Phase I and II Studies Give New Insights Into Targeting cMET in Advanced NSCLC

At ESMO Virtual Congress 2020, a number of studies reported promising results supporting the use of c-mesenchymal-epithelial transition factor (c-MET) inhibitors in some patients with advanced EGFR-mutated non-small-cell lung cancer (NSCLC). In two early phase trials, data show that MET inhibitors can be safely combined with other tyrosine kinase inhibitors (TKIs).

The phase I CHRYSALIS study investigated a combination of the EGFR-MET bispecific antibody amivantamab and the third-generation TKI lazertinib (Abstract 1258O). The overall response rate in treatment-naïve patients was 100% and in patients who failed osimertinib was 36%. Rash (85%), infusion-related reactions (65%) and paronychia (53%) were the main adverse events (AEs) and the incidence of grade ≥3 treatment-related events was 11%. In a phase Ib/II trial, overall response rates with the MET inhibitor capmatinib plus the TKI nazartinib demonstrated clinically relevant efficacy in pretreated MET-positive patients (objective response rate [ORR] 43.5%, n=23), compared with the pretreated whole subgroup (28.8%; n=52) and the pretreated MET-negative subgroup (27.9%; n=43) (Abstract 1284P). The most frequent treatment-related AEs among post-TKI-treated patients and treatment-naïve patients were, respectively, peripheral oedema (50.0% and 57.4%), nausea (42.3% and 48.9%) and diarrhoea (23.1% and 46.8%).

”These early data give indications that both agents are similarly active in pretreated EGFR-mutated NSCLC and have manageable toxicity profiles,” says Prof. Egbert Smit from the Netherlands Cancer Institute, Amsterdam, The Netherlands. “Given the comparable efficacy and toxicity profiles, while it is too early to speculate on the place of these agents in the treatment strategy for EGFR-mutated NSCLC, it may be that the orally administered capmatinib could offer more convenience for patients compared with the IV-administered amivantamab.”

Although emerging evidence suggests that MET inhibitors can play a role in the treatment of advanced NSCLC, identifying the patient subsets who may benefit from these agents is still a challenge due to the high molecular heterogeneity of NSCLC.

At the ESMO Virtual Congress 2020, extended analyses of two recently published phase II trials were presented, giving further insights into the role of MET inhibitors tepotinib and capmatinib in patients with NSCLC and MET exon 14 skipping mutations.

In the multi-cohort phase II VISION study of tepotinib, the ORR from 146 evaluated from an independent review committee (IRC) was 45.2%, with a duration of response of 11.1 months (Abstract 1283P). As Smit explains, “How the molecular alteration was determined did not influence the results; within the IRC- and investigator-assessed data, response rates were similar for MET alterations detected by tumour biopsy or liquid biopsy.” Interestingly, in the 22 patients with brain metastases at baseline, the IRC-assessed ORR of 57.1% was at least as good as that observed in the whole population (Abstract 1286P). Furthermore, preclinical animal studies showed high penetration of tepotinib in the brain and regression of brain-implanted patient-derived xenografts. “Ultimately, many of these patients with MET exon 14 skipping mutations will have brain metastases,” says Smit. “These data give some justification that treatment with TKIs and MET inhibitors may provide effective systemic therapy that avoids the side-effects associated with brain radiotherapy.” Data on intracranial responses are eagerly awaited.

Finally, results from a post hoc analysis of the GEOMETRY trial investigating capmatinib in 100 patients revealed that 23 of 32 patients receiving prior immunotherapy failed to respond to it (Abstract 1285P). The MET inhibitor was associated with responses in patients with prior immunotherapy (ORR 62.5%) and without prior immunotherapy (33.8%). The median duration of response was 9.95 months and 6.93 months, respectively. Study authors argue against the upfront use of immunotherapy in patients with NSCLC and MET exon 14 skipping mutations.

Smit concludes, “In Europe, where there are currently no targeted treatments approved for NSCLC with MET exon 14 skipping mutations, new agents are desperately needed for this aggressive form of lung cancer. Tepotinib and capmatinib appear to be on course to achieve approval. With comparable response rates and side-effect profiles, it will be interesting to observe which of these agents becomes the preferred standard.”

Abstracts and sessions details

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