Although the targeted drug crizotinib is very effective in causing rapid regression of ALK-rearranged non-small cell lung cancer (NSCLC), the tumours inevitably become resistant to the drug. Now a new drug ceritinib appears to be effective against advanced ALK-positive NSCLC, both in tumours that have become resistant to crizotinib and in those never treated with it, with mostly mild and manageable side effects. The results of a phase I clinical trial conducted at centers in 11 countries are reported in the 27th March 2014 issue of New England Journal of Medicine. Dr Alice Shaw of the Massachusetts General Hospital Cancer Center and associate professor of medicine at Harvard Medical School is a lead author of the report.
In 2011, crizotinib received accelerated approval to treat ALK-positive NSCLC, but as with other drugs directed against cancer-driving gene aberrations, its effectiveness proved to be temporary.
Laboratory studies indicated that ceritinib, which has a different molecular structure than crizotinib, could be as much as 20 times potent; and preclinical studies suggested it would be effective against both crizotinib-sensitive and crizotinib-resistant tumours.
The current study was designed to assess the drug's safety and tolerability, along with giving a first look at its antitumour activity in human patients.
Overcoming crizotinib resistance
The study's first phase was designed to determine the maximum tolerated dose of ceritinib. It enrolled 59 NSCLC patients harbouring genetic alterations in ALK, who received escalating daily doses ranging from 50 to 750 mg. The maximum tolerated dose of ceritinib was 750 mg once daily. Dose-limiting toxic events included diarrhoea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. However, the adverse events were generally mild and resolved when treatment stopped or the dose was reduced.
The second phase enrolled another 71 participants, eight of whom had other forms of cancer driven by ALK, for a total of 130 participants in the overall study. In this expansion phase of the study, patients received the maximum tolerated dose of drug. They took daily oral doses of ceritinib as long as the drug was effective in suppressing tumour growth, with dosage levels being adjusted to reduce side effects.
Tumour biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib.
Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58%. Among 80 patients who had received crizotinib previously, the response rate was 56%. Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months.
Patients whose tumours have kept responding to ceritinib treatments are still receiving the drug, some after two years.
Another Massachusetts General Hospital led study published online in Cancer Discovery finds that ceritinib is able to overcome several known ALK mutations that confer crizotinib resistance and identifies two additional mutations that cause tumours to become resistant to both drugs. "These findings help us understand both the benefit and limitations of ceritinib and the need to develop ALK inhibitors that can overcome these more recalcitrant mutants," says Dr Jeffrey Engelman of the Massachusetts General Hospital Cancer Center and Laurel Schwartz Associate Professor of Medicine at Harvard Medical School, who is a senior author of both the Cancer Discovery and the NEJM papers.
In particular, ceritinib effectively inhibited ALK harbouring L1196M, G1269A, I1171T and S1206Y mutations. However, in thier study the researchers observed that ceritinib did not overcome two crizotinib-resistant ALK mutations, G1202R and F1174C, and one of these mutations were identified in 5 out of 11 biopsies from patients with acquired resistance to ceritinib.
Breakthrough therapy designation
Dr Shaw explains that preliminary data from the NEJM study led to ceritinib's receiving 'breakthrough therapy' designation from the FDA last year. The drug's manufacturer, Novartis Pharmaceuticals, has applied for accelerated FDA approval based on results from this study. Dr Shaw is the principal investigator for two phase II clinical trials that are now underway, and two phase III trials are currently enrolling patients. Ceritinib, a next generation ALK inhibitor, is also known as LDK378.
The NEJM study was supported by Novartis, by National Cancer Institute grant 5R01CA164273, a V Foundation Translational Research Grant, by Be a Piece of the Solution and the Evan Spirito Memorial Foundation.
Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 2014; 370:1189-1197.
Friboulet L, Li N, Katayama R, et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discovery 2014; Published online first March 27 2014. doi:10.1158/2159-8290.CD-13-0846.