Combination therapy with lorlatinib and mitogen-activated protein kinase pathway inhibition in previously treated
Jaime L Schneider1, Alona Muzikansky2, Elizabeth Krueger2
1Massachusetts General Hospital Cancer Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA.
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.
Insights
This study combined lorlatinib with MEK or SHP2 inhibitors for ALK/ROS1 NSCLC, finding limited efficacy and progression in most patients. Further research is needed for effective, biomarker-driven treatments.
Area of Science:
- Oncology
- Molecular Biology
- Clinical Trials
Background:
- Anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1 (ROS1) rearranged non-small cell lung cancers (NSCLC) often develop resistance via mitogen-activated protein kinase (MAPK) pathway activation.
- Targeting bypass resistance mechanisms is crucial for improving treatment outcomes in ALK/ROS1 NSCLC.
Purpose of the Study:
- To evaluate the efficacy and safety of combining the ALK/ROS1 inhibitor lorlatinib with MAPK pathway inhibitors (binimetinib or TNO155).
- To determine the recommended phase 2 dose for these combination regimens in patients with advanced NSCLC.
Main Methods:
- A Phase IB, 3+3 design clinical trial.
- Patients with ALK/ROS1-positive NSCLC who progressed on prior ALK/ROS1 inhibitors received lorlatinib combined with either binimetinib (MEK inhibitor) or TNO155 (SHP2 inhibitor).
- Primary objectives included dose determination and objective response rate (ORR); secondary endpoints included safety, tolerability, and progression-free survival (PFS).
Main Results:
- The combination of lorlatinib and binimetinib showed limited efficacy, with one partial response (6.7%) and stable disease in eight patients (53.3%) among 15 evaluable patients.
- Median PFS for the lorlatinib-binimetinib arm was 51 days; common adverse events included rash, edema, and lipid abnormalities.
- The lorlatinib-TNO155 arm had too few patients for robust evaluation due to early treatment discontinuation for disease progression and pleural effusions.
Conclusions:
- Co-targeting the MAPK pathway with lorlatinib demonstrated limited efficacy in unselected patients with lorlatinib-resistant NSCLC.
- The study was terminated early due to slow accrual, preventing the phase 2 component.
- Biomarker-informed strategies are essential for developing more effective treatments for resistant NSCLC.
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