mg orally twice daily with food |
|---|---|
| Metastatic NSCLC | Until disease progression or unacceptable toxicity |
| |
Side Effects of Alecensa
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 ALECENSA as a single agent at 600 mg orally twice daily in 533 patients in Studies NP28761, NP28673, ALEX and ALINA. Among 533 patients who received ALECENSA, 75% were exposed for 6 months or longer and 64% were exposed for greater than one year. In this pooled safety population, the most common (≥ 20%) adverse reactions were hepatotoxicity (41%), constipation (39%), fatigue (36%), myalgia (31%), edema (29%), rash (23%) and cough (21%). The most common (≥ 2%) Grade 3 or 4 laboratory abnormalities were increased CPK (6%), decreased hemoglobin (4.4%), increased ALT (4.2%), increased bilirubin (4.0%) and increased AST (3.4%). Adjuvant Treatment of Resected ALK-Positive NSCLC The safety of ALECENSA was evaluated in ALINA, a multi-center, open-label, randomized trial for the adjuvant treatment of patients with resected ALK-positive NSCLC. At the time of DFS analysis, the median duration of exposure was 23.9 months for ALECENSA and 2.1 months for platinum-based chemotherapy.
Serious adverse reactions occurred in 13% of patients treated with ALECENSA; the most frequent serious adverse reactions (≥ 1%) were pneumonia (3.9%), appendicitis (3.1%), and acute myocardial infarction (1.6%). Permanent discontinuation of ALECENSA due to an adverse event occurred in 5% of patients; the most frequent adverse reactions (≥ 1%) that led to treatment discontinuation were pneumonitis and hepatotoxicity. Dosage interruptions of ALECENSA due to an adverse reaction occurred in 27% of patients. Adverse reactions which required dosage interruption in ≥ 2% of patients included hepatotoxicity, increased blood CPK, COVID-19, myalgia, abdominal pain, and pneumonia.
Dose reductions of ALECENSA due to an adverse reaction occurred in 26% of patients. Adverse reactions which required dose reductions in ≥ 2% of patients included hepatotoxicity, increased blood CPK, rash, bradycardia and myalgia. Table 4 and 5 summarize the common adverse reactions and laboratory abnormalities observed in ALINA. Table 4: Adverse Reactions (≥ 10%) in Patients Treated with ALECENSA in ALINA Adverse Reaction ALECENSA N=128 Chemotherapy N=120 All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Based on NCI CTCAE v5.0 Hepatobiliary System Disorders Hepatotoxicity Includes increased alanine aminotransferase, increased aspartate aminotransferase, increased bile acids, increased conjugated bilirubin, increased blood bilirubin, increased unconjugated blood bilirubin, increased gamma-glutamyltransferase, hepatotoxicity, hyperbilirubinemia, increased liver function test, ocular icterus and increased transaminases. 61
All events are Grade 3 13 0 Gastrointestinal Disorders Constipation 42 0.8
25
Abdominal pain Includes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal
pain, abdominal tenderness, epigastric discomfort and gastrointestinal pain. 13 0 10
Diarrhea Includes colitis and diarrhea. 13 0.8 9 1.7 Musculoskeletal Myalgia Includes
muscle fatigue, muscular weakness, musculoskeletal chest pain, musculoskeletal stiffness and myalgia. 34 0.8 1.7 0 Infections and Infestations COVID-19 29 0 0.8 0 General Disorders and Administration Site Conditions Fatigue Includes asthenia and fatigue. 25 0.8 28
Edema Includes edema, face edema, localized edema, peripheral edema, face swelling and
