Phase III Study of Crizotinib Versus Pemetrexed or Docetaxel Chemotherapy in Patients with Advanced Alk-Positive Non-Small Cell Lung Cancer (NSCLC) (Profile 1007)

  • Shaw A
  • Kim D
  • Nakagawa K
  • et al.
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Abstract

Background: Chromosomal rearrangements of anaplastic lymphoma kinase (ALK) are associated with marked clinical responses to crizotinib, an orally available tyrosine kinase inhibitor targeting ALK. This global randomized phase III study compared the efficacy and safety of crizotinib (C) with standard chemotherapy (pemetrexed or docetaxel [P/D]) as 2nd-line therapy for patients (pts) with advanced ALK+ NSCLC. Methods: Between Feb 2010 and Feb 2012, 347 pts with stage IIIB/IVALK+ NSCLC previously treated with 1 prior platinum-based regimen were randomized to receive C 250 mg PO BID (n = 173) or either P 500 mg/m2 or D 75 mg/m2 IV q3w (n = 174; 58% P, 42% D). ALK was detected by FISH in a central lab. Pts with progressive disease on P/D were offered C on PROFILE 1005. The primary endpoint was progression-free survival (PFS) per independent radiologic review; secondary endpoints included objective response rate (ORR), overall survival (OS), safety, and patient-reported outcomes. Results: The study met its primary objective by demonstrating the superiority of C over P/D in prolonging PFS (median 7.7 vs 3.0 mo; HR 0.49; 95% CI 0.37–0.64; P < 0.0001). ORR was significantly higher in pts treated with C (65% vs 20%; P < 0.0001). Interim analysis of OS (28% events) showed no statistically significant difference between C and P/D (preliminary median estimate 20.3 vs 22.8 mo; HR 1.02; 95% CI 0.68–1.5; P = 0.5394), but was not adjusted for crossover (108 pts [62%] crossed over to C). The most common treatment-related adverse events (TRAE) with C were visual disturbance (59%), diarrhea (53%), nausea (52%), vomiting (44%), and elevated transaminases (36%), and with P/D, nausea (35%), fatigue (29%), neutropenia (22%), decreased appetite (21%), and alopecia (20%). The incidence of grade 3/4 TRAE was the same for C vs P/D (31%). The incidence of TRAE leading to discontinuation was 6% for C vs 10% for P/D. Duration of treatment was longer for C vs P/D (median cycles started 11 vs 4). Conclusions: C showed significant improvement in PFS and ORR compared with P/D and had an acceptable safety profile. These findings establish C as the standard of care for pts with previously treated advanced ALK+ NSCLC

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Shaw, A. T., Kim, D. W., Nakagawa, K., Seto, T., Crinò, L., Ahn, M., … Jänne, P. (2012). Phase III Study of Crizotinib Versus Pemetrexed or Docetaxel Chemotherapy in Patients with Advanced Alk-Positive Non-Small Cell Lung Cancer (NSCLC) (Profile 1007). Annals of Oncology, 23, ixe21. https://doi.org/10.1016/s0923-7534(20)34338-6

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