Pfizer Inc. today announced full results from the Phase 2 clinical trial of the investigational, next-generation tyrosine kinase inhibitor lorlatinib that exhibited clinically meaningful activity against lung tumors and brain metastases in a range of patients with ALK-positive and ROS1-positive advanced non-small cell lung cancer (NSCLC), including those who were heavily pretreated. Further, side effects were generally manageable and primarily mild to moderate in severity. The results [Abstract #OA 05.06] were presented by Professor Benjamin Solomon, lead investigator and medical oncologist at Peter MacCallum Cancer Centre, Melbourne, Australia, today during an oral session at the International Association for the Study of Lung Cancer (IASLC) 18th World Conference on Lung Cancer (WCLC) in Yokohama, Japan. Pfizer will also present data from several other lung cancer clinical programs.

“The findings presented today suggest that lorlatinib, if approved, may represent an effective treatment option for patients with ALK-positive advanced non-small cell lung cancer across multiple lines of therapy. These are comprehensive data in non-small cell lung cancer patients previously treated with second-generation ALK inhibitors who currently have few available treatment options,” said Professor Benjamin Solomon, lead investigator and medical oncologist at Peter MacCallum Cancer Centre, Melbourne, Australia. “Controlling brain metastases is very important to these patients and an especially challenging aspect of treating this disease. We saw excellent intracranial responses in all patient groups, including those who were heavily pretreated.”

“Lorlatinib is an extraordinary example of what can be achieved through translational research and precision medicine development. Recall that Xalkori (crizotinib) was the first drug approved for patients with ALK-positive and ROS1-positive NSCLC. By understanding the mutations that occurred in patients that rendered their tumors resistant to Xalkori and other ALK inhibitors, medicinal chemists working at Pfizer were able to design a molecule with the potential to overcome that resistance and inhibit ALK despite these mutations. We are very encouraged by the results of this Phase 2 trial that provide the first clinical evidence of the activity of lorlatinib in this setting,” said Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development.

The Phase 2 study examined the antitumor activity and safety of lorlatinib in 275 patients with or without asymptomatic, untreated or treated brain metastases. Patients were enrolled in six cohorts based on biomarker (ALK-positive or ROS1-positive) and prior therapy. The primary endpoints were objective response rate (ORR) and intracranial ORR (IC-ORR) confirmed by independent central review (ICR). Results by clinically relevant groups showed:

ALK-positive treatment-naïve: ORR was 90% (27/30; 95% CI: 74, 98) and IC-ORR was 75% (6/8; 95% CI: 35, 97).

ALK-positive previously treated with crizotinib with or without chemotherapy: ORR was 69% (41/59; 95% CI: 56, 81) and IC-ORR was 68%(25/37; 95% CI: 50, 82).

ALK-positive previously treated with a non-crizotinib ALK inhibitor with or without chemotherapy: ORR was 33% (9/27; 95% CI: 16, 54) and IC-ORR was 42% (5/12; 95% CI: 15, 72).

ALK-positive previously treated with two or three prior ALK inhibitors with or without chemotherapy: ORR was 39% (43/111; 95% CI: 30, 49) and IC-ORR 48% (40/83; 95% CI: 37, 59).

ROS1-positive regardless of prior treatment: ORR was 36% (17/47; 95% CI: 23, 52) and IC-ORR was 56% (14/25; 95% CI: 35, 76).

Lorlatinib was generally tolerable. Most adverse events were mild to moderate and were managed by dose reductions or delay or with standard medical therapy. There were no treatment-related deaths and a low (3%) rate of discontinuation due to drug-related adverse events. The most common adverse events were: hypercholesterolemia (81%), hypertriglyceridemia (60%), edema (43%), peripheral neuropathy (30%), weight increase (18%), cognitive effects (18%), mood effects (15%), fatigue (13%), diarrhea (11%), arthralgia (10%), and increased AST (10%).

The Phase 2 data will form the basis of discussions with global regulatory authorities, including the U.S. Food and Drug Administration. On April 26, 2017, the FDA granted Breakthrough Therapy designation for lorlatinib for the treatment of patients with ALK-positive metastatic NSCLC previously treated with one or more ALK inhibitors.

Pfizer Oncology continues to build on its heritage in biomarker-driven therapies by investigating novel targeted therapies and immunotherapy combination approaches aimed at addressing significant unmet needs for patients. In addition to the lorlatinib results, Pfizer will present data at the conference from studies examining its current and investigational lung cancer medicines:

Plasma genomic profiling and outcomes of patients with MET exon-14 altered NSCLC treated with crizotinib on PROFILE 1001 (Late-breaker oral presentation: Abstract #OA 12.06)

First-line dacomitinib versus gefitinib in advanced non-small cell lung cancer with EGFR mutation subgroups (Oral presentation: Abstract #OA 05.01)

Next-generation sequencing shows mechanisms of intrinsic resistance in ALK-positive NSCLC patients treated with crizotinib (Poster presentation: Abstract #P1.01-016)

Dacomitinib versus gefitinib for first-line treatment of advanced EGFR NSCLC in Japanese patients (ARCHER 1050) (Poster presentation: Abstract #P3.01-072)

Symptom impact of first-line dacomitinib versus gefitinib in EGFR-positive NSCLC: Results from a randomized phase 3 study (Poster presentation: Abstract #P3.01-012)