Phase I/II Study of Capmatinib Plus Erlotinib in Patients With MET-Positive Non-Small-Cell Lung Cancer.

Purpose: MET dysregulation is an oncogenic driver in non-small-cell lung cancer (NSCLC), as well as a mechanism of TKI (tyrosine kinase inhibitor) resistance in patients with epidermal growth factor receptor ( EGFR )-mutated disease. This study was conducted to determine safety and preliminary efficacy of the combination EGFR and MET inhibitors as a strategy to overcome and/or delay EGFR-TKI resistance.
Methods: A standard 3 + 3 dose-escalation trial of capmatinib in combination with erlotinib in patients with MET-positive NSCLC was used. Eighteen patients in the dose-escalation cohort received 100-600 mg twice daily of capmatinib with 100-150 mg daily of erlotinib. There were two dose-expansion cohorts. Cohort A included 12 patients with EGFR -mutant tumors resistant to TKIs. Cohort B included five patients with EGFR wild-type tumors. The primary outcome was to assess safety and determine the recommended phase II dose (RP2D) of the combination.
Results: The most common adverse events of any grade were rash (62.9%), fatigue (51%), and nausea (45.7%). Capmatinib exhibited nonlinear pharmacokinetics combined with erlotinib, while showing no significant drug interactions. The RP2D was 400 mg twice daily capmatinib tablets with 150 mg daily erlotinib. The overall response rate (ORR) and DCR in dose-expansion cohort A was 50% and 50%, respectively. In cohort B, the ORR and disease control rate were 75% and 75%.
Conclusion: Capmatinib in combination with erlotinib demonstrated safety profiles consistent with prior studies. We observed efficacy in specific patient populations. Continued evaluation of capmatinib plus EGFR-TKIs is warranted in patients with EGFR activating mutations.
Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Caroline E. McCoachHonoraria: Novartis, Genentech, Guardant Health Consulting or Advisory Role: AstraZeneca Speaker’s Bureau: Novartis Research Funding: Novartis, Revolution Medicine Travel, Accommodations, Expenses: Loxo, Eli Lilly, Takeda PharmaceuticalsAiming YuStock and Other Ownership Interests: Johnson & Johnson Patents, Royalties, Other Intellectual Property: Patents: (1) Yu AM, Wang WP, Chen QX, Li MM. Hybrid tRNA/pre-miRNA molecules and methods of use. US Patent No. 10619156, Issue date: April 14, 2020. European Patent No. 3150980, Grant date: May 20, 2020. (2) Yu AM. Method for detection of RNase activity. US Patent No. 10422003. Issue date: September 24, 2019. (3) Yu AM, Jilek JL, Zhang QY, Ho PY, Tu MJ. tRNA/pre-miRNA compositions and methods for treating hepatocellular carcinoma. US Patent Application No. 62/660919, filed on April 20, 2018. (4) Yu AM, Ho PY, Tu MJ, Jilek JL, Zhang QY, Petrek HE. tRNA/pre-miRNA compositions and use in treating cancer. US Patent Application No. 62/674939, filed on May 22, 2018.David R. GandaraHonoraria: AstraZeneca Consulting or Advisory Role: AstraZeneca (I), Guardant Health (I), OncoCyte (I), Amgen, IO Biotech (I), Merck, Roche/Genentech, Boehringer Ingelheim, Inivata, Novartis Research Funding: Roche/Genentech (I), Merck (I), Amgen (I) Travel, Accommodations, Expenses: Boehringer IngelheimJonathan W. RiessConsulting or Advisory Role: Celgene, Medtronic, Spectrum Pharmaceuticals, Loxo, Boehringer Ingelheim, Novartis, Blueprint Medicines, Genentech Research Funding: Merck (I), AstraZeneca/MedImmune (I), Spectrum Pharmaceuticals (I), Boehringer Ingelheim (I), Novartis (I)Tiahong LiConsulting or Advisory Role: Foundation Medicine, Archer Diagnostics, Eisai Research Funding: Pfizer (I), Hengrui Therapeutics (I), Eureka (I), Merck (I), OncoImmune (I)Primo N. LaraConsulting or Advisory Role: Janssen Research Funding: Aragon Pharmaceuticals (I), Janssen Biotech (I), Tracon Pharma (I), Merck (I), Pharmacyclics (I), Incyte (I), Taiho Pharmaceutical (I)Matthew GubensConsulting or Advisory Role: Bristol Myers Squibb, Roche/Genentech, AstraZeneca, Heron, Boehringer Ingelheim, Takeda Pharmaceuticals, BeyondSpring Pharmaceuticals, Inivata Research Funding: Celgene (I), Merck (I), Novartis (I), Roche/Genentech (I), OncoMed (I)Philip C. MackHonoraria: Guardant Health Consulting or Advisory Role: AstraZeneca, Guardant Health, Amgen Research Funding: Boehringer IngelheimKaren KellyHonoraria: Merck Consulting or Advisory Role: Roche/Genentech, Regeneron, AbbVie, EMD Serono, Merck, Pfizer, AstraZeneca, Novartis, Symphogen, Inivata, Bristol Myers Squibb, Takeda Pharmaceuticals, Eli Lilly, Amgen, Genmab, Targeted Oncology, Genentech Research Funding: EMD Serono (I), Genentech (I), AbbVie (I), Five Prime Therapeutics (I), Regeneron (I), Astellas Pharma (I), Tizona Therapeutics, (I) Eli Lilly (I), Novartis (I), Amgen (I) Patents, Royalties, Other Intellectual Property: Author royalties for UpToDate, an evidence-based, peer-reviewed information resource, available via the web, desktop, and PDA Travel, Accommodations, Expenses: AstraZeneca, Roche/Genentech, Merck, Regeneron, Eli Lilly, AbbVie, EMD Serono No potential conflicts of interest were reported.
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