Abstract 74TiP
Background
MET amplification can arise as a bypass mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs) occurring in ∼5–26% of patients (pts) with EGFR TKI resistant EGFR-mutant non-small cell lung cancer (NSCLC). Few treatment options exist for these pts, particularly in the EGFR T790M negative (T790M−) setting. Capmatinib, a MET inhibitor, is approved in more than 10 countries for the treatment of metastatic MET exon 14 skipping NSCLC. Preliminary studies have shown that capmatinib plus EGFR TKIs demonstrated antitumor activity in pts with EGFR TKI resistant EGFR-mutant NSCLC. GEOMETRY-E (NCT04816214) evaluates the efficacy and safety of capmatinib + osimertinib vs platinum-pemetrexed doublet chemotherapy as second-line therapy in pts with locally advanced/metastatic NSCLC.
Trial design
This randomized, controlled, open-label, multicenter, phase 3 study is ongoing and recruiting adult pts with EGFR-mutant, T790M−, MET-amplified stage IIIB/IIIC/IV NSCLC who had progressed on either 1st/2nd generation EGFR TKIs, osimertinib or other 3rd generation EGFR TKIs. Pts with ≥1 measurable lesion per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and an Eastern Cooperative Oncology Group performance status of ≤1, are included. Pts with neurologically unstable, symptomatic CNS metastases or those requiring increasing doses of steroids ≤2 weeks prior to study entry to manage CNS symptoms are excluded. The study consists of an initial run-in Part 1 to confirm the recommended dose for the randomized Part 2 and evaluate the safety, tolerability of capmatinib + osimertinib. In Part 1, ∼10 pts will receive oral capmatinib 400 mg twice daily + osimertinib 80 mg once daily in 21-day cycles. Part 2 (∼225 pts, randomized 2:1) will evaluate the efficacy and safety of the combination vs platinum (cisplatin/carboplatin)-pemetrexed. Table: 74TiP
| Endpoint | ||
| Part 1 | Part 2 | |
| Primary | Incidence of dose limiting toxicities during 1st treatment cycle | Progression-free survival (PFS) by blinded independent review committee (BIRC) per RECIST 1.1 |
| Key Secondary | Overall response rate (ORR) by BIRC Overall intracranial response rate by BIRC per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) | |
| Secondary | Safety, tolerability Pharmacokinetics (PK) ORR, duration of response (DOR), time to response (TTR), disease control rate (DCR), PFS by investigator | DOR, TTR, DCR by BIRC PFS after next line of therapy Overall survival Duration of and time to intracranial response, intracranial DCR by BIRC per RANO-BM Safety PK Patient-reported outcomes |
Clinical trial identification
NCT04816214; EudraCT 2020-003677-21; Release date: 14 Sept 2021.
Legal entity responsible for the study
Novartis.
Funding
Novartis.
Disclosure
Y. Wu: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Other, honorarium: Novartis; Financial Interests, Personal, Advisory Role: Takeda; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Hengrui; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Personal, Other, honorarium: Sanofi; Financial Interests, Personal, Other, honorarium: Roche; Financial Interests, Personal, Other, honorarium: Pfizer; Financial Interests, Personal, Other, honorarium: Eli Lilly; Financial Interests, Personal, Other, honorarium: MSD; Financial Interests, Personal, Other, honorarium: Bristol Myers Squibb. J. Han: Financial Interests, Institutional, Research Grant: Hoffmann-La Roche Ltd; Financial Interests, Personal, Other, homorarium: Hoffmann-La Roche Ltd; Financial Interests, Institutional, Research Grant: Ono; Financial Interests, Personal, Invited Speaker: Ono; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Institutional, Research Grant: Takeda; Financial Interests, Personal, Advisory Role: Takeda; Financial Interests, Personal, Other, homorarium: Takeda; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Other, homorarium: AstraZeneca; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Other, homorarium: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: Eli Lilly; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Other, homorarium: MSD; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Other, homorarium: Novartis; Financial Interests, Personal, Advisory Role: Medpacto; Financial Interests, Personal, Advisory Role: Abion. T. Kato: Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Other, Honoraria for speaker; Honoraria for IDMC or advisory board meeting: AstraZeneca; Financial Interests, Institutional, Research Grant: AbbVie; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria for speaker: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Chugai; Financial Interests, Personal, Other, Honoraria for speaker; Honoraria for IDMC or advisory board meeting: Chugai; Financial Interests, Personal, Other, Honoraria for IDMC or advisory board meeting: AbbVie; Financial Interests, Personal, Other, Honoraria for IDMC or advisory board meeting: Amgen; Financial Interests, Institutional, Research