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Lung Cancer Drug Receives FDA ‘Breakthrough Therapy’ Designation for Patients Resistant to Crizotinib

Objective response rate is 72% in early trial

The investigational cancer treatment AP26113 (Ariad Pharmaceuticals) has received a “breakthrough therapy” designation from the FDA for patients with anaplastic lymphoma kinase positive (ALK+) metastatic non–small-cell lung cancer (NSCLC) who are resistant to crizotinib (Xalkori, Pfizer). This designation was based on results from an ongoing phase I/II trial that showed sustained anti-tumor activity of AP26113 in patients with ALK+ NSCLC, including patients with active brain metastases.

The 2012 Food and Drug Administration Safety and Innovation Act (FDASIA) established the “breakthrough therapy” designation to expedite the development and review of new drugs with preliminary clinical evidence demonstrating that they may offer a substantial improvement over available therapies for patients with serious or life-threatening diseases. As of September 3, 2014, the FDA listed 213 total requests for a “breakthrough therapy” designation, and 61 requests were granted. Approximately 41% of the designated products are cancer treatments.

Updated clinical data from the ongoing phase I/II trial of AP26113 were recently reported at the 2014 European Cancer Congress. A total of 137 patients have been enrolled in the study in the U.S. and Europe.

Objective responses were observed in ALK+ NSCLC patients, and responses were observed in patients who were either tyrosine kinase inhibitor (TKI)-naïve or resistant to crizotinib. Of the 72 ALK+ NSCLC patients evaluable for response, 52 (72%) demonstrated an objective response. The median duration of response was 49 weeks, and the median progression-free survival (PFS) was 56 weeks.

In a subgroup analysis, 10 of 14 (71%) ALK+ NSCLC patients with active, untreated, or progressive brain metastases had evidence of radiographic improvement in those metastases. Of the seven evaluable TKI-naïve ALK+ NSCLC patients treated with AP26113, all demonstrated an objective response, including two complete responses.

The most common adverse events (AEs), regardless of treatment relationship and including all grades, were nausea (45%), diarrhea (37%), and fatigue (37%). AEs of grade 3 or higher occurring in three or more patients included dyspnea (4%), increased lipase (4%), hypoxia (4%), fatigue (3%), increased alanine aminotransferase (ALT) (2%), and increased amylase (2%). Serious AEs of any cause occurring in three or more patients included dyspnea (7%), pneumonia (5%), hypoxia (4%), neoplasm progression (4%), pyrexia (2%), and pulmonary embolism (2%).

NSCLC is the most common form of lung cancer, accounting for approximately 85% of the estimated 228,190 new cases of lung cancer diagnosed each year in the U.S., according to the American Cancer Society. ALK was first identified as a chromosomal rearrangement in anaplastic large-cell lymphoma (ALCL). Genetic studies have indicated that abnormal expression of ALK is a key driver of certain types of NSCLC as well. Approximately 3% to 8% of patients with NSCLC have the ALK gene mutation.

AP26113 was designed to overcome mutation-based resistance, including the L1196M “gatekeeper” mutation and other resistance mutations that have been observed clinically in patients who initially responded to crizotinib and then relapsed.

Sources: Ariad Pharmaceuticals; October 2, 2014; and AP26113; 2014.

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