First-Line Crizotinib Superior to Pemetrexed‑Plus‑Platinum Chemotherapy in Patients With ALK‑Positive NSCLC

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Crizotinib (Xalkori) treatment “was superior to pemetrexed-plus-platinum chemotherapy with respect to progression-free survival, objective response rate, reduction in lung-cancer symptoms, and improvement in quality of life” in patients with previously untreated advanced anaplastic lymphoma kinase (ALK)–positive non–small cell lung cancer (NSCLC), according to an open-label, phase III trial reported in The New England Journal of Medicine. Progression-free survival, the primary endpoint of the trial, “was significantly longer with crizotinib than with chemotherapy,” reported Benjamin J. Solomon, MB, BS, PhD, of Peter MacCallum Cancer Centre in Melbourne, Australia, and colleagues. The median progression-free survival was 10.9 months in the group receiving crizotinib vs 7.0 months in the group receiving standard chemotherapy (hazard ratio [HR] progression or death with crizotinib, 0.45; 95% confidence interval [CI], 0.35–0.60; P < .001).

Crizotinib is an oral small-molecule tyrosine inhibitor of ALK and other kinases. Present in 3% to 5% of patients with NSCLC, rearrangements of ALK “define a distinct subgroup of NSCLC that typically occurs in younger patients who have never smoked or have a history of light smoking and that have adenocarcinoma histologic characteristics,” the authors explained.

Patients were randomly assigned to receive oral crizotinib at 250 mg twice daily or intravenous chemotherapy with pemetrexed (Alimta) plus, at the choice of the investigator, either cisplatin or carboplatin every 3 weeks for up to 6 cycles. Among the 340 patients receiving treatment, 171 were in the crizotinib group and 169 were in the chemotherapy group, with 91 receiving pemetrexed-cisplatin and 78 receiving pemetrexed-carboplatin. Treatment was continued until disease progression, unacceptable toxic effects, death, or withdrawal of consent. Patients receiving chemotherapy could cross over to crizotinib treatment after disease progression. 

The median age was 52 years in the crizotonib group and 54 years in the chemotherapy group. More than 60% of patients had never smoked.

“The objective response rate was significantly higher with crizotinib than with chemotherapy,” 74% vs 45% (P < .001), the investigators reported. “The median duration of response was 11.3 months vs 5.3 months.” The median overall survival was not reached. The authors estimated that “the probability of 1-year survival was 84% with crizotinib and 79% with chemotherapy.”

The most common adverse events were vision disorders, diarrhea, nausea, and edema among patients receiving crizotinib and nausea, fatigue, vomiting, and decreased appetite among those receiving chemotherapy. Adverse events associated with permanent discontinuation of treatment occurred in 12% of patients in the crizotinib group and 14% of the chemotherapy group, with 5% in the crizotinib group and 8% in the chemotherapy group “deemed by the investigator to be related to treatment.” Patients receiving crizotinib reported a greater improvement in quality of life and a greater reduction in pain, dyspnea, and insomnia. ■

Solomon BJ, et al: N Engl J Med 371:2167-2177, 2014.




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