First-line immunotherapy for lung cancer with MET exon 14 skipping and the relevance of TP53 mutations

• Published in: European journal of cancer (1990) Vol. 199; p. 113556
• Main Authors: Blasi, Miriam, Kuon, Jonas, Lüders, Heike, Misch, Daniel, Kauffmann-Guerrero, Diego, Hilbrandt, Moritz, Kazdal, Daniel, Falkenstern-Ge, Roger-Fei, Hackanson, Björn, Dintner, Sebastian, Faehling, Martin, Kirchner, Martina, Volckmar, Anna-Lena, Kopp, Hans-Georg, Allgäuer, Michael, Grohé, Christian, Tufman, Amanda, Reck, Martin, Frost, Nikolaj, Stenzinger, Albrecht, Thomas, Michael, Christopoulos, Petros
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2024
• Subjects: B7-H1 Antigen; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Exons; Humans; Immunotherapy; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Met exon 14 skipping; Mutation; TP53; Tumor Suppressor Protein p53 - genetics; Tyrosine kinase inhibitors; TP53; Lung cancer; Immunotherapy; Tyrosine kinase inhibitors; Met exon 14 skipping
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2024.113556

The efficacy of checkpoint inhibitors for non-small cell lung cancer (NSCLC) with MET exon 14 skipping (METΔ14ex) remains controversial. 110 consecutive METΔ14ex NSCLC patients receiving first-line chemotherapy (CHT) and/or immunotherapy (IO) in 10 German centers between 2016–2022 were analyzed. Combined CHT-IO was given to 35/110 (32%) patients, IO alone to 43/110 (39%), and CHT to 32/110 (29%) upfront. Compared to CHT, CHT-IO showed longer progression-free survival (median PFS 6 vs. 2.5 months, p = 0.004), more objective responses (ORR 49% vs. 28%, p = 0.086) and numerically longer overall survival (OS 16 vs. 10 months, p = 0.240). For IO monotherapy, OS (14 vs. 16 months) and duration of response (26 vs. 22 months) were comparable to those of CHT-IO. Primary progressive disease (PD) was more frequent with IO compared to CHT-IO (13/43 vs. 3/35, p = 0.018), particularly for never-smokers (p = 0.041). Higher PD-L1 TPS were not associated with better IO outcomes, but TP53 mutated tumors showed numerically improved ORR (56% vs. 32%, p = 0.088) and PFS (6 vs. 3 months, p = 0.160), as well as longer OS in multivariable analysis (HR=0.54, p = 0.034) compared to their wild-type counterparts. Any second-line treatment was administered to 35/75 (47%) patients, with longer survival for capmatinib or tepotinib compared to crizotinib (PFS 10 vs. 3 months, p = 0.013; OS 16 vs. 13 months, p = 0.270). CHT-IO is superior to CHT, and IO alone also effective for METΔ14ex NSCLC, especially in the presence of TP53 mutations and independent of PD-L1 expression, but never-smokers are at higher risk of primary PD. •Chemoimmunotherapy prolongs PFS compared to chemotherapy in METΔ14ex NSCLC.•IO monotherapy confer long responses and OS similar to that of CHT-IO.•PD-L1 expression does not correlate with immunotherapeutic efficacy.•TP53 mutations are linked to better IO outcomes and may assist therapeutic decisions.•The rate of second-line treatment in the real-world setting is approximately 50%.