AMSTERDAM – Crizotinib treatment boosted overall survival of selected patients with advanced non–small cell lung cancer by about a year compared with patients on standard chemotherapy in a historical control analysis, adding to the growing body of evidence for the efficacy of this novel targeted therapy.
"Crizotinib may prolong overall survival and fundamentally alter the natural history" of NSCLC that features alterations in the anaplastic lymphoma kinase (ALK) gene, Dr. Alice T. Shaw said at the World Conference on Lung Cancer. Results from several recent studies indicated that about 7% of patients with advanced NSCLC have ALK-positive tumors in which the gene is rearranged.
Dr. Alice T. Shaw
Results from Dr. Shaw’s new analysis also indicated that the overall survival of patients with ALK-positive NSCLC closely tracked the survival rate of patients with normal ALK genes and advanced NSCLC, suggesting that the presence of ALK mutation does not change prognosis.
"ALK-positive patients do not intrinsically do better on their own, but you can make them live a lot longer if you give them this targeted therapy, crizotinib," said Dr. Shaw, an oncologist at Harvard Medical School and Massachusetts General Hospital, both in Boston.
In May, the Food and Drug Administration began a priority review of crizotinib, an ALK inhibitor, for an indication to treat patients with advanced, ALK-positive NSCLC.
"For regulatory approval, people look at overall survival, but you’ll never get [overall survival] from the large randomized studies because it would be unethical not to let patients [who were initially randomized to not receive crizotinib] cross over. That’s why this analysis is important, even with its flaws, because it shows – or at least strongly suggests – that this drug improves overall survival, that we are really making a difference for these patients," Dr. Shaw said in an interview. Prior reports from crizotinib studies in ALK-positive patients documented a response rate of 50%-60%, and a median progression-free survival of 10 months.
Dr. Shaw and her associates used data on patients who were treated with crizotinib from the first, phase I study of the drug, because those patients have had the longest follow-up on the drug, a median of 18 months for those who remained alive (N. Engl. J. Med. 2010;363:1693-703).
The phase I crizotinib study included 82 ALK-positive patients who received the drug. To better match these patients with a control group of ALK-positive patients who never got crizotinib, the researchers focused on the 56 patients who came from study centers in the United States and Australia, and specifically on the 30 patients within this subgroup who received crizotinib as their second or third chemotherapy agent.
They compared overall survival of these 30 patients with 21 ALK-positive patients from the United States or Australia who had been assessed for potential enrollment in the phase I study but never received crizotinib. In addition, during follow-up all of these control patients remained on second-line chemotherapy.
The new analysis showed that the 30 crizotinib-treated patients had an overall 1-year survival rate of 74%, and a 2-year rate of 54%, with median survival not yet reached during the median 18-month follow-up. The 21 matched control patients had a 1-year survival rate of 44% and a 2-year rate of 12%, and median survival duration of 6 months. Calculations showed a hazard ratio for overall survival of 0.36 for the patients who did not get crizotinib compared with those who did (P = .004).
"These results suggest that crizotinib may significantly improve survival outcomes in patients with advanced ALK-positive NSCLC," Dr. Shaw said.
To confirm that ALK positivity itself played no role in overall survival, Dr. Shaw and her associates compared overall survival in the 21 control patients who never received crizotinib vs. 48 patients who had advanced NSCLC without any ALK mutations, who never received crizotinib, and who had been treated with standard, second-line chemotherapy. In addition, all 48 control patients and all 21 ALK-positive patients had tumors with adenocarcinoma histology, and they all had a history of being never or light smokers. The two groups had virtually identical overall survival rates, Dr. Shaw reported at the meeting, which was sponsored by the International Association for the Study of Lung Cancer.
The crizotinib study that provided much of the data used in this analysis was funded by Pfizer, the company developing the drug. Dr. Shaw said that she has been a consultant to Pfizer, Ariad, Chugai, and Millennium. She has received research support from Novartis and AstraZeneca.