Combination therapy with lorlatinib and mitogen-activated protein kinase pathway inhibition in previously treated ALK- or ROS1-rearranged lung cancer

Abstract

Background

Anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1 (ROS1) rearranged non-small cell lung cancers (NSCLC) develop bypass resistance mechanisms that activate mitogen-activated protein kinase (MAPK) pathway signaling. We conducted a study to evaluate the ALK/ROS1 inhibitor lorlatinib combined with MAPK pathway inhibitors: binimetinib (MEK inhibitor) or TNO155 (SHP2 inhibitor).

Patients and methods

This phase IB study employed a 3 + 3 design. Patients who had disease progression on ALK or ROS1 inhibitors received lorlatinib (50 mg or 75 mg daily) with binimetinib (30 mg or 45 mg BID) or TNO155 (40 mg or 50 mg daily). The primary objective of phase 1 was determining the recommended phase 2 dose for the combinations. The primary objective of the phase 2 portion was determining the objective response rate (ORR) of each combination. Secondary endpoints included safety and tolerability and progression-free survival.

Results

In this phase IB clinical trial, 17 patients received lorlatinib and binimetinib; two patients received lorlatinib with TNO155. All patients with ALK + NSCLC had received prior lorlatinib. Among 15 evaluable patients in the lorlatinib-binimetinib cohort, one (6.7%) had a partial response (duration of response: 114 days), eight (53.3%) had stable disease, and six (40%) experienced primary progression. Median progression-free survival on lorlatinib-binimetinib was 51 days (95% CI 39–107). Treatment-related adverse events associated with lorlatinib-binimetinib were primarily grade 1–2, including rash (65%), edema (47%), and lipid abnormalities (47%). One patient discontinued treatment for grade 2 retinopathy. In the lorlatinib-TNO155 arm, both patients stopped treatment due to rapid disease progression and pleural effusions, limiting efficacy evaluation. The study was terminated due to slow accrual before advancing to the phase 2 component.

Conclusions

Regimens co-targeting the MAPK pathway and ALK or ROS1 had limited efficacy in unselected patients with lorlatinib-resistant NSCLC, underscoring the need for more effective and biomarker-informed treatment strategies.