ELCC 2015 News: Safety and Efficacy Results with Selected Doses From a Phase I/II Trial of AP26113 in Patients with Advanced Malignancies, Including ALK–Positive NSCLC

Clinical activity observed at all dose levels of AP26113

AP26113, an inhibitor of anaplastic lymphoma kinase (ALK) that can be taken orally, showed clinical activity at each of three selected dose levels in patients with advanced ALK-rearranged non-small-cell lung cancer (NSCLC) who demonstrated similar response rates across all dose levels that were evaluated.

European Lung Cancer Conference 2015: Abstract 99O

Progression-free survival (PFS) with brigatinib by selected dosing regimens in ALK+ NSCLC patients in a phase 1/2 trial. Median PFS was 12.9 month for 90 mg qd (n=14), not reached for 90 mg qd escalated to 180 mg qd after 7 days (90→180 mg qd; n=26), and 11.1 month for 180 mg/d (n=25).
© Rafael Rosell

Lead investigator, Dr Rafael Rosell, Medical Oncology Service, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain, presented findings from a phase I/II study of AP26113 during the Advanced NSCLC Proffered Papers session at the European Lung Cancer Conference, 15-18 April  2015 in Geneva, Switzerland.

AP26113 is an investigational oral ALK inhibitor that has demonstrated preclinical activity against both native ALK and a broad range of crizotinib-resistant mutants.

The findings from this phase I/II study guided dose selection to be used for testing in the phase II ALTA (ALTA: ALK in Lung Cancer Trial of AP26113) trial of AP26113 in patients with advanced ALK-positive NSCLC.

This single-arm, multicentre study evaluated AP26113 at total daily oral doses that ranged from 30 to 300 mg in patients with advanced malignancies. Prof. Rosell presented findings from the efficacy and safety analysis of AP26113, which was administered to three cohorts of patients at daily doses of 90 mg (90 mg cohort), 90 mg escalating to 180 mg after 7 days (90–180 mg cohort), or 180 mg (180 mg cohort, which included patients receiving 90 mg bid).

By 4 August 2014, the trial had enrolled 137 patients; 79 patients had ALK-positive NSCLC and 71 (90%) of these patients had received prior treatment with crizotinib.

Similar response rates to AP26113 observed across all dose level cohorts

The overall response rate in 60 evaluable patients was 79%, 81%, and 68% in the 90 mg, 90 to 180 mg, and 180 mg cohorts, respectively. Of the 14 patients receiving AP26113 at 90 mg, no complete response (CR) was seen; 11 (79%) patients had a partial response (PR), 1 (7%) patients had stable disease (SD) and progressive disease (PD) was seen in no patients.

In the 26 patients receiving AP26113 in the 90 to 180 mg cohort, 3 (12%) patients had CR, 18 (69%) patients achieved PR, 2 (8%) had SD and PD was observed in one (4%) patient.

In 25 patients receiving AP26113 in the 180 mg cohort, there were two (8%) CR, 15 (60%) PR, 3 (12%) patients had SD, and PD was observed in 5 (20%) patients.

Progression-free survival (PFS) was median 12.9 month in patients receiving the lowest dose of AP26113. Median PFS had not been reached in the 90 to 180 cohort and the median PFS in patients in the 180 mg cohort was 11.1 month.

The most common adverse events (AEs) were mostly grade 1 or 2 and included nausea, diarrhoea, and fatigue, these were reported by patients across all three respective dose cohorts. AEs of grade ≥3 included increased lipase, neoplasm progression and increased amylase.

Events included dyspnoea, hypoxia, and new pulmonary opacities suggestive of pneumonia or pneumonitis occurred within 7 days of starting brigatinib (usually within 24–48 hours), required medical intervention and occurred at lower rates with lower doses. Early-onset pulmonary symptoms were observed in 4% of patients in the 90 mg cohort and in 14% of patients receiving 180 mg. None of the patients receiving the 90 mg dose that was escalated to 180 mg demonstrated early-onset pulmonary symptoms.

Dr Rafal Dziadziuszko of the Medical University of Gdańsk in Poland, who discussed the study results, said that resistance to ALK inhibitors in half of the cases is related on ALK dependence, and in other half to other pathways. He reviewed non-ALK targets of second generation ALK inhibitors and said that it might be necessary to perform a molecular testing at progression to first generation ALK inhibition therapy and then administer the second generation inhibitor. The open questions to be addressed in the future are: drug activity, particularly in the CNS and coverage of resistance mechanisms, toxicity profile and cost issue.

Conclusions

The efficacy of AP26113 was similar at daily doses of 90 mg and 180 mg in patients with advanced ALK-positive NSCLC. However, early-onset pulmonary symptoms were less frequent in the cohorts receiving AP26113 at doses of 90 mg and 90 mg escalated to 180 mg than in patients receiving 180 mg AP26113.

The investigators advanced the oral dose levels of 90 mg daily and 90 mg escalated to 180 mg daily for evaluation in the phase II ALTA trial of AP26113 in ALK-positive NSCLC patients who are resistant to crizotinib.

Reference

99O Phase 1/2 study of AP26113 in patients (Pts) with advanced malignancies, including anaplastic lymphoma kinase (ALK)–positive non-small cell lung cancer (NSCLC): Analysis of safety and efficacy at selected phase 2 doses

The study sponsor was ARIAD Pharmaceuticals, Inc.