Frontline Lorlatinib Induces 90% Response in ALK+ NSCLC

Benjamin Solomon, MBBS, PhD

Lorlatinib induced an objective response rate (ORR) of 90% (27/30; 95% CI, 74-98) in treatment-naïve patients with ALK-positive non—small cell lung cancer (NSCLC). Intracranial ORR (IC-ORR) was 75% (6/8; 95% CI, 35-97) in this population, according to Pfizer, the developer of the next-generation ALK/ROS1 tyrosine kinase inhibitor (TKI).

The findings were part of data from a phase II study presented at the 18th World Conference on Lung Cancer (WCLC) demonstrating activity with lorlatinib across a range of patients with ALK-positive and ROS1-positive advanced NSCLC.¹

“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,” Benjamin Solomon, MBBS, PhD, lead investigator and medical oncologist at Peter MacCallum Cancer Centre, Melbourne, Australia, said in a press release.

In the study, 275 patients with or without asymptomatic, untreated or treated brain metastases were enrolled in 6 cohorts based on biomarker, ALK-positive or ROS1-positive, and prior therapy.

ORR was 69% (41/59; 95% CI, 56-81) in ALK-positive patients previously treated with crizotinib (Xalkori) with or without chemotherapy, and IC-ORR was 68% (25/37; 95% CI, 50-82). ALK-positive patients previously treated with a non-crizotinib ALK inhibitor with or without chemotherapy had an ORR of 33% (9/27; 95% CI, 16-54) and the IC-ORR was 42% (5/12; 95% CI, 15-72). In ALK-positive patients previously treated with 2 or 3 ALK inhibitors with or without chemotherapy, ORR was 39% (43/111; 95% CI, 30-49) and IC-ORR was 48% (40/83; 95% CI, 37-59).

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

“Controlling brain metastases is very important to these patients and an especially challenging aspect of treating this disease,” said Solomon, who presented the results at the conference. “We saw excellent intracranial responses in all patient groups, including those who were heavily pretreated.”

Lorlatinib was generally tolerable, Pfizer reported in its press release. Most adverse events (AEs) were mild to moderate and managed with dose reductions, dose delays, or standard medical therapy. There were no treatment-related deaths and 3% of patients discontinued treatment due to drug-related AEs.

Hypercholesterolemia (81%) was the most common AE, followed by 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%).

Investigators are continuing their research into lorlatinib in NSCLC in the phase III CROWN trial, which began enrolling patients earlier this year. CROWN is an ongoing, open-label, randomized, 2-arm study comparing lorlatinib to crizotinib in the first-line treatment of patients with metastatic ALK-positive NSCLC.

In April 2017, the, FDA granted a breakthrough therapy designation to lorlatinib for use in patients with ALK-positive metastatic NSCLC who have previously received 1 or more ALK inhibitors. The designation was based on phase I/II data for 54 patients that were presented at the 17th World Conference on Lung Cancer. ²

The population included 41 patients who were ALK-positive, 12 who were ROS1-positive, and the mutation status of 1 patient was not recorded at the January 2016 cutoff.

The ORR was 47%, with 3 compete responses (CRs) and 22 partial responses (PRs). The ORR was 57% for ALK-positive patients with 1 prior TKI treatment (n = 14), with 1 CR (7%) and 7 PRs (50%). For ALK-positive patients with ≥2 prior TKI treatments (n = 26), ORR was 42% with 2 CRs (8%) and 9 PRs (34%).

For patients with target and nontarget lesions (n = 39) intracranial ORR was 36%. Ten patients had complete response (CR; 26%) and 1 had unconfirmed CR, while 4 patients (10%) had partial response (PR) and 2 others had unconfirmed PR.

Among patients with target lesions (n = 23), intracranial ORR was 47%. Seven patients (30%) had CR while 4 (17%) had PR and 2 others had unconfirmed PR.

Median duration of response was 10.5 months (95% CI 2.9— not reached [NR]) among ALK-positive patients and 12.4 months (95% CI 6.5—NR) among ALK+/ROS1+ patients.

References

1. Solomon BJ, Shaw A, Ignatius Ou S-H, et al. Phase 2 Study of lorlatinib in patients with advanced ALK+/ROS1+ non-small-cell lung cancer. Presented at: the IASLC 18th World Conference on Lung Cancer; October 15-18; Yokohama, Japan. Abstract 8573.
2. Felip E, Bauer TM, Solomon B, et al. Safety and efficacy of lorlatinib (PF-06463922) in patients with advanced ALK+ or ROS1+ non-small-cell lung cancer (NSCLC). Presented at: 17th World Conference on Lung Cancer; Dec. 4-7, 2016; Vienna, Austria. Abstract MA07.11.