Ceritinib Demonstrates Impressive Response Rates in ALK-Positive NSCLC

Alice T. Shaw, MD, PhD

Ceritinib (LDK378), a highly selective inhibitor of ALK, demonstrated an overall response rate (ORR) of 58% and a median progression-free survival (PFS) of 7 months as a treatment for patients with ALK-positive non-small cell lung cancer (NSCLC), according to results from a single-arm phase I trial published in The New England Journal of Medicine (NEJM).

"Crizotinib has become a standard treatment agent for patients with advanced, ALK-rearranged NSCLC, but patients invariably develop resistance, leaving their treatment options limited," Alice Shaw, MD, PhD, of the Massachusetts General Hospital (MGH) Cancer Center, lead author of the report, said in a press release. "We found ceritinib to be highly effective in the majority of crizotinib-resistant patients, as well as those who had never received the drug, with mostly mild and manageable side effects."

The trial consisted of two stages and was funded by Novartis, the manufacturer of the drug. A total of 59 patients with NSCLC were enrolled in a dose-escalation phase, which administered ceritinib from 50 mg daily to the maximum tolerated dose of 750 mg per day.

In the expansion phase, 71 patients were added (N = 130), eight with other types of cancer driven by the ALK alterations. Participants took daily oral doses of ceritinib for as long as the drug was effective in suppressing tumor growth, with dosage levels being adjusted to reduce side effects. A total of 114 ALK-rearranged patients with NSCLC were treated with ceritinib at 400 mg or higher per day, 80 patients were resistant or refractory to crizotinib and 34 patients were crizotinib-naïve.

The ORR for all patients was 58% (95% CI; 48%-67%), which included 1 complete response and 65 partial responses. Patients who had progressed during or after crizotinib therapy experienced an ORR of 56% (95% CI; 45%-67%) and those who were crizotinib-naïve had an ORR of 62% (95% CI; 44%-78%).

The median PFS was 7.0 months (95% CI, 5.6-9.5) and the median duration of response was 8.2 months (95% CI; 6.9-11.4).

"The majority of patients in the study experienced a clinical response to LDK378. In addition, responses were seen in untreated lesions in the central nervous system in patients who previously received crizotinib,” Shaw said in a release. “These results are important because most patients experience a disease relapse less than a year after starting crizotinib and have limited treatment options.”

The most frequent adverse events were nausea (82%), diarrhea (75%), vomiting (65%), fatigue (47%) and increased alanine aminotransferase levels (35%). These adverse events were generally mild and resolved when treatment stopped or the dose was reduced.

The most common grade 3 or 4 drug-related adverse events were increased alanine aminotransferase levels (21%), increased aspartate aminotransferase levels (11%), diarrhea (7%) and increased lipase levels (7%), all of which were reversible upon treatment discontinuation.

Sixty-six of 130 patients (51%) required at least one dose reduction, and in 8 of 130 patients (6%) the study drug was permanently discontinued due to an adverse event. At the 750 mg dose level, 50 of 81 patients (62%) required at least one dose reduction, 32 of which occurred in cycle 3 or later. No treatment-related deaths occurred.

In January, Novartis announced that a regulatory application was submitted to the FDA for ceritinib in ALK-positive NSCLC based on results from the expansion cohort. The regulatory submission follows a Breakthrough Therapy Designation from the FDA last year for the treatment of patients with ALK-positive metastatic NSCLC who have already received treatment with crizotinib.

“These pivotal data published in NEJM served as the basis for our first regulatory filing for LDK378,” Alessandro Riva, president, ad interim, and Global Head, Oncology Development & Medical Affairs, Novartis Oncology, said in a press release. “We are pleased that the FDA has accepted our application, and we look forward to working with the FDA and health authorities worldwide to bring this important treatment option to patients in need as swiftly as possible.”

There are currently several major studies evaluating treatment with ceritinib being conducted in more than 300 centers across more than 30 countries. Two phase II clinical trials are actively recruiting patients worldwide to further evaluate ceritinib in patients with ALK-positive NSCLC.