peripheral swelling. 16 0 1.7 0 Skin and Subcutaneous Tissue Disorders Rash Includes acneiform dermatitis, bullous dermatitis, drug eruption, eczema, rash, erythematous rash, maculo-papular rash, papular rash, seborrheic dermatitis, urticaria and xeroderma. 23 1.6 10 0 Respiratory System Disorders Cough Includes cough and productive cough. 20 0.8 3.3 0 Dyspnea Includes dyspnea and exertional dyspnea. 13 0.8 2.5 0 Renal Renal Impairment Includes azotemia, increased blood creatinine, decreased renal creatinine clearance, decreased glomerular filtration rate, hypercreatininemia, renal impairment and renal failure. 16 0.8 9 0 Nervous System Disorders Dysgeusia Includes dysgeusia and taste disorder. 13 0 3.3 0 Headache 11 0 7 0 Investigations Increased weight 13 0.8 0.8 0 Cardiac Disorders Bradycardia Includes bradycardia and sinus bradycardia. 12 0 0 0 Clinically significant adverse reactions in < 10% of patients who received ALECENSA in ALINA: nausea (8%), vomiting (7%), vision disorders (4.7%; includes blurred vision, visual acuity reduced and photopsia), stomatitis (4.7%; includes stomatitis and mouth ulceration), photosensitivity reaction (3.9%) and pneumonitis (2.3%). Table 5: Worsening in Laboratory Values from Baseline Occurring in ≥ 20% of Patients in Treated with ALECENSA in ALINA Parameter ALECENSA N=128 Chemotherapy N=120 All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Based on NCI CTCAE v5.0 Chemistry Increased CPK 77 8 8
All events were Grade 3 Increased
AST 75 0.8 25 0 Increased bilirubin 68 2.3 4.2 0 Increased alkaline phosphatase 64 0 14 0 Increased ALT 57 2.3 28 0 Increased creatinine 41 0 23 0 Increased uric acid 30 0 19 0 Hematology Decreased hemoglobin 69 0 67
Previously Untreated Metastatic
ALK-Positive NSCLC The safety of ALECENSA was evaluated in 152 patients with ALK-positive NSCLC in the ALEX study. The median duration of exposure to ALECENSA was 17.9 months. Patient characteristics of the ALEX study population (n=303) were: median age 56 years, age less than 65 (77%), female (56%), Caucasian (50%), Asian (46%), adenocarcinoma histology (92%), never smoker (63%), and ECOG PS 0 or 1 (93%). Serious adverse reactions occurred in 28% of patients treated with ALECENSA; serious adverse reactions reported in 2% or more of patients treated with ALECENSA were pneumonia (4.6%), and renal impairment (3.9%). Grade ≥ 3 adverse events were reported for 41% of patients in the ALECENSA arm.
Fatal adverse reactions occurred in 3.3% of patients treated with ALECENSA; these were renal impairment (2 patients), sudden death, cardiac arrest, and pneumonia (1 patient each). Permanent discontinuation of ALECENSA for adverse reactions occurred in 11% of patients. Adverse drug reactions that led to discontinuation of ALECENSA in 1% or more of patients were renal impairment (2.0%), hyperbilirubinemia (1.3%), increased ALT (1.3%), and increased AST (1.3%). Dosage interruptions of ALECENSA due to an adverse reaction occurred in 20% of patients. Adverse reactions which required dosage interruption in > 2% of patients included increased ALT, pneumonia.
Dose reductions of ALECENSA due to an adverse reaction occurred in 17% of patients. Adverse reactions which required dose reductions in > 2% of patients included hyperbilirubinemia, increased AST and increased ALT. Tables 6 and 7 summarize the common adverse reactions and laboratory abnormalities observed in ALEX. Table 6: Adverse Drug Reactions (>10% for all NCI CTCAE Grades or ≥2% for Grades 3-4) in Patients Treated with ALECENSA in ALEX Adverse Reaction ALECENSA N=152 Crizotinib N=151 All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; MedDRA = Medical Dictionary for Regulatory Activities; SOC = System Organ Class. Gastrointestinal Constipation 34 0 33 0 Nausea 14 0.7 48
Diarrhea 12 0 45 2.0 General Fatigue Includes fatigue and asthenia. 26
1.3 23
Edema Includes peripheral edema, edema, eyelid edema, localized edema, and face edema.
