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CHICAGO -- Progression of a subtype of non-small cell lung cancer (NSCLC) slowed significantly with a targeted drug as compared with conventional chemotherapy, results of a large, randomized trial showed.

Patients treated with crizotinib (Xalkori) had a median progression-free survival of 7.7 months, more than twice as long as patients treated with either of two chemotherapy regimens. Symptoms also improved significantly more with crizotinib than with chemotherapy, according to Alice T. Shaw, MD, PhD, of Massachusetts General Hospital in Boston, and co-authors.

However, overall survival did not improve with targeted therapy, they reported online in the New England Journal of Medicine and simultaneously at the American Society of Clinical Oncology meeting here.

"The apparent lack of a survival benefit probably reflects the confounding effects of crossover, effects that have been observed in other randomized trials of molecularly targeted agents in patients with non-small cell lung cancer," the investigators concluded in the journal article.

The results confirm the outcome first reported last year at the European Society of Medical Oncology meeting.

A second report published simultaneously by the journal described the first evidence of crizotinib resistance in NSCLC.

About 5% of NSCLC tumors have rearrangements of anaplastic lymphoma kinase (ALK). Given the estimated 1.3 million new cases of NSCLC that occur worldwide each year, ALK-positive tumors account for more than 60,000 cases of NSCLC each year.

Crizotinib, an oral small-molecule agent, inhibits ALK, MET, and ROS1 tyrosine kinases and demonstrated marked activity in two studies involving patients with advanced ALK-positive NSCLC. The trials showed an objective response rate of about 60% and median progression-free survival of 8 to 10 months. In contrast, standard chemotherapy has been associated with response rates of less than 10% and median progression-free survival of 2 to 3 months, the authors noted in their introduction.

Retrospective studies have provided evidence that pemetrexed (Alimta)-based chemotherapy regimens are active in ALK-positive NSCLC, including response durations similar to those observed with crizotinib. To confirm the observations and increase experience with crizotinib, investigators in North America, Europe, Australia, and Asia conducted a phase III, open-label trial to compare crizotinib and chemotherapy in advanced NSCLC.

The trial involved 347 patients with advanced or metastatic ALK-positive NSCLC previously treated with platinum-based chemotherapy. They were randomized to crizotinib or to chemotherapy with either pemetrexed or docetaxel. Patients in the chemotherapy arm could cross over to crizotinib at progression.

The primary endpoint was median progression-free survival (PFS), and when the trial ended, the crizotinib group had a median PFS of 7.7 months versus 3.0 months for the chemotherapy arm. The difference represented a 51% reduction in the hazard for progression (P<0.001). Separate comparisons of crizotinib and the individual chemotherapy regimens yielded a hazard ratio of 0.59 versus pemetrexed (P<0.001) and 0.30 versus docetaxel (P<0.001).

Response rates were 65% with crizotinib and 20% with chemotherapy (P<0.001).

Analysis of safety and adverse events showed that patients in the crizotinib group had a median duration of treatment of 31 weeks compared with 12 weeks for the chemotherapy arm. The most common adverse events that occurred at least 5% more often in the crizotinib group were visual disturbance, diarrhea, nausea, vomiting, constipation, elevated liver aminotransferase levels, edema, upper respiratory infection, dysgeusia, and dizziness. Most were grade 1/2 severity.

Adverse events that occurred more often with chemotherapy included fatigue, alopecia, dyspnea, and rash.

Grade 3/4 neutropenia occurred in 13% of the crizotinib arm and 19% of the chemotherapy group. One patient treated with crizotinib developed febrile neutropenia as compared with 16 in the chemotherapy group.

An interim analysis of overall survival showed no difference between groups (HR 1.02).

The second report from the same study involved a patient who developed crizotinib resistance after a "dramatic" response to the treatment. Biopsy of the resistant tumor revealed an acquired mutation at codon 2032 in the ROS1 kinase domain, Jeffrey A. Engelman, MD, PhD, also of Massachusetts General Hospital, and co-authors reported. The mutation confers resistance by interfering with drug binding.

"The same resistance mutation was observed at all metastatic sites examined at autopsy, suggesting that this mutation was an early event in the clonal evolution of resistance," according to the authors.

The findings suggest that "a potent inhibitor of this mutant kinase may have been clinically effective after the failure of crizotinib," they added.

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