Management of advanced non-small cell lung cancer with MET-exon-14-skipping alterations: challenges remain after the Chrysalis study

Since the first reports of mesenchymal-to-epithelial transition (MET) exon-14 (METex14) mutations in primary lung cancer samples, more than 500 different mutations have been reported. According to a systematic literature review (1), METex14-skipping was found in 2.0% of unselected non-small cell lung cancers (NSCLCs), ranging from 2.4% to 2.6% of adenocarcinoma or non-squamous subgroups, 1.3% of squamous histology, and 12.0% to 31.8% of sarcomatoid carcinomas. Typically, patients with tumors harboring METex14-skipping mutations are 70 years old or older and often have a history of tobacco use (1-3). METex14-skipping is mutually exclusive with other known proto-oncogenic genes. Notably, METex14-mutation, indicative of a dominant role of the mutant c-MET in driving tumor development, was not found in normal human lung samples (3). Importantly, METex14 mutations and MET amplification are associated with poor prognoses, and those MET alterations can be found together, with the co-occurrence rate ranging from 0% to 40.5% (3).

Several targeted therapies have shown relevant efficacies in these patients. The first, studied as of 2014, was crizotinib. Among the 69 patients with crizotinib-treated advanced NSCLCs harboring METex14 alterations, 62% as second-line-or-more therapy, 65 (94.2%) could be evaluated. Crizotinib obtained an overall response rate (ORR) of 32% [95% confidence interval (CI): 21–45%], with 5% complete responses (CRs) and 28% partial responses (PRs); 45% of the patients had stable disease (4,5). Then highly specific, second-generation targeted therapies against c-MET became available (6,7).

The non-randomized, multi-cohort, open-label, phase 2 GEOMETRY mono-1 trial (6), conducted in 95 centers in 20 countries, tested capmatinib efficacy against advanced NSCLC harboring METex14-skipping. Its final outcomes were: ORRs in 41 (68%; 95% CI: 55.0–79.7%) of 60 treatment-naïve patients and 44 (44%; 95% CI: 34.1–54.3%) of 100 previously treated patients. Median progression-free survival (PFS) lasted 12.5 months (95% CI: 8.3–18.0) and 5.5 months (95% CI: 4.2–8.1), respectively, for naïve and previously treated patients. A post-hoc analysis (6) showed high intracranial activity of brain metastases, in the 13 evaluated patients; about 92% of patients had intracranial disease control and 54% had intracranial responses, with 31% of the patients achieving CRs.

Tepotinib is another second-generation tyrosine-kinase inhibitor (TKI) that has obtained encouraging results (7). In the framework of a non-comparative, phase 2 study, among the 99 patients with advanced NSCLC carriers of METex14-skipping, the ORR was 46% (95% CI: 36–57%); all responses were partial, with no patient having a CR; ORRs were similar, regardless of the number of previous therapy lines. The US Food and Drug Administration approved capmatinib and tepotinib in 2020 and 2021, respectively, under accelerated approval, and they are currently considered first-line therapies for NSCLC patients with METex14 mutations (8).

Finally, the Chrysalis trial results demonstrated amivantamab efficacy in these patients (9). Amivantamab, a human, bispecific antibody that simultaneously targets the epidermal growth factor receptor (EGFR) and c-MET genes, is currently approved to treat NSCLC patients with an EGFRex20-insertion mutation. Amivantamab’s bispecificity enables it to bind to two different antigens or epitopes, making it a potential candidate agent to treat METex14-skipping tumors. In that non-randomized, phase 2 study, the 97 participants—16 treatment-naïve, 28 with prior treatment but not anti-MET therapies and 53 with prior anti-MET therapies—their respective ORRs were: 32% overall, 50%, 46% and 19%, with observed clinical benefit rates of 88%, 64% and 66%, respectively. Median duration of response (DoR) was 11.2 months; median PFS was 5.3 months (95% CI: 4.3–7.0) and median overall survival (OS) lasted 15.8 months (95% CI: 14.6–not reached). The most common adverse events were rash (79%) and infusion-related reactions (72%), mostly grades 1–2 (52%). Thus, amivantamab is another therapeutic option for patients with advanced NSCLCs harboring METex14-skipping mutations, including those who progressed on prior anti-MET therapies (9,10).

Beyond those results, what are the clinical challenges today of managing patients with advanced NSCLCs harboring METex14-skipping mutations? The first is that all patients managed for metastatic NSCLCs have access to molecular testing. Under-prescription of testing persists, as shown by the American Surveillance, Epidemiology, and End Results (SEER) study findings (11). Among 28,511 NSCLC patients analyzed, only 39.3% had benefited from diagnostic molecular testing, with particularly marked race and place-of-residence access disparities. More importantly, that same study’s results confirmed the significantly lower risk of death for tested patients. Beyond access, management organization should also assure that test results be obtained in time compatible with starting first-line therapy.

