Immune checkpoint inhibitor (ICI) therapy prolonged overall survival (OS) compared with chemotherapy in patients with MET-amplified non–small cell lung cancer (NSCLC); however, the survival benefit did not appear to extend to patients with a MET exon 14 (METex14) mutation. These findings, from a cohort study, were published in the Journal of Thoracic Oncology.
MET alterations are heterogenic in NSCLC. Whereas some tumors harbor MET amplifications, approximately 3% to 4% harbor METex14. MET kinase inhibitors have demonstrated efficacy against tumors harboring METex14, but their role against tumors with MET amplifications is less clear. The study authors therefore sought to “analyze a real-world cohort of patients with advanced NSCLC and METex14 or MET amplification.”
The investigators evaluated 337 tumor specimens from patients with stage IIIB or IV NSCLC with a MET alteration who were diagnosed with NSCLC at a single center in Cologne, Germany between 2015 and 2018. Next-generation sequencing, fluorescence in-situ hybridization, and immunohistochemistry were used to assess alterations, co-occurring mutations, and PD-L1 expression.
METex14 alterations were present in 17.5% of the specimens. Of these patients, 32.2% harbored both a METex14 skipping mutation and a MET amplification; these patients were classified as having MET mutations.
MET amplifications were present in 82.4% of specimens, including 43.9% with low-level amplification (gene copy number [GCN] <4), 7.1% with intermediate-level amplification (GCN=4-5), 9.2% with category I high-level amplification (MET/CEN7 ratio ≥2 and GCN < 6), 12.2% with category II high-level amplification (GCN=6-9), and 10.1% with category III high-level amplification (GCN ≥10).
None of the tumors harbored EGFR, ALK, or ROS1 alterations, but 12 tumors carried BRAF mutations. High PD-L1 expression (≥50%) was found in 34.8% of the 227 patients assessed for PD-L1 status. There was no difference in expression level between specimens with METex14 vs MET amplification. Similarly, there was also no difference between the different levels of MET amplification.
For the OS analysis, patients were separated into cohorts based on MET amplification level or the presence of METex14. At a median follow-up of 34 months, the median OS was 12.0 months (95% CI, 9.4-14.6) in cohort A (MET amplification; GCN<10), 4.0 months (95% CI, 1.9-6.0) in cohort B (MET amplification; GCN≥10), and 10.0 months (95% CI, 6.9-13.0) in cohort C (METex14). There was no significant difference in OS between the cohorts.
Patients with MET amplifications who received ICIs either as monotherapy or in combination with chemotherapy were found to experience prolonged OS compared with patients who received chemotherapy alone. Among patients with low to high MET amplification (GCN <10), the median OS was 19.0 months with ICI therapy vs 8.0 months with chemotherapy (P <.0001). Among patients with very high levels of amplification (GCN ≥10), the median OS was 36.0 months with ICIs compared with 4.0 months with chemotherapy (P =.004). However, “no significant difference” in median OS was seen with ICI therapy or chemotherapy in patients with METex14 (16.0 months vs 10.0 months; P =.147).
Patients with MET amplification “have a survival benefit with immunotherapy compared with chemotherapy alone,” the study authors said, adding that “future studies will have to focus on the definition of patients that benefit from immunotherapy or targeted therapy.”
Disclosure: Some of the study authors disclosed financial relationships with the pharmaceutical industry and/or the medical device industry. For a full list of disclosures, please refer to the study.
Kron A, Scheffler M, Heydt C, et al. Genetic heterogeneity of MET-aberrant non-small cell lung cancer and its impact on the outcome of immunotherapy. J Thorac Oncol. Published online December 9, 2020. doi:10.1016/j.jtho.2020.11.017