Pfizer Inc. announced encouraging new data from a phase 1/2 study of lorlatinib, the proposed generic name for PF-06463922, Pfizer’s investigational, next-generation ALK/ROS1 tyrosine kinase inhibitor. The study showed clinical response in patients with ALK-positive or ROS1-positive advanced non-small cell lung cancer (NSCLC), including patients with brain metastases. These data were presented in an oral presentation at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

The results presented are from the dose escalation component of an ongoing phase 1 study of patients with ALK-positive or ROS1-positive NSCLC, with or without brain metastases, who were treatment-naïve or had disease progression after at least one prior tyrosine kinase inhibitor (TKI). Among patients with ALK-positive metastatic NSCLC, the overall response rate (ORR) with lorlatinib was 46 per cent, with three patients achieving complete responses and 16 patients achieving a partial response (95% CI: 31-63). The median progression free survival (PFS) was 11.4 months (95% CI: 3.4 – 16.6). The majority of patients had received two or more prior ALK TKIs. Additionally, lorlatinib showed the ability to decrease the size of brain metastases in patients with ALK-positive or ROS1-positive metastatic NSCLC.

“Many patients with ALK-positive or ROS1-positive metastatic NSCLC will progress beyond initial therapy and potentially develop brain metastases,” said Benjamin Solomon, MBBS, Associate Professor, Peter MacCallum Cancer Centre, Australia. “These early data suggest lorlatinib may be effective in a broad range of patients, including those who are heavily pre-treated or develop brain metastases. We are encouraged by these results and look forward to further investigating the full effects of lorlatinib in ALK-positive and ROS1-positive NSCLC.”

“We are excited by these data and the potential of lorlatinib to overcome resistance to ALK inhibitors, which remains a significant challenge for patients with ALK-positive NSCLC,” said Mace Rothenberg, MD, senior vice president, head of development, Pfizer Oncology. “Pfizer pioneered precision medicine in ALK-positive advanced NSCLC through the introduction of Xalkori (crizotinib), which is widely recognized as a first-line standard of care for these patients, and we are committed to developing next-generation treatments that meet these patients’ evolving needs.”

In the phase 1 portion of the study, patients received lorlatinib on a continuous basis, once or twice daily. The primary objective was to identify the maximum tolerated dose and recommended Phase 2 dose. Patients were treated across 10 dose levels (10–200 mg). The recommended phase 2 dose was 100 mg once daily. Other objectives included safety and efficacy by RECIST v1.1 including intracranial activity. Of 54 patients treated as of January 15, 2016, 41 were ALK-positive, 12 were ROS1-positive and one was unconfirmed. The majority of patients were previously treated with a TKI, including 20 with one prior TKI and 27 with more than one TKI. Additionally, 39 patients had brain metastases at baseline.

The most common treatment-related adverse events (AEs) were hypercholesterolemia (69%) and peripheral edema (37%). Hypercholesterolemia was the most common (11%) grade 3 or higher treatment-related AE and the most frequent reason for dose delay or reduction. No patients discontinued due to treatment-related AEs. At the recommended phase 2 dose, 4 out of 17 patients (24%) experienced a treatment-related AE of any grade that led to a dose delay or hold.

The ongoing phase 2 study is expected to enroll a total of 240 patients across six cohorts (five for ALK-positive and one for ROS1-positive patients with NSCLC), with enrollment defined by degree and type of prior treatment.

Lorlatinib, the proposed generic name for PF-06463922, is an investigational next-generation ALK/ROS1 tyrosine kinase inhibitor that has been shown to be highly active in preclinical lung cancer models harboring chromosomal rearrangements of both ALK and ROS1. Lorlatinib was specifically designed to inhibit tumor mutations that drive resistance to other ALK inhibitors and to penetrate the blood brain barrier. A phase 1/2 clinical trial of lorlatinib in patients with ALK-positive or ROS1-positive advanced NSCLC is currently ongoing. Lorlatinib has not yet been approved by any regulatory agency.

Xalkori is a kinase inhibitor indicated in the US for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test, and for the treatment of patients with metastatic NSCLC whose tumors are ROS1-positive.