Analysis of Capmatinib Response in Advanced NSCLC Patients With METex14 Mutation

The METex14 mutation is a driver mutation observed in approximately 3-4% of non-small cell lung cancer cases. This mutation is typically observed without other driver mutations and is linked to an unfavorable prognosis. Capmatinib is a potent and highly selective inhibitor of the MET protein, which has demonstrated antitumor activity in patients with advanced non-small cell lung cancer (NSCLC) harboring METex14 mutations. This includes patients with central nervous system (CNS) involvement, both those who have received prior treatment and those who have not. This study represents the initial comprehensive transcriptome analysis of patients who underwent capmatinib therapy as part of the GEOMETRY Mono-1 clinical trial (NCT02414139). Patients diagnosed with advanced NSCLC with METex14 mutation were administered oral capmatinib at 400 mg twice daily.

Messenger RNA (mRNA) was extracted and enriched from the baseline tumor samples, followed by sequencing. The study evaluated the variance in MET and PD-L1 expression between individuals who responded and those who did not respond to treatment, as per main RECIST 1.1 criteria, using a t-test. A gene set enrichment analysis was conducted, taking into account the patient’s prior therapy status, estimated tumor purity score, and false discovery rate. A multivariate regression analysis was performed to establish a correlation between the expression of MET and gene expression signatures (GES) about tumor response.

RNA sequencing successfully profiled baseline tumor biopsies from 111 out of 160 patients with METex14 non-small cell lung cancer. Among these patients, 41 received capmatinib as a first-line treatment, while 70 received it as a second or third-line treatment. The baseline expression of MET and PD-L1 was comparable between the first-line and dual/third-line patients. Elevated baseline MET expression levels (above the median value) exhibited a significant correlation with the most favorable overall response in first-line patients (with a nominal P< 0.01). A similar tendency was observed in second or third-line patients (with a nominal P=0.08). Patients with high MET expression in the first-line setting exhibited a statistically significant prolongation in progression-free survival (PFS) compared to those with low MET expression (P<0.01, Cox proportional hazards model). There was no observed correlation between PD-L1 expression and response. The gene expression signature (GES) related to cell proliferation significantly correlated with treatment response. However, after adjusting for the expression of MET through multivariate regression analysis, it was found that the GES was not an independent predictor of treatment response. A comprehensive transcriptome analysis was conducted on baseline METex14 non-small cell lung cancer (NSCLC) tumors from patients who received capmatinib treatment. The study revealed that a higher baseline expression of MET was significantly correlated with a favorable response.

The study conducted by Socinski et al. in the Journal of Clinical Oncology Precision Oncology 2021, with a DOI of https://doi.org/10.1200/PO.20.00516, is noteworthy. The research conducted by Wolf et al. in the New England Journal of Medicine 2020, with a DOI of https://doi.org/10.1056/NEJMoa2002787, is significant. The study conducted by Koshihara et al. in Nature Communications 2013, with a volume of 4 and page number 2612, is noteworthy.

Source:https://oncologypro.esmo.org/meeting-resources/esmo-congress/response-to-capmatinib-in-patients-pts-with-advanced-non-small-cell-lung-cancer-nsclc-and-met-exon-14-skipping-metex14-mutation-whole-transc

Clinical Trial:https://clinicaltrials.gov/ct2/show/NCT02414139

J. Wolf, H.J.M. Groen, D.S.W. Tan, E.B. Garon, D. Demanse, A. Robeva, A. Yovine, L. Fairchild, A.D. Boran, R. Heist/Response to capmatinib in patients (pts) with advanced non-small cell lung cancer (NSCLC) and MET exon 14 skippings (METex14) mutation: Whole transcriptome analysis from phase II GEOMETRY Mono-1 study/Annals of Oncology (2022) 33 (suppl_7): S448-S554. 10.1016/annonc/annonc1064