Crizotinib Superior to Standard Chemotherapy in Patients with ALK-Positive Lung Cancer

JHOP - June 2013 VOL 3, NO 2 - From the Literature
Robert J. Ignoffo, PharmD, FASHP, FCSHP

Professor of Pharmacy
College of Pharmacy
Touro University–California, Mare Island
Vallejo, CA
Clinical Professor Emeritus
University of California
San Francisco, CA

Background: Crizotinib, an inhibitor of the anaplastic lymphoma kinase (ALK) gene, has shown significant response rates in patients with advanced non–small-cell lung cancer (NSCLC) and the ALK rearrangement. Compared with low response rates with standard chemotherapy in this patient population, one study with crizotinib in patients with ALK-positive advanced NSCLC showed a 60% objective response rate and a median progression-free survival (PFS) of 8.1 months; in a second study, the PFS was 9.7 months with crizotinib. The objective of a new study was to compare the response rates of standard chemotherapy versus crizotinib in patients with ALK-positive advanced NSCLC.

Methods: This phase 3, open-label clinical trial included 374 patients with locally advanced or meta- static ALK-positive NSCLC who had previously received 1 platinum-based regimen. The patients were randomized in a 1:1 ratio to oral crizotinib 250 mg twice daily or to intravenous chemotherapy with pemetrexed 500 mg/m2 of body surface area or with docetaxel 75 mg/m2 every 3 weeks. Patients receiving chemotherapy whose disease progressed were allowed to cross over to receive crizotinib as a separate study. The primary end point was PFS. Patients were screened from February 2010 through February 2012 for study eligibility. The prespecified number of progression events or death was reached in March 2012, and the data cutoff date was March 30, 2012.

Results: The median PFS was 7.7 months with crizotinib and 3.0 months with chemotherapy, resulting in a hazard ratio for progression or death of 0.49 (95% confidence interval [CI], 0.37-0.64; P <.001) with crizotinib. The response rates were 65% (95% CI, 58-72) with crizotinib versus 20% (95% CI, 14-26) with chemotherapy, a significant difference (P <.001). At the time of the data cutoff, the median follow-up for overall survival (OS) was similar between the 2 groups: 12.2 months in the crizotinib group and 12.1 months in the chemotherapy group. Also at that time, 85 (49%) patients in the crizotinib group and 28 (16%) patients in the chemotherapy group were still receiving therapy. Overall, 58 patients receiving crizotinib continued therapy beyond the predefined period of progression compared with 17 of those receiving chemotherapy, and the therapy duration was also long- er with crizotinib than with chemotherapy—median 15.9 weeks (range, 2.9-73.4) versus 6.9 weeks (range, 6.0-42.0), respectively. Common adverse events reported with crizotinib included visual disorders, gastrointestinal events, and elevated aminotransferase levels. In addition, 23 (13%) patients receiving crizotinib had grade 3 or 4 neutropenia compared with 33 (19%) patients receiving chemotherapy. Febrile neutropenia occurred in 1 patient receiving crizotinib and in 16 patients receiving chemotherapy. In general, patients reported greater reductions in symptoms of lung cancer, including chest pain, cough, and fatigue, and greater improvement in global quality of life with crizotinib than with chemotherapy.

Takeaway: The response rate to second-line chemotherapy in patients with ALK-positive lung cancer is poor, at only approximately 10%. The use of crizotinib in first relapse after a platinum-based regimen demonstrated a significantly higher response rate, PFS, and duration to time receiving crizotinib compared with the chemotherapy drug pemetrexed. Although OS was not different between the 2 groups, it is unknown what additional therapies were used after patient relapse. In a retrospective review of a phase 1 study by the same author, OS was prolonged in patients with ALK gene rearrangements whether they were given crizotinib as first-line or second-line therapy (Shaw AT, et al. Lancet Oncol. 2011;12:1004-1012). In the current study, the symptoms of disease were significantly improved with crizotinib. One potential fault of this study is that the comparator group received single-agent pemetrexed.

The National Comprehensive Cancer Network recommends crizotinib as first-line therapy in patients with advanced NSCLC with ALK rearrangements, as well as a 2-drug combination after relapse with crizotinib.
Shaw AT, Kim D-W, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013 June 1 [Epub ahead of print].

 

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