22 0.7 34
Musculoskeletal Myalgia Includes myalgia and musculoskeletal pain. 23 0 4.0 0 Skin
Rash Includes rash, rash maculo-papular, dermatitis acneiform, erythema, generalized rash, rash macular, rash papular, exfoliative rash, and pruritic rash. 15 0.7 13 0 Cardiac Bradycardia Includes reported cases of bradycardia and sinus bradycardia but is not based on serial ECG assessment. 11 0 15 0 Renal Renal impairment Includes increased blood creatinine, creatinine renal clearance decreased, glomerular filtration rate decreased, and acute kidney injury. 12
Includes two Grade 5 events. 0 0
The following additional clinically significant adverse drug reactions were observed in patients treated with ALECENSA: weight gain (9.9%), vomiting (7%), photosensitivity reaction (5.3%), vision disorders (4.6%; includes blurred vision, visual impairment, vitreous floaters reduced visual acuity and diplopia), stomatitis (3.3%), dysgeusia (3.3%; includes hypogeusia), interstitial lung disease (1.3%), and drug-induced liver injury (1.3%). Table 7: Worsening in Laboratory Values Occurring in > 10% of Patients in ALEX Parameter ALECENSA N=152 Crizotinib N=151 All Grades (%) Grades 3–4 (%) All Grades (%) Grades 3–4 (%) Note: Based on National Cancer Institute Common Terminology Criteria for Adverse Events v4.03. Excludes patients with no post-baseline lab assessments. Chemistry Hyperbilirubinemia n=147 for alectinib (with baseline values missing for 1 of these patients), n=148 for crizotinib. 54 5 4.7 0 Increased AST n=147 for alectinib (with baseline values missing for 2 of these patients), n=148 for crizotinib. 50 6 56 11 Increased alkaline phosphatase n=147 for alectinib, n=148 for crizotinib. 50 0 44 0 Increased ALT 40 6 62 16 Increased creatinine, Only patients with creatinine increases based on ULN definition. 38 4.1 23
Increased
CPK n=143 for alectinib (with baseline values missing for 14 of these patients), n=143 for crizotinib (with baseline values missing for 13 of these patients). 37 2.8 52
Hypocalcemia 29 0 61 1.4 Hyperglycemia n=134 for alectinib (with baseline values
missing for 18 of these patients), n=131 for crizotinib (with baseline values missing for 8 of these patients). 22 2.2 19
Hyponatremia n=147 for alectinib, n=148 for crizotinib (with baseline values missing for
1 of these patients). 18 6 20
Hypokalemia 17 2 12 0.7 Hypoalbuminemia n=146 for alectinib (with baseline values
missing for 1 of these patients), n=148 for crizotinib (with baseline values missing for 1 of these patients). 14 0 57
Hyperkalemia 12 1.4 16 1.4 Hypophosphatemia n=145 for alectinib (with baseline values
missing for 2 of these patients), n=148 for crizotinib (with baseline values missing for 4 of these patients). 9 1.4 25
Increased gamma glutamyl transferase n=143 for alectinib (with baseline values missing for
4 of these patients), n=148 (with baseline values missing for 5 of these patients). 7 0.7 39
Hematology Anemia 62 7 36 0.7 Lymphopenia 14 1.4 34 4.1 Neutropenia
14 0 36 7 Metastatic ALK-Positive NSCLC Previously Treated with Crizotinib The safety of ALECENSA was evaluated in 253 patients with ALK-positive non-small cell lung cancer (NSCLC) treated with ALECENSA in two clinical trials, Studies NP28761 and NP28673. The median duration of exposure to ALECENSA was 9.3 months. One hundred sixty-nine patients (67%) were exposed to ALECENSA for more than 6 months, and 100 patients (40%) for more than one year. The population characteristics were: median age 53 years, age less than 65 (86%), female (55%), White (74%), Asian (18%), NSCLC adenocarcinoma histology (96%), never or former smoker (98%), ECOG Performance Status (PS) 0 or 1 (91%), and prior chemotherapy treatment (78%). Serious adverse reactions occurred in 19% of patients; the most frequently reported serious adverse reactions were pulmonary embolism (1.2%), dyspnea (1.2%), and hyperbilirubinemia (1.2%). Fatal adverse reactions occurred in 2.8% of patients and included hemorrhage (0.8%), intestinal perforation (0.4%), dyspnea (0.4%), pulmonary embolism (0.4%), and endocarditis (0.4%). Permanent discontinuation of ALECENSA for adverse reactions occurred in 6% of patients.
