118MO - Trastuzumab deruxtecan (T-DXd) and pembrolizumab in immuno-oncology (IO)-naive HER2-expressing or HER2-mutant non-small cell lung cancer (NSCLC): Interim analysis of a phase Ib study

Background

T-DXd is approved in patients (pts) with NSCLC and activating HER2 mutations (HER2m) who received prior systemic therapy. Combining HER2-targeted therapy and immunotherapy may have synergistic effects on tumor cell death and tumor immunogenicity. We report interim results of T-DXd + pembrolizumab (PEM) in IO-based treatment-naive HER2-expressing (HER2E) or HER2m NSCLC.

Methods

DS8201-A-U106 (NCT04042701) is an open-label, phase 1b study. Part 1 determined recommended dose for expansion (RDE) of T-DXd + PEM. In part 2, pts with NSCLC were assigned to cohort 3 (HER2E; immunohistochemistry 1+, 2+, or 3+) or cohort 4 (HER2m). The primary endpoint was confirmed objective response rate (cORR) by independent central review.

Results

At data cutoff Nov 18, 2023, 55 pts (22 cohort 3; 33 cohort 4) received RDE of T DXd 5.4 mg/kg + PEM 200 mg every 3 weeks. Median duration of follow-up was 5.9 mo in cohort 3 and 15.2 mo in cohort 4. cORR was 54.5% (12/22; 95% CI, 32.2-75.6) in cohort 3 and 66.7% (22/33; 95% CI, 48.2-82.0) in cohort 4; median duration of response was 20.2 mo (95% CI, 4.2-not evaluable [NE]) and 15.1 mo (95% CI, 8.1-22.1), respectively. Median progression-free survival was 15.1 mo (95% CI, 5.6-NE) in cohort 3 and 11.3 mo (95% CI, 5.8-21.3) in cohort 4. Treatment duration was 5.2 mo in cohort 3 and 9.7 mo in cohort 4 for both T-DXd and PEM. Safety is shown in the Table. Adjudicated drug-related (T-DXd and/or PEM) interstitial lung disease (ILD)/pneumonitis occurred in 11 pts; 2 in cohort 3 (grades 2 and 3), 9 in cohort 4 (8 grade 2 and 1 grade 5); 8 recovered/resolved, 2 recovering/resolving, 1 not recovered/not resolved. Table: 118MO

^aIncludes pts from parts 1 and 2 treated with RDE. ^bDrug-related TEAEs may be related to T-DXd and/or PEM. ^cAll events were related to T-DXd.

Conclusions

T-DXd + PEM showed antitumor activity in IO-based treatment-naive pts with HER2E or HER2m NSCLC. Preliminary safety results were consistent with the known profiles of each drug and generally manageable. Further research with a larger dataset is needed.

Clinical trial identification

NCT04042701.

Editorial acknowledgement

Under the guidance of authors, assistance in medical writing and editorial support was provided by Andre Wang, PharmD, and Sara Duggan, PhD, of ApotheCom, and was funded by Daiichi Sankyo.

Legal entity responsible for the study

Daiichi Sankyo.

Funding

This study was funded by Daiichi Sankyo, Inc., and AstraZeneca. Pembrolizumab is being provided under agreement by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc., Rahway, NJ, USA.