The second challenge is, as for other groups of patients with oncogenic mutation(s), the therapeutic sequence, especially first-line efficacy for patients receiving immunotherapy combined or not with platin-based chemotherapy. The efficacy of immune checkpoint inhibitors in these patients remains controversial. The most informative results come from a German retrospective series (12). Among the 110 consecutive NSCLC patients with METex14-skipping mutations who had received first-line chemotherapy (ChT) and/or immunotherapy (IO) in 10 German centers between 2016 and 2022, compared to ChT, ChT–IO obtained longer median PFS (6 vs. 2.5 months, p=0.004), higher ORR (49% vs. 28%, P=0.086) and a trend towards longer OS (16 vs. 10 months, P=0.240). For IO monotherapy, OS (14 vs. 16 months) and DoR (26 vs. 22 months) were comparable to those of ChT–IO recipients. Primary progressive disease was more frequent with IO than ChT–IO, especially for never-smokers. Higher programmed death-ligand-1 tumor proportion scores were not associated with better IO outcomes. However, according to multivariable analyses, tumor protein-53 (TP53)-mutated tumors achieved higher ORRs (56% vs. 32%, P=0.088) and longer PFS (6 vs. 3 months, P=0.160), and longer OS. Almost half of the patients (35/75, 47%) received second-line therapy: median OS was longer for capmatinib or tepotinib than crizotinib (16 vs. 13 months, P=0.27; with PFS 10 vs. 3 months, P=0.013). After first-line therapy, IO was able to obtain durable responses but no clinical phenotype could be clearly established (13). The therapeutic sequence choice (IO first or targeted therapy) should also consider the probable risk of over-toxicity when targeted therapy closely follows IO (14).

The third issue is mastering new toxicities induced by these new therapeutic agents and the vigilance necessary when these agents are administered routinely to older patients with more comorbidities than those included in the clinical trials. Common adverse events associated with amivantamab included cutaneous reactions, diarrhea, infusion-related reactions, vascular thrombosis and pneumonitis (15). Its subcutaneous injection which will become the new standard-of-use, considerably limits those events (16). For the MET-selective TKIs, the more frequent adverse events were gastrointestinal disorders, respiratory toxicity, hepatotoxicity, and metabolism and nutrition disturbances. Particularly notable were peripheral edema, nausea, dysphagia, fatigue and dyspnea, which were as the five most frequently reported adverse events (17). Pertinently, capmatinib and the rates of hearing loss or swallowing difficulty were significantly associated. More exceptionally, cases of severe maculopapular rash associated with MET-inhibitory have been described (18). The majority of those toxicities occurred within the first months following treatment onset. Attentive monitoring and the implementation of supportive care strategies are essential to managing toxicities (17). Certainly, closer monitoring of treatment-related adverse events is mandatory, as older participants (over 75 years old) had more frequent frequencies of higher-grade (grade 3 or higher) events than younger patients.

Finally, as with other therapies, cancer cells can develop resistance to c-MET-targeting agents through a variety of on- and off-target mechanisms. Secondary mutations identified in the kinase domain of METex14-skipping NSCLCs have been associated with resistance to c-MET inhibitors. For example, secondary mutations in the A-loop residues D1228 and Y1230 have been found to increase resistance to type-1 c-MET inhibitors by altering ATP-binding in the kinase domain (10), and make re-biopsy and/or liquid biopsies necessary at progression (19).

In conclusion, Chrysalis trial results showed that amivantamab is a major therapeutic option for the management of patients with advanced NSCLCs harboring METex14-skipping mutations—as much for first- as second-line-and-more therapy—including when patients have previously received anti-MET agents. Additional studies are needed to better understand the heterogeneity of this population and to determine the most effective and best tolerated therapeutic sequence.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease. The article has undergone external peer review.

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1784/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1784/coif). C.C. declares grants, travel expenses, consulting with AZ, BI, GSK, Roche, Sanofi Aventis, BMS, MSD, Lilly, Novartis, Pfizer, Takeda, Bayer, Janssen and Amgen. Jean-Baptiste Assié declares grants, travel expenses, consulting with BMS, GSK and Sanofi. Jean-Bernard Auliac declares grants, travel expenses, consulting with Boehringer Ingelheim, Hoffman-Roche, Takeda, BMS, MSD, Astra Zeneca, Amgen, Janssen and Pfizer. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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