Next-Generation ALK/ROS1 Inhibitor Lorlatinib Shows Strong, Durable Responses in Advanced NSCLC

TON Web Exclusives - Lung Cancer

Resistance to treatment and tumor complexity make disease progression—which frequently occurs in the brain—a challenge for patients with metastatic non–small-cell lung cancer (NSCLC) and ALK mutations.1 Lorlatinib, an investigational, next-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), was designed to inhibit tumor mutations that help create resistance to other ALK inhibitors, and to penetrate the blood–brain barrier.1,2 Granted breakthrough therapy designation from the FDA in April 2017 for the treatment of patients with ALK-positive, metastatic NSCLC who received previous treatment with ≥1 ALK inhibitors, lorlatinib showed promise in this patient population, whose treatment options are limited.2,3

Demonstrating clinically meaningful activity against lung tumors and brain metastases with manageable side effects, lorlatinib appears effective in treating patients with ALK-positive NSCLC, according to lead investigator Benjamin Solomon, MBBS, PhD, FRACP, medical oncologist, Peter MacCallum Cancer Centre, Melbourne, Australia, who presented the results of a phase 2 study of lorlatinib at the International Association for the Study of Lung Cancer 18th World Conference on Lung Cancer in Yokohama, Japan.3

“Controlling brain metastases is very important to these patients and an especially challenging aspect of treating this disease,” Dr Solomon said. “We saw excellent intracranial responses in all patient groups, including those who were heavily pretreated.”3

Dr Solomon and colleagues enrolled 275 patients with NSCLC, with or without asymptomatic central nervous system metastases, in 6 expansion cohorts. Treatment arms 1 through 5 were comprised of patients with ALK-positive NSCLC stratified by prior treatment, and treatment arm 6 consisted of patients with ROS1-positive disease.3,4 The study’s primary end points were objective response rate (ORR) and intracranial ORR (IC-ORR) by independent central review.3,4 The investigators also assessed safety, patient-reported outcomes, and molecular profiling.4 All patients received lorlatinib 100 mg once daily.4

In treatment-naïve patients with ALK mutations, the ORR was 90% (27/30; 95% confidence interval [CI], 74-98) and the IC-ORR was 75% (6/8; 95% CI, 35-97).3,4 Among the remaining ALK-positive cohorts, patients who had received previous crizotinib therapy alone had a 74% ORR (20/27) and a 59% IC-ORR (10/17); those who had received 1 prior ALK TKI, with or without chemotherapy, had a 51% ORR (30/59) and a 63% IC-ORR (20/32); patients who had received prior crizotinib with chemotherapy had an ORR of 66% (21/32) and an IC-ORR of 75% (15/20); those who had received any ALK TKI other than crizotinib, with or without chemotherapy, had an ORR of 33% (9/27; 95% CI, 16-54) and an IC-ORR of 42% (5/12; 95% CI, 15-72); those who had received 2 prior ALK TKIs, with or without chemotherapy, had an ORR of 42% (27/65) and an IC-ORR of 56% (25/45); and those who had received 3 prior ALK TKIs, with or without chemotherapy, had an ORR of 35% (16/46) and an IC-ORR of 39% (15/38).4

In the ROS1-positive cohort, regardless of previous treatment, the ORR was 36% (17/47; 95% CI, 23-52) and IC-ORR was 56% (14/25; 95% CI, 35-76).3

The most common treatment-related adverse events (TRAEs) and grade 3/4 TRAEs were hypercholesterolemia (81% and 16%, respectively) and hypertriglyceridemia (60% and 16%, respectively).4 Of the patients who reported TRAEs, 30% required dose interruptions and 22% required dose reductions.4 Treatment discontinuation because of TRAEs occurred in 3% (7) of patients; no treatment-related deaths occurred.4 At data cutoff, 57% (157/275) of patients remained on treatment.4 Most patients reported stable or improved global quality of life (40% and 43%, respectively).4

The investigators concluded that lorlatinib showed clinically meaningful activity among patients who were ALK/ROS1-positive and either treatment-naïve or had experienced treatment failure with ≥1 ALK TKIs.4 Lorlatinib was generally well-tolerated, with most TRAEs being mild to moderate and manageable with dose delay or reduction, or with standard medical therapy.3 The open-label, randomized, phase 3 CROWN study of lorlatinib versus crizotinib in the first-line setting for patients with metastatic ALK-positive NSCLC is ongoing.3

References
1. Lorlatinib [fact sheet]. New York, NY: Pfizer, Inc; May 2017.
2. Pfizer’s next-generation ALK/ROS1 inhibitor, lorlatinib, granted breakthrough therapy designation from FDA for ALK-positive metastatic non-small cell lung cancer. April 2017. http://press.pfizer.com/press-release/pfizers-next-generation-alkros1-inhibitor-lorlatinib-granted-breakthrough-therapy-desi. Accessed January 13, 2018.
3. Pfizer presents full results from phase 2 study of next-generation investigational ALK-inhibitor lorlatinib in ALK-positive and ROS1-positive advanced non-small cell lung cancer. October 16, 2017. www.pfizer.com/news/press-release/press-release-detail/pfizer_presents_full_results_from_phase_2_study_of_next_generation_investigational_alk_inhibitor_lorlatinib_in_alk_positive_and_ros1_positive_advanced_non_small_cell_lung_cancer. Accessed January 13, 2017.
4. Solomon BJ, Shaw A, Ou SI, et al. Phase 2 study of lorlatinib in patients with advanced ALK+/ROS1+ non-small-cell lung cancer. Presented at the International Association for the Study of Lung Cancer 18th World Conference on Lung Cancer; October 2017; Yokohama, Japan. Abstract OA 05.06.

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Last modified: February 14, 2018