Carlson, Robert H.
CHICAGO—ALK (anaplastic lymphoma kinase) represents one of the newest tyrosine kinase targets in lung cancer. A Phase I trial reported last fall (Kwak et al: NEJM 2010;363-1693-1703) showed that the ALK tyrosine kinase inhibitor crizotinib had significant antitumor activity in patients with advanced ALK-positive non-small-cell lung cancer (NSCLC), but any impact on overall survival was not established.
The study reported b...Image Tools
Now, data from an expansion cohort of that trial reported in an oral session at the ASCO Annual Meeting show that crizotinib therapy is indeed associated with a longer overall survival compared with ALK-negative patients and with ALK-positive patients not treated with crizotinib (Abstract 7507).
“Crizotinib may prolong overall survival and fundamentally alter the natural history of ALK-positive NSCLC,” said lead author Alice T. Shaw, MD, PhD, attending physician in the Thoracic Cancer Program at Massachusetts General Hospital and Assistant Professor of Medicine at Harvard Medical School. She and her co-researchers proposed in their abstract that crizotinib represents a new standard of care for patients with ALK-positive NSCLC.
In her presentation, Dr. Shaw explained that crizotinib is an oral compound that inhibits the therapeutic target of ALK as well as c-MET, a mesenchymal-epithelial transition factor.
The expansion cohort trial, which was sponsored by Pfizer, included 82 ALK-positive patients. For comparators, 36 ALK-positive patients who were not treated with crizotinib were chosen from other Phase I sites, as well as 253 ALK-negative and EGFR-negative patients from one site. All ALK-positive and ALK-negative controls had advanced NSCLC.
ALK-positive patients treated with crizotinib had a one-year overall survival rate of 74% and a two-year overall survival rate of 54%. Median overall survival had not been reached. This compared with outcomes for the ALK-positive controls of one-year overall survival of 73% and two-year overall survival of 33%. Median overall survival was 20 months.
And survival in patients treated with second- and third-line crizotinib was significantly better that in ALK-positive controls: 70% and 44%, respectively, at one year; and 55% and 12%, respectively, at two years.
For the ALK-negative controls in the second-line setting, the survival rates were 47% at one year and 32% at two years.
The Phase I outcomes are important because the true activity of crizotinib on overall survival may be difficult to establish in ongoing randomized Phase III trials that allow crossover, Dr. Park explained. “In the absence of randomized data, determination of survival benefit requires a comparator population of ALK-positive crizotinib-naïve patients.”
Dr. Shaw acknowledged that the study was retrospective and non-randomized, and that there is potential for confounding survival outcomes by post-crizotinib therapies. A randomized, controlled trial is now already under way to confirm the survival outcomes.
Discussant: Chance & the Prepared Mind
The study's Discussant, Ramaswamy Govindan, MD, Professor and Co-Director of the Section of Medical Oncology at Washington University School of Medicine Siteman Cancer Center, first congratulated Dr. Shaw on all her work with the ALK translocation since 2007, when it was identified. In only four years, he explained, a mouse model was developed, a drug went into Phase II testing, and the mechanisms of resistance became recently understood. The short time is in contrast with the 41 years from target recognition to drug therapy for BCR-ABL, 26 years for EGFR, and eight years for BRAF.
“Chance certainly favored the prepared mind here,” he said, adding that this rapid development is despite clinical trials with very small numbers of patients, since only about 3% of NSCLC patients have tumors with the ALK translocation.
The majority of ALK-positive patients are men; about two-thirds are never smokers, similar to the percentage of patients with an EGFR mutation; and the disease is predominantly adenocarcinoma, possibly a mucin-producing subtype.
Dr. Govindan, OT's Clinical Advisory Editor for Oncology, noted that it is difficult to say whether the presence of ALK translocation actually predicts worse outcomes, since there are few data related to that, and most of the research there is comes from patients with early-stage disease.
But the data do show that “outcomes in patients with advanced NSCLC treated with chemotherapy are not good, and outcomes in patients with advanced disease treated with standard EGFR-TK-inhibitors are not at all good.”
Dr. Govindan said the research by Dr. Shaw and others is important because it shows that ALK-positive patients in fact do well with crizotinib.
“Patients with ALK-rearranged NSCLC do better with crizotinib than without crizotinib. It is quite clear—if you give targeted drugs to targeted populations they do quite well.”
© 2011 Lippincott Williams & Wilkins, Inc.