Grant: Eli Lilly; Financial Interests, Personal, Other, Honoraria for speaker; Honoraria for IDMC or advisory board meeting: Eli Lilly; Financial Interests, Institutional, Research Grant: Merck Biopharma; Financial Interests, Personal, Other, Honoraria for speaker; Honoraria for IDMC or advisory board meeting: Merck Biopharma; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Personal, Other, Honoraria for speaker; Honoraria for IDMC or advisory board meeting: MSD; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Personal, Other, Honoraria for speaker; Honoraria for IDMC or advisory board meeting: Novartis; Financial Interests, Institutional, Research Grant: Ono; Financial Interests, Personal, Other, Honoraria for speaker; Honoraria for IDMC or advisory board meeting: Ono; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Personal, Other, Honoraria for speaker; Honoraria for IDMC or advisory board meeting: Pfizer; Financial Interests, Institutional, Research Grant: Taiho; Financial Interests, Personal, Other, Honoraria for IDMC or advisory board meeting: Taiho; Financial Interests, Institutional, Research Grant: Regeneron; Financial Interests, Personal, Other, Honoraria for speaker; Honoraria for IDMC or advisory board meeting: Daiichi Sankyo; Financial Interests, Personal, Other, Honoraria for speaker; Honoraria for IDMC or advisory board meeting: Nippon Kayaku; Financial Interests, Personal, Other, Honoraria for IDMC or advisory board meeting: Takeda. F. Barlesi: Financial Interests, Personal, Other, personal fees: AstraZeneca; Financial Interests, Personal, Other, personal fees: Bayer; Financial Interests, Personal, Other, personal fees: Bristol Myers Squibb; Financial Interests, Personal, Other, personal fees: Boehringer Ingelheim; Financial Interests, Personal, Other, personal fees: Eli Lilly Oncology; Financial Interests, Personal, Other, personal fees: F. Hoffmann–La Roche Ltd; Financial Interests, Personal, Other, personal fees: Novartis; Financial Interests, Personal, Other, personal fees: Merck; Financial Interests, Personal, Other, personal fees: MSD; Financial Interests, Personal, Other, personal fees: Pierre Fabre; Financial Interests, Personal, Other, personal fees: Pfizer; Financial Interests, Personal, Other, personal fees: Takeda. E.B. Garon: Financial Interests, Personal, Advisory Role: ABL Bio; Financial Interests, Institutional, Research Grant: ABL Bio; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: Dracen Pharmaceuticals; Financial Interests, Personal, Advisory Role: Eisai; Financial Interests, Personal, Advisory Role: Eli Lilly; Financial Interests, Personal, Advisory Role: EMD Serono; Financial Interests, Personal, Advisory Role: Gilead; Financial Interests, Personal, Advisory Role: GSK; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Natera; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Personalis; Financial Interests, Personal, Advisory Role: Regeneron; Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Advisory Role: Shionogi; Financial Interests, Personal, Advisory Role: Xilio Therapeutics; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Role: Dynavax Technologies; Financial Interests, Institutional, Research Grant: EMD Serono; Financial Interests, Institutional, Research Grant: Genentech; Financial Interests, Institutional, Research Grant: Iovance Biotherapeutics; Financial Interests, Institutional, Research Grant: Eli Lilly; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Mirati Therapeutics; Financial Interests, Institutional, Research Grant: Novartis. F. Cappuzzo: Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: AstraZeneca K.K.; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: PharmaMar; Financial Interests, Personal, Advisory Board: Novocure; Financial Interests, Personal, Advisory Board: MSD. Y. Shibata: Financial Interests, Institutional, Research Grant: Pfizer Inc.; Financial Interests, Personal, Other, honorarium: Pfizer Inc.; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb K.K; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Other, honorarium: Ono Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Research Grant: AstraZeneca K.K.; Financial Interests, Personal, Other, honorarium: AstraZeneca K.K.; Financial Interests, Personal, Other, honorarium: Eli Lilly. N. Smith: Financial Interests, Personal, Full or part-time Employment: Novartis Pharma AG. S. Khanna: Financial Interests, Personal, Full or part-time Employment: Novartis Pharma S.A.S. R. Belli: Financial Interests, Personal, Full or part-time Employment: Novartis Pharma AG; Financial Interests, Personal, Stocks/Shares: Novartis Pharma AG. A. Yovine: Financial Interests, Personal, Full or part-time Employment: Novartis Pharma AG. D. Shao-Weng Tan: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: ACM Biolabs; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Personal, Advisory Role: Takeda; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Novartis.