Disclosure

A. Italiano: Financial Interests, Personal, Research Grant: Daiichi Sankyo, GSK, Merck, MSD, Bayer, Roche, AstraZeneca, Parthenon, Daiichi Sankyo; Financial Interests, Personal, Other, Honoraria: GSK, Merck, MSD, Bayer, Roche, AstraZeneca, Parthenon; Financial Interests, Personal, Advisory Board: Daiichi Sankyo, GSK, Merck, MSD, Bayer, Roche, AstraZeneca, Parthenon. B. Besse: Financial Interests, Institutional, Advisory Board: Amgen, AstraZeneca, Beigene, Blueprint Medicine, Cergentis, Chugai Pharmaceutical, Daiichi Sankyo, F. Hoffmann-La Roche, Inivata, Pfizer, PharmaMar, Sanofi Aventis, Springer Healthcare Ltd, 4d Pharma, AbbVie, Da Voltera, Eli Lilly, Ellipse Pharma Ltd, F-Star, GSK, Janssen, Onxeo, Ose Immunotherapeutics, Socar Research, Taiho oncology, Turning Point Therapeutics; Financial Interests, Institutional, Invited Speaker: Genzyme Corporation, Hedera Dx, Medscape, MSD; Financial Interests, Institutional, Local PI: AbbVie, Amgen, Blueprint Medicines, Daiichi Sankyo, Pfizer, Roche-Genentech, Turning Point Therapeutics, Nuvalent, Enliven, Prelude Therapeutics; Financial Interests, Institutional, Coordinating PI: AstraZeneca, OSE immunotherapeutics, Sanofi, Taiho; Financial Interests, Institutional, Steering Committee Member: BeiGene, GSK, Janssen, Takeda, Genmab; Financial Interests, Institutional, Funding: Cristal Therapeutics. H. Borghaei: Financial Interests, Personal, Other, Writing support: Daiichi Sankyo, AstraZeneca; Financial Interests, Institutional, Research Funding: BMS, Lilly; Financial Interests, Personal, Advisory Board: BMS, Lilly, Genentech, Pfizer, EMD-Serono, Merck, BioNTech, Amgen, Boehringer Ingelheim, AstraZeneca, Novartis, Genmab, Regeneron, Axiom, Daiichi Sankyo, Mirati, Takeda, PharmaMar, Guardant, Jazz, iTEO, Beigene, Oncocyte, Natera, Novartis, Springworks, Incyte, Takeda, CAR T Program, University of Pennsylvania; Financial Interests, Personal, Other, Honoraria: Amgen, Pfizer, Daiichi, Regeneron; Financial Interests, Personal, Other, Manuscript writing support: Amgen, Amgen, AstraZeneca, BMS, Mirati; Financial Interests, Personal, Other, Travel: Mirati, EMD-Serono; Financial Interests, Personal, Stocks/Shares: Sonnetbio, Insigna, Nucleai. S. Popat: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Novartis, Amgen, Janssen, Daiichi Sankyo, AstraZeneca, Bayer, BMS, Blueprint, Merck Serono, Guardant Health, Takeda, Lilly, Roche, Turning Point Therapeutics, GSK, MSD, Pfizer, Sanofi, EQRx, AnHeart, Arcus Biosciences, Ellipses, Gilead, IO Biotech, Mirati; Financial Interests, Personal, Invited Speaker: Medscape, VJ Oncology, Novocure, PharmaMar; Financial Interests, Institutional, Other, Sub-investigator: Amgen; Financial Interests, Institutional, Coordinating PI: Ariad, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Takeda, Turning Point Therapeutics, Roche, Janssen, BMS, Lilly; Financial Interests, Institutional, Local PI: AstraZeneca, Roche, GSK, Trizel; Financial Interests, Institutional, Other, Sub-Investigator: MSD, Blueprint; Financial Interests, Institutional, Research Grant: Guardant Health; Non-Financial Interests, Personal, Leadership Role, Chair of Steering Committee, Unpaid: British Thoracic Oncology Group; Non-Financial Interests, Personal, Officer, Thoracic Faculty, Unpaid: European Society of Medical Oncology; Non-Financial Interests, Personal, Leadership Role, Foundation Council Member, Unpaid: European Thoracic Oncology Platform; Non-Financial Interests, Personal, Advisory Role, Mesothelioma Committee, Unpaid: International Association for the Study of Lung Cancer; Non-Financial Interests, Personal, Member of Board of Directors, Unpaid: Mesothelioma Applied Research Foundation; Non-Financial Interests, Personal, Advisory Role, Honorary Clinical Advisor, Unpaid: ALK Positive UK; Non-Financial Interests, Personal, Advisory Role, Research