The most frequent adverse reactions that led to permanent discontinuation were hyperbilirubinemia (1.6%), increased ALT levels (1.6%), and increased AST levels (1.2%). Overall, 23% of patients initiating treatment at the recommended dose required at least one dose reduction. The median time to first dose reduction was 48 days. The most frequent adverse reactions that led to dose reductions or interruptions were elevations in bilirubin (6%), CPK (4.3%), ALT (4.0%), AST (2.8%), and vomiting (2.8%). Tables 8 and 9 summarize the common adverse reactions and laboratory abnormalities observed in Studies NP28761 and NP28673. Table 8: Adverse Reactions in ≥ 10% (All Grades) or ≥ 2% (Grades 3–4) of Patients in Studies NP28761 and NP28673 Adverse Reactions ALECENSA N=253 All Grades (%) Grades 3–4 (%) Per Common Terminology Criteria for Adverse Events (CTCAE) version
Fatigue Includes fatigue and asthenia. 41 1.2 Constipation 34 0 Edema Includes
peripheral edema, edema, generalized edema, eyelid edema, and periorbital edema. 30
Myalgia Includes myalgia and musculoskeletal pain. 29 1.2 Cough 19 0 Rash
Includes rash, maculopapular rash, acneiform dermatitis, erythema, generalized rash, papular rash, pruritic rash, and macular rash. 18
Nausea 18 0 Headache 17 0.8 Diarrhea 16 1.2 Dyspnea 16 3.6
Includes one Grade 5 event. Back pain 12 0 Vomiting 12
Increased weight 11 0.4 Vision disorder Includes blurred vision, vitreous floaters, visual
impairment, reduced visual acuity, asthenopia, and diplopia. 10 0 An additional clinically significant adverse drug reaction was photosensitivity, which occurred in 9.9% of patients exposed to ALECENSA in Studies NP28761 and NP28673. Patients were advised to avoid sun exposure and to use broad-spectrum sunscreen. The incidence of Grade 2 photosensitivity was 0.4%; the remaining events were Grade 1 in severity. Table 9: Treatment-Emergent Worsening in Laboratory Values Occurring in > 20% of Patients in Studies NP28761 and NP28673 Parameter ALECENSA N=250 All Grades (%) Grades 3–4 (%) Per CTCAE version
Chemistry Increased
AST 51
Increased Alkaline Phosphatase 47 1.2 Increased
CPK n=218 for CPK (with baseline values missing for 91 of these patients). 43
Hyperbilirubinemia 39 2.4 Hyperglycemia n=152 for fasting blood glucose (with baseline values
missing for 5 of these patients). 36
Increased
ALT 34
Hypocalcemia 32 0.4 Hypokalemia 29 4.0 Increased Creatinine Only patients with creatinine
increases based on ULN definition. 28 0 Hypophosphatemia 21
Hyponatremia 20 2.0 Hematology Anemia 56 2.0 Lymphopenia n=217 for lymphocytes (with
baseline values missing for 5 of these patients). 22 4.6
Warnings & Cautions for Alecensa
Hepatotoxicity Severe hepatotoxicity, including drug-induced liver injury, occurred in patients treated with
ALECENSA. In the pooled safety population of patients who received ALECENSA, hepatotoxicity occurred in 41% of patients and the incidence of Grade ≥ 3 hepatotoxicity was 8%. In the ALINA study, hepatotoxicity occurred in 61% of patients treated with ALECENSA and the incidence of Grade ≥ 3 hepatotoxicity was 4.7%. The majority (72% of 136 patients) of elevated transaminases occurred during the first 3 months of treatment. Treatment discontinuation due to hepatotoxicity occurred in 3.6% of patients who received ALECENSA in the pooled safety population and 1.6% of patients treated in the ALINA study. In the pooled safety population, concurrent elevations in ALT or AST greater than or equal to 3 times the ULN and total bilirubin greater than or equal to 2 times the ULN, with normal alkaline phosphatase, occurred in less than 1% of patients treated with ALECENSA. Three patients with Grades 3–4 AST/ALT elevations had drug-induced liver injury (documented by liver biopsy in two cases). Monitor liver function tests including ALT, AST, and total bilirubin every 2 weeks during the first 3 months of treatment, then once a month and as clinically indicated, with more frequent testing in patients who develop transaminase and bilirubin elevations.
Based on the severity of the adverse drug reaction, withhold ALECENSA and resume at a reduced dose or permanently discontinue ALECENSA as described in Table 3.
Interstitial Lung Disease (ILD)/Pneumonitis
ILD/pneumonitis occurred in patients treated with ALECENSA. In the pooled safety population , ILD/pneumonitis occurred in 1.3% of patients treated with ALECENSA with 0.4% of patients experiencing Grade 3 ILD/pneumonitis. Five patients (0.9%) in the pooled safety population discontinued ALECENSA due to ILD/pneumonitis. The median time-to-onset of Grade 3 or higher ILD/pneumonitis was 2.1 months (range: 0.6 months to 3.6 months). Promptly investigate for ILD/pneumonitis in any patient who presents with worsening of respiratory symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, and fever). Immediately withhold ALECENSA treatment in patients diagnosed with ILD/pneumonitis and permanently discontinue ALECENSA if no other potential causes of ILD/pneumonitis have been identified .
Renal Impairment Renal impairment, including fatal cases, occurred in patients treated with
ALECENSA. In the pooled safety population , renal impairment occurred in 12% of patients treated with ALECENSA, including Grade ≥ 3 in 1.7% of patients, of which 0.4% were fatal events. The median time to Grade ≥ 3 renal impairment was 3.7 months (range 0.5 to 31.8 months). Dosage modifications for renal impairment were required in 2.4% of patients. Permanently discontinue ALECENSA for Grade 4 renal toxicity.
