1412TiP - Mobocertinib (TAK-788) as first-line treatment vs platinum-based chemotherapy (CT) for NSCLC with EGFR exon 20 insertions (exon20ins)

Background

∼6% of EGFR-mutated NSCLC tumors have EGFR exon20ins. There are no approved targeted treatments for these patients (pts); approved EGFR TKIs are ineffective, with low response rates and PFS ∼2 mo. Mobocertinib is an oral EGFR TKI under investigation for treatment of NSCLC with EGFR exon20ins. In a phase 1/2 study in previously treated NSCLC with EGFR exon20ins, mobocertinib 160 mg qd demonstrated antitumor activity, with confirmed ORR 43%, mPFS 7.3 mo, and a manageable AE profile similar to other EGFR TKIs. First-line combination CT in this setting yields 1-yr OS 15%–30% and PFS <7 mo. The EXCLAIM-2 trial (NCT04129502) compares efficacy of first-line mobocertinib vs platinum-based CT in NSCLC with EGFR exon20ins.

Trial design

This is a phase 3, open-label trial in adults with locally advanced, recurrent, or metastatic NSCLC with documented EGFR exon20ins with no previous systemic treatment for their disease. Locally advanced disease must be unsuitable for definitive therapy. Pts are randomized 1:1 to receive oral mobocertinib 160 mg qd (arm A) or CT Day 1 every 21 days (arm B; pemetrexed 500 mg/m² IV with cisplatin 75 mg/m² or carboplatin AUC 5 mg·min/mL IV for 4 cycles, then pemetrexed maintenance). Pts are stratified by baseline CNS metastases (yes vs no) and race (Asian vs non-Asian) and treated until progressive disease, toxicity, or another discontinuation criterion. Treatment beyond progression or crossover from arm B to arm A following independent review committee (IRC)-assessed PD and meeting crossover eligibility criteria is permitted. Primary endpoint: IRC−assessed PFS per RECIST 1.1 (Table). The study design employs an adaptive event-size reassessment approach for the primary endpoint and a sequential testing procedure for type I error control. The study was initiated in Jan 2020, with ∼170 sites in North America, Europe, Middle East, and Asia-Pacific; ∼318 pts will be randomized. Accrual is ongoing. Table: 1412TiP

Secondary endpoints

Clinical trial identification

NCT04129502 Release date: October 16, 2019.

Editorial acknowledgement

Professional medical writing assistance was provided by Lauren Gallagher, RPh, PhD, of Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, and funded by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Legal entity responsible for the study

Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Funding

Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Disclosure

P.A. Jänne: Advisory/Consultancy: Araxes Pharmaceuticals; Advisory/Consultancy: ARIAD/Takeda; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy, Research grant/Funding (self): Boehringer Ingelheim; Advisory/Consultancy: Chugai; Advisory/Consultancy: Ignyta; Advisory/Consultancy, Research grant/Funding (self): Lilly; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Loxo Oncology; Advisory/Consultancy: Merrimack; Advisory/Consultancy: Mirati Therapeutics; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: Novartis; Advisory/Consultancy: Voronoi; Advisory/Consultancy, Research grant/Funding (self): Daiichi Sankyo; Advisory/Consultancy: SFJ Pharmaceuticals; Advisory/Consultancy: Biocartis; Research grant/Funding (self): Astellas; Research grant/Funding (self): Puma Biotechnology; Shareholder/Stockholder/Stock options: Gatekeeper; Licensing/Royalties: Dana-Farber Cancer Institute. T. Kato: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Spouse/Financial dependant: Eli Lilly; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Merck Biopharma; Honoraria (self), Research grant/Funding (self): MSD; Honoraria (self), Research grant/Funding (self): Chugai; Honoraria (self), Research grant/Funding (self): Ono; Honoraria (self), Research grant/Funding (self): Pfizer; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Takeda; Honoraria (self), Research grant/Funding (self): AbbVie; Honoraria (self), Research grant/Funding (self): Novartis; Honoraria (self), Research grant/Funding (self): Taiho; Honoraria (self), Research grant/Funding (self): Bristol-Myers Squibb; Honoraria (self): Daiichi Sankyo; Honoraria (self): Shionogi; Honoraria (self): Nippon Kayaku; Research grant/Funding (self): Regeneron; Research grant/Funding (self): Amgen. B. Besse: Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): BeiGene; Research grant/Funding (institution): Blueprint Medicines; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Cristal Therapeutics; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): GSK; Research grant/Funding (institution): Ignyta; Research grant/Funding (institution): Ipsen; Research grant/Funding (institution): Inivata; Research grant/Funding (institution): Janssen; Research grant/Funding (institution): Merck KGaA; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Nektar; Research grant/Funding (institution): Onxeo; Research grant/Funding (institution): OSE Immunotherapeutics; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): PharmaMar; Research grant/Funding (institution): Roche-Genentech; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Servier; Research grant/Funding (institution): Spectrum Pharmaceuticals; Research grant/Funding (institution): Takeda; Research grant/Funding (institution): Tiziana Pharma; Research grant/Funding (institution): Tolero Pharmaceuticals. S. Peters: Advisory/Consultancy: AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, Bioinvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp and Dohme, M; Speaker Bureau/Expert testimony: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Illumina, Merck Sharp and Dohme, Novartis, Pfizer, Sanofi, Takeda; Research grant/Funding (institution): Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, F. Hoffmann-La Roche, Illumina, Merck Sharp and Dohme, Merck Serono, Novartis, Pfizer. D. Berg, J. Lin, Z. Feng: Full/Part-time employment: Takeda. T. Mok: Full/Part-time employment: The Chinese University of Hong Kong; Advisory/Consultancy: AstraZeneca, Roche/Genentech, Lilly, Merck Serono, BMS, Pfizer, Boehringer Ingelheim, Novartis, Clovis Oncology, Vertex, SFJ Pharmaceuticals Group, ACEA Biosciences, MSD, geneDecode, Oncogenex, Celgene, Ignyta, Cirina, Hutchison MediPharma; Leadership role: Sanomics Limited, Hutchison MediPharma, AstraZeneca; Shareholder/Stockholder/Stock options: Sanomics Limited, Hutchison MediPharma; Honoraria (self): AstraZeneca, Roche/Genentech, Lilly, Merck Serono, BMS, Pfizer, Boehringer Ingelheim, Novartis, Vertex, SFJ Pharmaceuticals Group, ACEA Biosciences, MSD, Celgene, Ignyta, Hutchison MediPharma, Fishawack Facilitate, Takeda, Janssen; Research grant/Funding (institution): AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, SFJ Pharmaceuticals Group, Roche, MSD, Clovis Oncology, BMS, Xcovery. All other authors have declared no conflicts of interest.