1523P - Phase II dose optimization results from MOUNTAINEER-02: A study of tucatinib, trastuzumab, ramucirumab, and paclitaxel for HER2+ gastroesophageal cancer (GEC)

Background

Approximately 12%-23% of pts with GEC have HER2+ tumours. Ramucirumab (R) + paclitaxel (P) is commonly used in the 2L setting for GEC; however, overall response and survival rates remain low. Tucatinib (TUC) is a highly selective, HER2-directed TKI. Here, we report safety and efficacy results from the dose optimization phase of MOUNTAINEER-02 (NCT04499924), a trial evaluating TUC in combination with trastuzumab (T), P, and R.

Methods

MOUNTAINEER-02 is a global trial evaluating TUC 300 mg BID + T (6 then 4 mg/kg D1,15) + P (D1, 8, 15) + R (8 mg/kg D1, 15) every 28 days in pts with previously treated, locally advanced unresectable or metastatic HER2+ GEC. In the open-label phase II dose optimization stage, two P doses were explored (60 mg/m² and 80 mg/m²). HER2+ status was confirmed by ctDNA or IHC/ISH assay. The primary endpoint is safety/tolerability of TUC+T+P+R. Secondary endpoints are ORR, confirmed ORR (cORR), DOR, DCR, PFS (all investigator-assessed), and PK.

Results

As of Jan 20, 2023, 17 pts (median age 59 yrs) received study tx (n=8 in 60 mg/m² vs n=9 in 80 mg/m²). Ten pts (58.8%) remain on study after a median of 8 TUC cycles. All pts treated with 80 mg/m² P were DLT-evaluable; 2 experienced a DLT event (1 pt with G3 mucositis and 1 pt with G2 fatigue and diarrhea leading to dose holds). No DLTs were observed in 7 DLT-evaluable pts treated with 60 mg/m² P. TEAEs stratified by two P doses are summarized in the table. ORR was 76.5% (95% CI, 50.1-93.2), with cORR of 70.6% (44-89.7) and DCR of 94.1% (71.3-99.9). Median DOR was 10.6 months (95% CI, 6.7-inestimable), and median PFS was 11.9 months (4.1-inestimable) after 7 PFS events. Plasma concentrations of P were not affected by TUC administration. Table: 1523P

Most Common TEAEs (≥30%)

Conclusions

Coadministration with TUC did not impact the PK of P. Based on the preliminary data from MOUNTAINEER-02, the combination of TUC+T+P+R was tolerable with encouraging antitumor activity in pts with previously treated HER2+ GEC.

Clinical trial identification

NCT04499924.

Editorial acknowledgement

The authors thank Elizabeth Burke, MS, of MMS Holdings, Canton, MI, supported by Seagen Inc., for providing medical writing and editorial support in accordance with Good Publication Practice guidelines.

Legal entity responsible for the study

Seagen Inc.

Funding

This study was sponsored by Seagen Inc., Bothell, WA, USA in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

