Efficacy and Tolerability of ALK/MET Combinations in Patients With ALK-Rearranged Lung Cancer With Acquired MET Amplification: A Retrospective Analysis.

Introduction: MET amplification is a potentially actionable resistance mechanism in ALK-rearranged (ALK+) lung cancer. Studies describing treatment outcomes of this molecular subgroup are lacking. Methods: We assembled a cohort of patients with ALK+ lung cancer and acquired MET amplification (identified by tissue or plasma) who received regimens targeting both ALK and MET. Efficacy and safety were assessed using the Response Evaluation Criteria in Solid Tumors version 1.1 and Common Terminology Criteria for Adverse Events version 4.03, respectively. Results: A total of 12 patients were included in the series. MET amplification was detected after a median of 1.5 (range 1-5) lines of therapy. Four distinct regimens were implemented to address MET amplification: crizotinib (n = 2), lorlatinib plus crizotinib (n = 6), alectinib plus capmatinib (n = 3), and alectinib plus crizotinib (n = 1). Partial responses were observed in five (42%) of 12 patients, including patients who received crizotinib (n = one of two), lorlatinib plus crizotinib (n = three of six), and alectinib plus capmatinib (n = one of three). Primary progression was observed in four patients (33%). Grades 1 to 2 peripheral edema, occurring in seven (58%) patients, was found with both crizotinib and capmatinib. One patient required dose reduction of capmatinib plus alectinib for persistent grade 2 edema. Across the regimens, one patient discontinued therapy for toxicity, specifically neurocognitive toxicity from lorlatinib plus crizotinib. At progression on ALK+ MET therapy, potential resistance mechanisms included MET copy number changes and ALK kinase domain mutations. Conclusions: Combined ALK and MET inhibition is associated with moderate antitumor activity in patients with ALK+ NSCLC with concurrent MET amplification. Prospective studies are indicated to confirm activity and identify individuals most likely to benefit from the treatment.

Factors Associated With Developing Neurocognitive Adverse Events in Patients Receiving Lorlatinib After Progression on Other Targeted Therapies.

INTRODUCTION: The safety profile of lorlatinib includes neurocognitive adverse events (NAEs). Baseline factors associated with developing NAEs remain poorly characterized. METHODS: Records from patients who received lorlatinib through prospective studies at Massachusetts General Hospital (MGH, n = 124) or the phase 1/2 B7461001 (NCT01970865; n = 248) study were reviewed to identify potential associations between comorbidities, baseline medications, and NAEs. RESULTS: Most patients experienced a NAE (MGH: 60%, B7461001: 49%). Cognitive effects occurred in 40% and 29% of patients in the MGH and B7461001 cohorts, respectively. Brain metastases (p = 0.008), brain radiation (p = 0.033), psychiatric illness (p = 0.008), psychiatric medications (p < 0.001), antiepileptics (p < 0.001), and stimulants (p = 0.026) were associated with developing cognitive effects in B7461001. Mood effects occurred in 36% and 23% of patients in the MGH and B7461001 cohorts, respectively. In the MGH cohort, psychiatric illness (p = 0.02) and stimulants (p = 0.01) were associated with developing mood effects whereas brain surgery (p = 0.020), psychiatric medications (p < 0.001), benzodiazepines (p = 0.002), and sedatives (p = 0.034) were associated with developing mood effects in B7461001. Psychotic effects were infrequent (MGH: 3%, B7461001: 9%) and were associated with brain surgery in the MGH cohort (p = 0.001) and age in B7461001 (p = 0.014). Speech effects were observed in 23% and 11% of patients in the MGH and B7461001 cohorts, respectively. Brain radiation (p = 0.012) and antiepileptics (p < 0.001) were associated with speech effects in B7461001. Dose reductions were implemented for 52% and 18% of patients with NAEs in MGH and B7461001 cohorts, respectively, with mitigating effect. CONCLUSIONS: Neurocognitive effects from lorlatinib are common. Lorlatinib-related NAEs may be influenced by multiple factors, including brain metastases, brain radiation, psychiatric illness, and use of neurotropic medications.

A Phase 2 Study of Lorlatinib in Patients With ROS1-Rearranged Lung Cancer With Brain-Only Progression on Crizotinib.

Introduction: The central nervous system (CNS) is a common site of progression among patients with ROS1-rearranged lung cancer receiving crizotinib. We conducted a phase 2 study to evaluate the intracranial efficacy of lorlatinib in patients with ROS1-rearranged lung cancer who developed CNS-only progression on crizotinib. Methods: Patients with metastatic ROS1-rearranged lung cancer with CNS-only progression on crizotinib received lorlatinib 100 mg daily. The primary end point was intracranial disease control rate at 12 weeks per modified Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included intracranial and extracranial progression-free survival, intracranial objective response rate, and safety/tolerability. Results: A total of 16 patients were enrolled between November 2016 and January 2019. Nine patients (56%) had received prior CNS radiation, with a median of 10.9 months between radiation and lorlatinib. At 12 weeks, the intracranial disease control rate was 100% and intracranial objective response rate was 87%. While on study, the complee intracranial response rate was 60%. With median follow-up of 22 months, seven patients experienced disease progression, including five patients with CNS relapse. The median intracranial and extracranial progression-free survivals were 38.8 months (95% confidence interval: 16.9-not reported) and 41.1 months (95% confidence interval: 17.6-not reported), respectively. Molecular analysis of plasma or tissue from patients with extracranial progression on lorlatinib revealed ROS1 G2032R (n = 1), ROS1 L2086F (n = 1), and CCDC6-RET fusion plus ROS1 G2032R (n = 1). The safety profile of lorlatinib was consistent with prior studies. There were 11 patients (69%) who required dose reduction, including one patient who discontinued treatment for grade 3 edema. No grade greater than or equal to 4 adverse events were observed. Conclusions: Lorlatinib induced durable intracranial responses in patients with ROS1-rearranged NSCLC and prior isolated CNS progression on crizotinib.