Alecensa Adverse Reactions

Clinical Trials: For the clinical development program of Alecensa as a whole an estimated total of 928 patients have received Alecensa and 203 patients have received blinded Alecensa.
The safety of Alecensa has been evaluated in 253 patients in pivotal phase II clinical trials (NP28761, NP28673) with ALK-positive non-small cell lung cancer (NSCLC) treated with the recommended dose of 600 mg twice daily. The median duration of exposure to Alecensa was 11 months  (range 0-35 months). The safety of Alecensa was also evaluated in 152 patients with ALK-positive NSCLC treated with a dose of 600 mg twice daily in the phase III clinical trial BO28984. The median duration of exposure to Alecensa was 17.9 months.
The most common adverse reactions (≥20%) were constipation (36%), edema (34% including peripheral, generalized, eyelid, periorbital); myalgia (31% including myalgia and musculoskeletal pain), nausea (22%), increased bilirubin (21% including increased blood bilirubin, hyperbilirubinemia and increased bilirubin conjugated), anemia (20%, including anemia and hemoglobin decreased), and rash (20%, including rash, rash maculopapular, dermatitis acneiform, erythema, rash generalized, rash papular, rash pruritic and rash macular).
Table 7 lists the adverse drug reactions (ADRs) occurring in patients who received Alecensa in clinical trials (NP28761, NP28673) and phase III clinical trial BO28984. Adverse drug reactions from clinical trials are listed by MedDRA system organ class. The corresponding frequency category for each adverse drug reaction is based on the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000). (See Table 7.)

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Further information on selected adverse reactions: The safety profile of Alecensa was generally consistent across the phase III clinical trial (BO28984) and the pivotal phase II trials (NP28761, NP28673); however, relevant differences between studies are described below.
Interstitial Lung Disease (ILD)/pneumonitis: Severe ILD/pneumonitis occurred in patients treated with Alecensa. In the pivotal phase II clincal trials (NP28761, NP28673), 1 out of 253 patients treated with Alecensa (0.4%) had a an ILD event, which was Grade 3, leading to withdrawal from Alecensa treatment. There were no fatal cases of ILD in any of the clinical trials.
Hepatotoxicity: In the pivotal phase II clinical trials (NP28761, NP28673) two patients with Grade 3-4 AST/ALT elevations had documented drug induced liver injury by liver biopsy. Adverse reactions of increased AST and ALT levels (16% and 14% respectively) were reported in patients treated with Alecensa in pivotal phase II clinical trials (NP28761, NP28673). The majority of these events were of Grade 1 and 2 intensity, and events of Grade ≥3 were reported in 2.8% and 3.2% of the patients, respectively. The events generally occurred during the first 3 months of treatment, were usually transient and resolved upon temporary interruption of Alecensa treatment (reported for 1.2% and 3.2% of the patients, respectively) or dose reduction (1.6% and 0.8%, respectively). In 1.2% and 1.6% of the patients, AST and ALT elevations, respectively, led to withdrawal from Alecensa treatment.
Adverse reactions of bilirubin elevations were reported in 17% of the patients treated with Alecensa in pivotal phase II clincal trials (NP28761, NP28673). The majority of the events were of Grade 1 and 2 intensity; Grade 3 events were reported in 3.2% of the patients. The events generally occurred during the first 3 months of treatment, were usually transient and resolved upon temporary interruption of Alecensa treatment (4.7% of the patients) or dose reduction (2.8%). In 4 patients (1.6%), bilirubin elevations led to withdrawal from Alecensa treatment.
Concurrent elevations in ALT or AST greater than or equal to three times the ULN and total bilirubin greater than or equal to two times the ULN, with normal alkaline phosphatase, occurred in 1 patient treated in Alecensa clinical trials.
Bradycardia: Cases of bradycardia (7.9%) have been reported in patients treated with Alecensa in pivotal phase II clinical trials (NP28761, NP28673); all cases were of Grade 1 or 2 intensity. There were 44 of 221 patients (20%) treated with Alecensa who had post-dose heart rate values below 50 beats per minutes [bpm].
Severe Myalgia and CPK elevation: Cases of myalgia (31%) including myalgia events (25%) and musculoskeletal pain (7.5%) have been reported in patients treated with Alecensa in pivotal phase II clinical trials (NP28761, NP28673). The majority of events were Grades 1 or 2 and three patients (1.2%) had a Grade 3 event. Dose modifications due to these events were only required for two patients (0.8%). Elevations of CPK occurred in 46% of 219 patients with CPK laboratory data available in pivotal phase II clinical trials (NP28761, NP28673) with Alecensa. The incidence of Grade 3 elevations of CPK was 5.0%. Median time to Grade 3 CPK elevation was 14 days in the pivotal phase II trials (NP28761, NP28673). Median time to Grade 3 CPK elevation was 27.5 days in the pivotal phase III clinical trial (BO28984). Dose modifications for elevation of CPK occurred in 4.0% of patients.
Laboratory Abnormalities: The following table displays treatment-emergent shifts in laboratory abnormalities occurring in patients treated with Alecensa in phase II clinical trials (NP28761, NP28673) and phase III trial BO28984. (See Table 8.)

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Postmarketing Experience: The adverse drug reaction of increased alkaline phosphatase was reported with Alecensa in the post marketing period. Cases of increased alkaline phosphatase have been reported in Alecensa clinical trials (7.5% in patients treated with Alecensa in pivotal phase II clinical trials (NP28761, NP28673)).