FDA Grants Breakthrough Therapy Designation to AP26113 in NSCLC

Harvey J. Berger, MD

The highly selective ALK inhibitor AP26113 has been granted a Breakthrough Therapy Designation by the FDA for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) who received prior treatment with crizotinib (Xalkori).

The designation was based on data from a phase I/II study exploring AP26113 in crizotinib-pretreated and naïve patients with ALK-positive NSCLC. In the study, which was presented at the 2014 ESMO Congress, AP26113 demonstrated promising antitumor activity across all patients populations enrolled, including those with brain metastases.

“We are very pleased that the FDA has granted Breakthrough Therapy designation to AP26113,” Harvey J. Berger, MD, chairman and chief executive officer of Ariad, the company developing AP26113, said in a statement. “We are encouraged by the clinical data on AP26113 that were presented recently at the European Cancer Congress, particularly in patients whose tumor had spread to the brain."

The phase I/II study examined treatment with AP26113 at various doses in 137 patients with ALK-positive NSCLC. In the phase I portion, 66 patients were treated at doses ranging from 30 to 300 mg. In the phase II portion of the study, 59 patients received AP26113 at 90 mg or 180 mg daily.

The objective response rate (ORR) in 72 evaluable patients with ALK-positive NSCLC was 72%. The median duration of response was 49 weeks. The median progression-free survival (PFS) was 56 weeks. In the 65 evaluable patients treated with prior crizotinib, the ORR was 69% with a median PFS of 47.3 weeks.

In 7 evaluable patients with treatment-naïve ALK-positive NSCLC, AP26113 demonstrated 2 complete and 5 partial responses, for an ORR of 100%. In patients with untreated or progressing brain metastases (n = 14), 71% of patients had evidence of radiographic disease improvement.

“The updated data from the ongoing trial continue to demonstrate the antitumor activity of AP26113 in patients with crizotinib-resistant ALK rearranged NSCLC, as well as TKI-naïve ALK rearranged NSCLC,” lead investigator Scott N. Gettinger, MD, associate professor of medicine at Yale School of Medicine, said in a statement. “One of the distinguishing features of the data is the evidence for antitumor activity in the brain, a common site of treatment failure.”

The most common all-grade adverse events with AP26113 were nausea (40%), fatigue (34%), diarrhea (34%), cough (26%), headache (25%), and vomiting (21%). The most common serious adverse events were dyspnea (7%), pneumonia (5%), hypoxia (4%), neoplasm progression (4%), pyrexia (2%) and pulmonary embolism (2%).

The randomized phase II ALTA trial is currently evaluating AP26113 at 90 mg daily or 90 mg escalated to 180 mg daily in crizotinib-resistant ALK-positive NSCLC. The trial plans to enroll 218 patients, including those with brain metastases. (NCT02094573).

The ALTA study hopes to discover an optimal dose for AP26113 to potentially resolve the early onset pulmonary symptoms that were present in 10% of patients in the phase I/II study. These pulmonary events included dyspnea with hypoxia and/or new findings on chest imaging. The authors of the phase I/II study observed that pulmonary symptoms occurred at lower rates with lower doses of AP26113.

“We anticipate full patient enrollment in the ALTA trial in the third quarter of next year,” Frank G. Haluska, MD, PhD, senior vice president of clinical research and development and chief medical officer at Ariad, said in a statement. “Based on the continued responses seen in the ongoing phase I/II trial of AP26113, and in particular, the 100% response rate and durability of response in the TKI-naïve patients, we are also actively planning a clinical trial to evaluate the potential of AP26113 in the newly diagnosed ALK-positive lung cancer setting.&rdquo