Withhold ALECENSA for Grade 3 renal toxicity until recovery to less than or equal to 1.5 times ULN, then resume at reduced dose .
Bradycardia Symptomatic bradycardia occurred in patients treated with
ALECENSA. In the pooled safety population , bradycardia occurred in 11% of patients treated with ALECENSA. Twenty percent of 521 patients treated with ALECENSA, for whom serial electrocardiograms (ECGs) were available, had post-dose heart rates of less than 50 beats per minute (bpm). Monitor heart rate and blood pressure regularly. For asymptomatic bradycardia dose modification is not required. For symptomatic bradycardia that is not life-threatening, withhold ALECENSA until recovery to asymptomatic bradycardia or to a heart rate ≥ 60 bpm and evaluate concomitant medications known to cause bradycardia, as well as anti-hypertensive medications.
If bradycardia is attributable to a concomitant medication, resume ALECENSA at a reduced dose (see Table 2 ) upon recovery to asymptomatic bradycardia or to a heart rate of ≥ 60 bpm, with frequent monitoring as clinically indicated. Permanently discontinue ALECENSA in cases of life-threatening bradycardia if no contributing concomitant medication is identified . Permanently discontinue ALECENSA for recurrence of life-threatening bradycardia.
Severe Myalgia and Creatine Phosphokinase (CPK) Elevation Severe myalgia and creatine phosphokinase
(CPK) elevation occurred in patients treated with ALECENSA. In the pooled safety population , myalgia (including muscle- and musculoskeletal-related reactions) occurred in 31% of patients treated with ALECENSA, including Grade ≥ 3 in 0.8% of patients. Dosage modifications for myalgia events were required in 2.1% of patients. In the pooled safety population, of the 491 patients with CPK laboratory data available, elevated CPK occurred in 56% of patients treated with ALECENSA, including 6% Grade ≥ 3. The median time to Grade ≥ 3 CPK elevation was 15 days (interquartile range - 15 –337 days). Dosage modifications for elevation of CPK occurred in 5% of patients.
In the ALINA study, elevated CPK occurred in 77% of 128 patients with CPK laboratory data, including 6% Grade ≥ 3 elevations. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Assess CPK levels every 2 weeks for the first month of treatment and as clinically indicated in patients reporting symptoms.
Based on the severity of the CPK elevation, withhold ALECENSA, then resume or reduce dose.
Hemolytic Anemia Hemolytic anemia occurred in patients treated with
ALECENSA. Hemolytic anemia was initially reported with ALECENSA in the postmarketing setting, including cases associated with a negative direct antiglobulin test (DAT) result. Assessments for the determination of hemolytic anemia were subsequently collected in the ALINA study, where hemolytic anemia was observed in 3.1% of patients treated with ALECENSA. If hemolytic anemia is suspected, withhold ALECENSA and initiate appropriate laboratory testing. If hemolytic anemia is confirmed, consider resuming at a reduced dose upon resolution or permanently discontinue ALECENSA.
Embryo-Fetal Toxicity
Based on findings from animal studies and its mechanism of action, ALECENSA can cause fetal harm when administered to pregnant women. Oral administration of alectinib to pregnant rats and rabbits during the period of organogenesis resulted in embryo-fetal toxicity and abortion at maternally toxic doses with exposures approximately 2.7-fold those observed in humans with alectinib 600 mg twice daily. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
Advise females of reproductive potential to use effective contraception during treatment with ALECENSA and for 5 weeks following the last dose .
Pregnancy Safety for Alecensa
Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, ALECENSA can cause fetal harm when administered to a pregnant woman . There are no available data on ALECENSA use in pregnant women. Administration of alectinib to pregnant rats and rabbits by oral gavage during the period of organogenesis resulted in embryo-fetal toxicity and abortion at maternally toxic doses with exposures approximately 2.7-fold those observed in humans treated with alectinib at 600 mg twice daily (see Data ). Advise pregnant women 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 2% to 4% and 15% to 20%, respectively.
Data Animal Data In a preliminary rabbit embryo-fetal study, administration of alectinib by oral gavage during the period of organogenesis resulted in abortion or complete embryo-fetal mortality at a maternally toxic dose of 27 mg/kg/day (approximately 2.9-fold the estimated area under the curve (AUC 0-24h,ss ) in humans treated with alectinib 600 mg twice daily) in three of six pregnant rabbits. The remaining three pregnant rabbits in this group had few live fetuses, decreased fetal and placental weights, and retroesophageal subclavian artery. In a rat preliminary embryo-fetal development study, administration of alectinib during organogenesis resulted in complete litter loss in all pregnant rats at 27 mg/kg/day (approximately 4.5-fold the estimated AUC 0-24h,ss in humans treated with alectinib 600 mg twice daily). Doses greater than or equal to 9 mg/kg/day (approximately 2.7-fold the estimated human AUC 0-24h,ss in humans treated with alectinib 600 mg twice daily), resulted in maternal toxicity as well as developmental toxicities including decreased fetal weight, dilated ureter, thymic cord, small ventricle and thin ventricle wall, and reduced number of sacral and caudal vertebrae.
