Alectinib versus Crizotinib in Untreated ALK-Positive Non–Small-Cell Lung Cancer

Abstract

BACKGROUNDAlectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system (CNS) efficacy in the treatment of ALK-positive non-small-cell lung cancer (NSCLC). We investigated alectinib as compared with crizotinib in patients with previously untreated, advanced ALK-positive NSCLC, including those with asymptomatic CNS disease. METHODSIn a randomized, open-label, phase 3 trial, we randomly assigned 303 patients with previously untreated, advanced ALK-positive NSCLC to receive either alectinib (600 mg twice daily) or crizotinib (250 mg twice daily). The primary end point was investigatorassessed progression-free survival. Secondary end points were independent review committee-assessed progression-free survival, time to CNS progression, objective response rate, and overall survival. RESULTSDuring a median follow-up of 17.6 months (crizotinib) and 18.6 months (alectinib), an event of disease progression or death occurred in 62 of 152 patients (41%) in the alectinib group and 102 of 151 patients (68%) in the crizotinib group. The rate of investigator-assessed progression-free survival was significantly higher with alectinib than with crizotinib (12-month event-free survival rate, 68.4% [95% confidence interval (CI), 61.0 to 75.9] with alectinib vs. 48.7% [95% CI, 40.4 to 56.9] with crizotinib; hazard ratio for disease progression or death, 0.47 [95% CI, 0.34 to 0.65]; P<0.001); the median progression-free survival with alectinib was not reached. The results for independent review committee-assessed progression-free survival were consistent with those for the primary end point. A total of 18 patients (12%) in the alectinib group had an event of CNS progression, as compared with 68 patients (45%) in the crizotinib group (cause-specific hazard ratio, 0.16; 95% CI, 0.10 to 0.28; P<0.001). A response occurred in 126 patients in the alectinib group (response rate, 82.9%; 95% CI, 76.0 to 88.5) and in 114 patients in the crizotinib group (response rate, 75.5%; 95% CI, 67.8 to 82.1) (P = 0.09). Grade 3 to 5 adverse events were less frequent with alectinib (41% vs. 50% with crizotinib). CONCLUSIONSAs compared with crizotinib, alectinib showed superior efficacy and lower toxicity in primary treatment of ALK-positive NSCLC. (Funded by F. Hoffmann-La Roche; ALEX ClinicalTrials.gov number, NCT02075840.

Moving more potent and less toxic options to the frontline in the management of advanced lung cancer

“…Again, the median PFS (primary outcome) with alectinib was not reached (95% CI: 17.7 months to not reached) as compared with 11.1 months (95% CI: 9.1-13.1 months) with crizotinib (HR of 0.47 95% CI: 0.34-0.65; P<0.001). These two studies were the first trials to compare headto-head the efficacy and safety of a next generation ALK inhibitor to crizotinib (46,47). The trials convincingly show that alectinib is superior in prolonging median PFS with lesser toxicity than crizotinib.…”

“…Given the promising efficacy and tolerability of alectinib in the AF-001JP study, a phase III trial (J-ALEX, JapicCTI-132316) was designed to directly compare the efficacy and safety of alectinib 300 mg twice daily versus crizotinib 250 mg twice daily in Japanese patients with advanced ALK-rearranged NSCLC (46) J-ALEX's data was further supported by the multi-center international ALEX trial (NCT02075840), comparing alectinib 600 mg twice daily versus crizotinib 250 mg twice daily in TKI-naïve, ALK-rearranged advanced NSCLC (47). Again, the median PFS (primary outcome) with alectinib was not reached (95% CI: 17.7 months to not reached) as compared with 11.1 months (95% CI: 9.1-13.1 months) with crizotinib (HR of 0.47 95% CI: 0.34-0.65; P<0.001).…”

The J-ALEX trial—is frontline alectinib a new standard of care?

“…ORR was 82.9% (95% CI 76-88.5) in the alectinib arm versus 75.5% (95% CI 67.8-82.1) in the crizotinib arm with 41% patients in the alectinib arm experiencing grade 3-5 adverse events versus 50% in the crizotinib arm. Median OS data at the time of analysis was immature but did not clearly favor either arm (9).…”

“…The ALEX trial was an international phase III trial launched across 161 locations in 31 countries, with 303 treatment naïve ALK positive metastatic NSCLC patients randomized to alectinib 600 mg twice daily or crizotinib 250 mg twice daily, with PFS again being the primary endpoint (9). Secondary endpoints included time to CNS progression, ORR, DOR, OS, quality of life, and safety.…”

The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions

“…In this study, the dosage of alectinib was 600 mg orally twice daily. Alectinib led to a significant reduction in risk of progression/death with HR 0.47 ( p < 0.0001); the mPFS for crizotinib was 11.1 months, but had not yet been reached for alectinib [45, 46]. The intracranial response for patients with measurable CNS lesions at baseline was 50% for crizotinib and 81% for alectinib; the time to progression in the CNS also favored alectinib with a HR of 0.16 ( p < 0.0001).…”