M. Tehfe: Financial Interests, Personal, Advisory Board: BMS, Merck, Pfizer, Taiho, Incyte; Financial Interests, Personal, Invited Speaker: BMS, Taiho; Financial Interests, Institutional, Local PI: BMS, Amgen, Novartis, BioNTech; Financial Interests, Institutional, Research Grant: Pfizer, Taiho. J. Lee: Financial Interests, Steering Committee Member: Seattle Genetics, AZ; Non-Financial Interests, Principal Investigator: AstraZeneca, Daiichi Sankyo, Merck MSD, BMS, Leaptherapeutics; Non-Financial Interests, Project Lead: Samsung Bioepis, Genome and Company, OncXerna; Non-Financial Interests, Advisory Role: Mirati Therapeutics; Non-Financial Interests, Member: KSMO; Non-Financial Interests, Other, AP Council: ASCO. S.Y. Rha: Financial Interests, Personal, Advisory Board: Indivumed, Amgen, LG biochemical, Astellas; Financial Interests, Personal, Invited Speaker: MSD, Lilly, Daiichi Sankyo; Financial Interests, Personal, Steering Committee Member: Amgen; Financial Interests, Institutional, Funding: MSD, Lilly; Financial Interests, Institutional, Research Grant: BMS, Daiichi Sankyo; Financial Interests, Institutional, Local PI: Indivumed, AstraZeneca; Financial Interests, Other, Durg supply for clinical trial: Merck; Financial Interests, Institutional, Coordinating PI, Drug supply for clinical trial: MSD; Financial Interests, Institutional, Local PI, drug supply for clinical trial: Zymeworks; Financial Interests, Institutional, Local PI, drug supply for clinical trial: BeiGene; Financial Interests, Coordinating PI, Drug supply for clinical trial: Incyte. Y. Nakamura: Financial Interests, Personal, Invited Speaker: Chugai, Merck Biopharma, Guardant Health AMEA; Financial Interests, Institutional, Funding: Taiho, Chugai, Guardant Health, Genomedia, Daiichi Sankyo, Roche Diagnostics; Financial Interests, Institutional, Coordinating PI: Seagen. J. Tabernero: Financial Interests, Personal, Advisory Board, scientific consultancy role: Orion Biotechnology, Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd., Genentech Inc., HalioDX SAS, Ikena Oncology, IQVIA, Lilly, Menarini, Merck, Merus, MSD, Mirati, Neophore, Novartis, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics, TheraMyc, Hutchinson MediPharma International, Scandion Oncology, Ona Therapeutics, Sotio Biotech, Inspirna Inc, Scorpion Therapeutics, Tolremo Therapeutics; Financial Interests, Personal, Invited Speaker, educational collaboration: Medscape Education, Physicians Education Resource (PER), PeerView Institute for Medical Education, Imedex / HMP; Financial Interests, Personal, Invited Speaker, educational collaboration: MJH Life Sciences; Financial Interests, Personal, Advisory Board: Cardiff Oncology; Financial Interests, Personal, Stocks/Shares: Oniria Therapeuics; Financial Interests, Institutional, Research Grant, ACRCelerate: Colorectal Cancer Stratified: Fundación Científica de la Asociación Española Contra el Cáncer; Financial Interests, Institutional, Research Grant, OPTIMISTICC: Opportunity to Investigate the Microbiome’s Impact on Science and Treatment In Colorectal Cancer: Cancer Research UK; Financial Interests, Institutional, Funding, Clinical Trials & Research: Amgen Inc, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, Bristol Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc, Janssen-Cilag International NV, Merck Health KGAA, Merck, Sharp & Dohme de España, SA, Novartis Farmacéutica SA, PharmaMar SA, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA, Inc, BeiGene, Boehringer Ingelheim, HalioDX SAS, Hutchinson Medipharma, MedImmune, Menarini, Merus N V, Pfizer, Mirati; Non-Financial Interests, Member of Board of Directors, Board of Directors: Cancer Core Europe, Spanish Association Against Cancer -AECC; Non-Financial Interests, Member of Board of Directors, General Assembly: Horizon Europe Cancer Mission; Non-Financial Interests, Leadership Role, External Scientific Committee: Institute for Health Research INCLIVA – Clinical Hospital of Valencia, IdiSNA –Universidad de Navarra; Non-Financial Interests, Leadership Role, Scientific Advisory Board: Spanish National Cancer Research Centre (CNIO); Non-Financial Interests, Advisory Role, International Scientific Evaluation Committee: Bosch Health Campus (BHC); Non-Financial Interests, Advisory Role, Review Board: National Decade Against Cancer (NCT) - German Consortium for Translational Cancer Research (DKTK); Non-Financial Interests, Advisory Role, Scientific Advisory Board: Karolinska Comprehensive Cancer Centre; Non-Financial Interests, Advisory Role, International Review Committee (IRC): Oncode Institute; Non-Financial Interests, Advisory Role, Scientific Advisory Board (SAB): Oslo University Hospital Comprehensive Cancer Centre (OUH CCC); Non-Financial Interests, Other, Coordinating PI & Steering Committee Member. Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutical LP, Boehringer Ingelheim, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Pfizer, Servier; Non-Financial Interests, Principal Investigator, Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutics LP, BeiGene, Boehringer Ingelheim, Celgene International SARL, Bristol Myers Squibb International Corporation, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Menarini, Janssen-Cilag International NV, MedImmune, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc; Non-Financial Interests, Leadership Role, Governance Advisory Committee: European Organization for Research and Treatment of Cancer -EORTC; Non-Financial Interests, Leadership Role, Vice Chairman: World Innovative Networking (WIN) Consortium in Personalized Cancer Medicine; Non-Financial Interests, Other, Steering Committee Member. Clinical Trials & Research: Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Janssen-Cilag International NV, Merus NV, Taiho Pharma USA Inc; Non-Financial Interests, Other, Coordinating PI. Clinical Trials & Research: Mirati; Non-Financial Interests, Member: AACR, ASCO, EACR, EORTC, SEOM; Other, Other, President: Oncology Master Plan – Catalonia Department of Health; Other, Other, Advisory Committee: Advisory Committee on Pharmaceutical Provision Financing under the Spanish National Health System. K. Shitara: Financial Interests, Personal, Advisory Board: Lilly, Bristol Myers Squibb, Takeda, Pfizer, Ono Pharmaceutical, MSD, Taiho Pharmaceutical, Novartis, AbbVie, GSK, Daiichi Sankyo, Amgen, Boehringer Ingelheim, Guardant Health Japan Corp, Astellas Pharma Inc.; Financial Interests, Personal, Invited Speaker: Janssen Pharmaceutical K.K.; Financial Interests, Institutional, Research Grant: Astellas, ONO Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical, MSD, Eisai, Amgen. D. Oh: Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis, Genentech/Roche, Merck, Bayer, Taiho, P, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, MSD; Financial Interests, Institutional, Research Grant: AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok. J. Eads: Financial Interests, Personal, Invited Speaker, Educational session: American Society of Clinical Oncology; Financial Interests, Personal, Invited Speaker: Great Debates and Updates in GI Oncology; Financial Interests, Personal, Full or part-time Employment, husband is an employee: Janssen; Financial Interests, Personal, Full or part-time Employment, husband is a prior employee: Bristol Meyers Squibb; Financial Interests, Personal, Stocks/Shares, Husband received stocks as part of employment: Bristol Myers Squibb; Financial Interests, Institutional, Local PI, Clinical trial PI: Genentech, Seagen, Merck, HUTCHMED, AstraZeneca, MedImmune, Oncolys; Non-Financial Interests, Other, Member on Board of Scientific Advisors: Neuroendocrine Tumor Research Foundation; Non-Financial Interests, Other, Member of Educational Committee-Colorectal Cancer: American Society of Clinical Oncology; Other, Other, Young investigator award recipient: Eastern Cooperative Oncology Group. J. Marshall: Financial Interests, Personal, Advisory Board: AstraZeneca, Merck, Bayer, Taiho, Seagen, Caris, 2CureX, OnDose; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Other, CMO: Indivumed; Financial Interests, Personal, Full or part-time Employment: Indivumed; Financial Interests, Institutional, Coordinating PI: Genentech; Non-Financial Interests, Advisory Role: Colorectal Cancer Alliance. Z.A. Wainberg: Financial Interests, Personal, Other, Honoraria: Amgen, Arcus, AstraZeneca, Daiichi Sankyo, Bayer, BMS, Merck, Ipsen, Gilead, Astellas, Seagen, Novartis; Financial Interests, Personal, Advisory Role: Amgen, Arcus, AstraZeneca, Daiichi Sankyo, Bayer, BMS, Merck, Ipsen, Novartis, Gilead, Astellas, Seagen; Financial Interests, Institutional, Research Funding: Amgen, AstraZeneca, Daiichi Sankyo, Bayer, BMS, Merck, Ipsen, Five Prime, Gilead, Arcus, Astellas, Molecular Templates, Roche/Genentech, Array/Pfizer. K. Lee: Financial Interests, Personal, Advisory Board: BMS (Korea), Bayer (Korea), Daiichi Sankyo (Korea), Merck Sharp & Dohme (Korea), Metafines, Vifor pharma (Korea), Astellas (Korea); Financial Interests, Personal, Invited Speaker: Boryung Co.; Financial Interests, Institutional, Local PI: ABLBIO, ALX Oncology, Amgen, Arcus Biosciences, Astellas Pharma, AstraZeneca, BeiGene, Bolt therapeutics, Daiichi Sankyo, Exelixis, Genexine, Green Cross Corp, InventisBio, LSK BioPharma, Leap therapeutics, Macrogenics, MedPacto, Merck KGaA, Merck Sharp & Dohme, Oncologie, Ono Pharmaceutical, Pfizer, Pharmacyclics, Seagen, Taiho Pharmaceutical, Trishula therapeutics, Y-BIOLOGICS, Zymeworks,; Non-Financial Interests, Leadership Role, SMC chair of ASPEN-06 study: ALX Oncology. Y. Kang: Financial Interests, Personal, Advisory Board: ALX Oncology, Zymeworks, Amgen, Novartis, Macrogenics, Daehwa, Blueprint, Surface Oncology, BMS, Merck, Roche, LISCure. C. Liao: Financial Interests, Personal, Advisory Board: Incyte, AstraZeneca, Lantheus, Eli Lilly, Transthera, Ipsen; Financial Interests, Personal, Trial Chair: BMS. K. Yeh: Financial Interests, Personal, Advisory Board: Daiichi Sankyo, PhytoHealth, Novartis, Ono, Merck, AstraZeneca; Non-Financial Interests, Member: American Society of Clinical Oncology, American Association for Cancer Research. M.M. Ubowski; K. Zhao: Financial Interests, Personal, Full or part-time Employment: Seagen Inc; Financial Interests, Personal, Stocks/Shares: Seagen Inc. J.H. Strickler: Financial Interests, Personal, Advisory Board: SeaGen, AstraZeneca, Amgen, Pfizer, Bayer, AbbVie, Natera, Viatris, BeiGene, Silverback Therapeutics, Daiichi Sankyo, Eli Lilly, Roche Genentech, Takeda, Zentalis, Taiho; Financial Interests, Personal, Other, Consulting: GSK, Pionyr Immunotherapeutics; Financial Interests, Institutional, Coordinating PI: Seagen, Amgen; Financial Interests, Institutional, Local PI: Roche Genentech, AbbVie, AstraZeneca, AStar D3, Bayer, Curegenix, Nektar, Leap Therapeutics, Daiichi Sankyo, Erasca, BeiGene, Silverback Therapeutics. All other authors have declared no conflicts of interest.