Pediatric Use of Alecensa
Pediatric Use The safety and effectiveness of ALECENSA in pediatric patients have not been established. Animal Data Juvenile animal studies have not been conducted using alectinib. In general toxicology studies, treatment of rats with doses of alectinib resulting in exposures greater than or equal to approximately 4.5-fold those in humans treated with alectinib at 600 mg twice daily resulted in changes in the growing teeth and bones.
Findings in teeth included discoloration and changes in tooth size along with histopathological disarrangement of the ameloblast and odontoblast layers. There were also decreases in the trabecular bone and increased osteoclast activity in the femur and sternum.
Overdosage Information for Alecensa
No experience with overdose is available. There is no specific antidote for overdose with ALECENSA. Alectinib and its major active metabolite M4 are > 99% bound to plasma proteins; therefore, hemodialysis is likely to be ineffective in the treatment of overdose.
Clinical Studies of Alecensa
Adjuvant Treatment of Resected
ALK-Positive NSCLC The efficacy of ALECENSA for the adjuvant treatment of patients with ALK-positive NSCLC following complete tumor resection was evaluated in a global, randomized open-label clinical trial (ALINA: NCT03456076). Eligible patients were required to have resectable ALK-positive NSCLC, Stage IB (tumors ≥ 4 cm) – IIIA per the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) Staging System, 7 th Edition. ALK rearrangements were identified by a locally performed FDA-approved ALK test or by a centrally performed VENTANA ALK (D5F3) CDx assay. Randomization was stratified by race (Asian vs. other races) and stage of disease (IB vs.
II vs. IIIA). Patients were randomized (1:1) to receive ALECENSA 600 mg orally twice daily or platinum-based chemotherapy following tumor resection. Treatment with ALECENSA continued for a total of 2 years, or until disease recurrence or unacceptable toxicity.
Platinum-based chemotherapy was administered intravenously for 4 cycles, with each cycle lasting 21 days, according to one of the following regimens: Cisplatin 75 mg/m 2 on Day 1 plus vinorelbine 25 mg/m 2 on Days 1 and 8 Cisplatin 75 mg/m 2 on Day 1 plus gemcitabine 1250 mg/m 2 on Days 1 and 8 Cisplatin 75 mg/m 2 on Day 1 plus pemetrexed 500 mg/m 2 on Day 1 In the event of intolerance to a cisplatin-based regimen, carboplatin was administered instead of cisplatin in the above combinations at a dose of AUC 5 mg/mL/min or 6 mg/mL/min. The major efficacy outcome measures were disease-free survival (DFS) in patients with stage II-IIIA NSCLC and DFS in patients with stage IB-IIIA NSCLC (intent-to-treat population) as assessed by investigator. DFS was defined as the time from 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.
An additional efficacy outcome measure was overall survival (OS) in the ITT population. A total of 257 patients were randomized to ALECENSA (N=130) or to chemotherapy (N=127). The median age was 56 years (range: 26 to 87), 24% were ≥ 65 years old; 52% were female; 56% were Asian, 42% were White, 0.4% were Black or African American, 2.3% were race unknown; 0.4% were Hispanic or Latino; 60% were never smokers; 53% had an ECOG PS of 0; 10% of patients had Stage IB, 35% had Stage II and 55% had Stage IIIA disease. ALINA demonstrated a statistically significant improvement in DFS for patients treated with ALECENSA compared to patients treated with chemotherapy.
OS data were not mature at the time of DFS analysis with 2.3% of deaths reported in the ITT population. The efficacy results from ALINA are summarized in Table 10 and Figure 1. Table 10: Investigator-Assessed DFS Results in ALINA Efficacy Parameter Stage II-IIIA Population ITT Population ALECENSA N=116 Chemotherapy N=115 ALECENSA N=130 Chemotherapy N=127 DFS = Disease-Free Survival; ITT = Intent-to-Treat; CI = Confidence Interval; NR = Not Reached; NE = Not Estimable. DFS events (%) 14 45 15 50 Disease recurrence (%) 14 44 15 49 Death 0 1 0 1 Median DFS, months (95% CI) Kaplan-Meier method.
NR (NE, NE) 44.4 (27.8, NE) NR (NE, NE) 41.3 (28.5, NE) Hazard Ratio (95% CI) Stratified Cox model, stratified by race (Asian vs. other races) in Stage II-IIIA and stratified by race (Asian vs. other races) and tumor stage (Stage IB vs. II vs. IIIA) in ITT. 0.24 0.24 p-value Stratified log-rank test stratified by race (Asian vs. other races) in Stage II-IIIA and stratified by race (Asian vs. other races) and tumor stage (Stage IB vs.
II vs. IIIA) in ITT. <0.0001 <0.0001 Figure 1: Kaplan-Meier Curves of Investigator-Assessed DFS (ITT Population) in ALINA In an exploratory analysis of site(s) of relapse, the proportion of patients with brain involvement at the time of disease recurrence was 4 patients (3.1%) in the ALECENSA arm and 14 patients (11%) in the chemotherapy arm. Figure 1
Treatment of Metastatic
ALK-Positive NSCLC Previously Untreated Metastatic ALK-Positive NSCLC The efficacy of ALECENSA for the treatment of patients with ALK-positive NSCLC who had not received prior systemic therapy for metastatic disease was established in an open-label, randomized, active-controlled, multicenter study (ALEX: NCT02075840). Patients were required to have an ECOG performance status of 0-2 and ALK-positive NSCLC as identified by the VENTANA ALK (D5F3) CDx assay. Neurologically stable patients with treated or untreated central nervous system (CNS) metastases, including leptomeningeal metastases, were eligible; patients with neurologic signs and symptoms due to CNS metastases were required to have completed whole brain radiation or gamma knife irradiation at least 14 days prior to enrollment and be clinically stable. Patients with a baseline QTc > 470 ms were ineligible.
Patients were randomized 1:1 to receive ALECENSA 600 mg orally twice daily or crizotinib 250 mg orally twice daily. Randomization was stratified by ECOG performance status (0/1 vs. 2), race (Asian vs. other races), and the presence or absence of CNS metastases at baseline. Treatment on both arms was continued until disease progression or unacceptable toxicity.
The major efficacy outcome measure was progression-free survival (PFS) as determined by investigator assessment according to RECIST v1.1. Additional efficacy outcome measures were PFS as determined by independent review committee (IRC), time to CNS progression by IRC based on RECIST v1.1, objective response rate (ORR) and duration of response (DOR), and OS. Additional exploratory outcome measures were CNS objective response rate (CNS-ORR) and CNS duration of response (CNS-DOR) by IRC in patients with CNS metastases at baseline. A total of 303 patients were randomized to ALECENSA (n=152) or crizotinib (n=151). The demographic characteristics of the study population were 56% female, median age 56 years (range: 18 to 91 years), 50% White, 46% Asian, 1% Black, and 3% other races. The majority of patients had adenocarcinoma (92%) and never smoked (63%). CNS metastases were present in 40% (n=122) of patients: of these, 43 patients had measurable CNS lesions as determined by an IRC. The ALEX study demonstrated a significant improvement in PFS. The time to cause-specific CNS progression as assessed by IRC was also significantly improved; there was a lower incidence of progression in the CNS as the first site of disease progression, alone or with concurrent systemic progression, in the ALECENSA arm (12%) as compared to the crizotinib arm (45%). Efficacy results from ALEX are summarized in Table 11 and Figure 2. Table 11: Efficacy Results in ALEX per IRC Assessment ALECENSA N=152 Crizotinib N=151 CNS: central nervous system, ORR: overall response rate, IRC: independent review committee, CI: confidence interval, NE: not estimable.
Progression-Free Survival Number of events (%) 63 (41%) 92 (61%) Progressive disease (%) 51 (34%) 82 (54%) Death (%) 12 (8%) 10 (7%) Median in months (95% CI) 25.7 (19.9, NE)
Hazard ratio (95% CI) Stratified by race (Asian vs. other races) and
CNS metastases at baseline (yes vs. no) for Cox model, log-rank test and Cochran Mantel-Haenszel test, respectively 0.53 P-value < 0.0001 Overall Response Rate Overall response rate, % (95% CI) Clopper and Pearson exact binomial 95% confidence interval. 79% 72% P-value 0.1652 Complete response, % 13% 6% Partial response, % 66% 66% Duration of Response Number of responders n=120 n=109 Response duration ≥6 months 82% 57% Response duration ≥12 months 64% 36% Response duration ≥18 months 37% 14% Figure 2: Kaplan-Meier Plot of Progression-Free Survival (IRC) in ALEX Results for PFS as determined by investigator assessment (HR=0.48, stratified log-rank p<0.0001) were similar to that observed by IRC. At the data cutoff point overall survival data was not mature. The results of prespecified exploratory analyses of CNS response rate in patients with measurable CNS lesions at baseline are summarized in Table 12. Table 12: IRC-Assessed CNS Responses in Patients with Measurable CNS Lesions at Baseline in ALEX ALECENSA Crizotinib IRC: Independent Review Committee; CI: Confidence Interval; NE: Not Estimable CNS Tumor Response Assessment N = 21 N = 22 CNS Objective Response Rate, % (95% CI Clopper and Pearson exact binomial 95% confidence interval ) 81% 50% Complete Response 38% 5% Duration of CNS Response Number of responders 17 11 CNS response duration ≥ 12 months 59% 36% Figure 2 Metastatic ALK-Positive NSCLC Previously Treated with Crizotinib The safety and efficacy of ALECENSA were established in two single-arm, multicenter clinical trials: NP28761 (NCT01588028) and NP28673 (NCT01801111). Patients with locally advanced or metastatic ALK-positive NSCLC, who have progressed on crizotinib, with documented ALK-positive NSCLC based on an FDA-approved test, and ECOG PS of 0-2 were enrolled in both studies. Eligibility criteria permitted enrollment of patients with prior chemotherapy and prior CNS radiotherapy provided that CNS metastases were stable for at least two weeks.
All patients received ALECENSA 600 mg orally twice daily. The major efficacy outcome measure in both studies was objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated per Independent Review Committee (IRC). Additional outcome measures as evaluated by the IRC included duration of response (DOR), CNS ORR, and CNS DOR. NP28761 was conducted in North America and enrolled 87 patients. Baseline demographic and disease characteristics in NP28761 were median age 54 years old (range 29 to 79, 18% 65 and over), 84% White and 8% Asian, 55% female, 35% ECOG PS 0 and 55% ECOG PS 1, 100% never or former smokers, 99% Stage IV, 94% adenocarcinoma, and 74% prior chemotherapy.
The most common sites of extra-thoracic metastasis included 60% CNS (of whom 65% had received CNS radiation), 43% lymph nodes, 36% bone, and 34% liver. NP28673 was conducted internationally and enrolled 138 patients. Baseline demographic and disease characteristics in NP28673 were median age 52 years old (range 22 to 79, 10% 65 and over), 67% White and 26% Asian, 56% female, 32% ECOG PS 0 and 59% ECOG PS 1, 98% never or former smokers, 99% Stage IV, 96% adenocarcinoma, and 80% prior chemotherapy.
The most common sites of extra-thoracic metastasis included 61% CNS (of whom 73% had received CNS radiation), 51% bone, 38% lymph nodes, and 30% liver. Efficacy results from NP28761 and NP28673 in all treated patients are summarized in Table 13. The median duration of follow-up on Study NP28761 was 4.8 months for both IRC and Investigator assessments and on Study NP28673, 10.9 months for IRC assessment and 7.0 months for Investigator assessment. All responses were partial responses.
Table 13: Efficacy Results in Studies NP28761 and NP28673 Efficacy Parameter NP28761 (N=87) NP28673 (N=138) IRC 18 patients in NP28761 and 16 patients in NP28673 did not have measurable disease at baseline as per IRC assessment and were classified as non-responders in the IRC analysis. Assessment Investigator Assessment IRC Assessment Investigator Assessment Objective Response Rate (95% CI) 38% (28; 49) 46% (35; 57) 44% (36; 53) 48% (39; 57) Number of Responders 33 40 61 66 Duration of Response, median in months (95% CI) 7.5 (4.9, Not Estimable) NE (4.9, Not Estimable) 11.2 (9.6, Not Estimable)
An assessment of
ORR and duration of response for CNS metastases in the subgroup of 51 patients in NP28761 and NP28673 with baseline measurable lesions in the CNS according to RECIST v1.1 are summarized in Table 14. Thirty-five (69%) patients with measurable CNS lesions had received prior brain radiation, including 25 (49%) who completed radiation treatment at least 6 months before starting treatment with ALECENSA. Responses were observed irrespective of prior brain radiation status. Table 14: CNS Objective Response in Patients with Measurable CNS Lesions in Studies NP28761 and NP28673 Efficacy Parameter N=51 CNS Objective Response Rate (95% CI) 61% Complete Response 18% Partial Response 43% CNS Duration of Response, median in months (95% CI) 9.1 (5.8, Not Estimable)
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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