Advisory Group Member, Unpaid: Ruth Strauss Foundation; Non-Financial Interests, Personal, Advisory Role, Scientific Adivsory Board Member, Unpaid: Lung Cancer Europe. G. Anguera Palacios: Financial Interests, Personal, Other, medical writing support: Daiichi Sankyo; Financial Interests, Personal, Speaker’s Bureau: Ipsen, Merck, Janssen, Bristol Myers Squibb, Astellas; Financial Interests, Personal, Other, Travel: Ipsen, Janssen, Merck, Bristol Myers Squibb, MSD; Financial Interests, Personal, Advisory Board: Merck. A. Goncalves: Financial Interests, Personal, Other, Medical writing support: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Daiichi Sankyo, Roche/Genentech, AstraZeneca, Gilead, Novartis; Financial Interests, Personal, Other, Consulting Fee's: Novartis, AstraZeneca, MSD, Gilead; Financial Interests, Institutional, Speaker’s Bureau: Novartis; Financial Interests, Personal, Other, Travel: Mylan, Menarini. J. Mazieres: Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Pierre Fabre; Financial Interests, Personal and Institutional, Other, Board and Expertise: Merck, AstraZeneca, MSD, Roche, Novartis, Daiichi, Pfizer; Financial Interests, Institutional, Other, Board and Expertise: BMS. C. Chouaid: Financial Interests, Personal, Advisory Board: AZ, BI, GSK, Roche, Sanofi Aventis, BMS, MSD, Lilly, Novartis, Pfizer, Takeda, Bayer, Janssen and Amgen; Financial Interests, Institutional, Funding: AZ, BI, GSK, Roche, Sanofi Aventis, BMS, MSD, Lilly, Novartis, Pfizer, Takeda, Bayer, Janssen and Amgen. J. Soberino García: Financial Interests, Personal, Other, Honoraria: MSD; Financial Interests, Personal, Other, Travel: MSD. L. Garcia Estevez: Financial Interests, Personal, Research Grant: Roche; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Daiichi Sankyo, Gilead Science, Lilly, Roche; Financial Interests, Personal, Other, Travel: Daiichi Sankyo, Gilead Science; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Other, Receipt of equipment, materials, drugs, medical writing, gifts or other services: Roche. A. Calles Blanco: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche, Lilly, Merck Sharp & Dohme, Novartis, Bristol Myers Squibb, Takeda, Sanofi, Janssen, Regeneron; Financial Interests, Personal, Other, Speaker honoraria: Bayer; Financial Interests, Personal, Invited Speaker: PharmaMar; Financial Interests, Institutional, Research Grant, Drug-only for Investigator-initiated trial; Merck Sharp & Dohme. D. Vicente Baz: Financial Interests, Personal, Other, Consulting Fee's: AstraZeneca, Daiichi Sankyo, Roche, MSD, Pfizer, Takeda, Amgen, Merck; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Daiichi Sankyo, Roche, MSD, Pfizer, Takeda, Amgen, Merck; Financial Interests, Personal, Other, Travel: AstraZeneca, Daiichi Sankyo, Roche, MSD; Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Roche, MSD. M.J. Chisamore: Financial Interests, Institutional, Full or part-time Employment: Merck & Co. Inc; Financial Interests, Institutional, Stocks/Shares: Merck & Co. Inc. D. Barrios, D. Haribhai, M. Rosen, B. Cunningham: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. K. Abe: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo; Financial Interests, Personal, Stocks/Shares: Daiichi Sankyo. L. Paz-Ares: Financial Interests, Personal, Advisory Board, Speaker fees: Roche, MSD, BMS, AZ, Lilly, PharmaMar, Beigene, Daiichi Sankyo, Medscape, PER; Financial Interests, Personal, Advisory Board: Merck Serono, Pfizer, Bayer, Amgen, Janssen, GSK, Novartis, Takeda, Sanofi, Mirati, Boehringer; Financial Interests, Personal, Other, Board member: Genomic, Altum sequencing; Financial Interests, Personal, Other, lectures: AICME; Financial Interests, Personal, Other, Lectures: CCO; Financial Interests, Personal, Member of Board of Directors, Board member: Stab Therapeutics; Financial Interests, Personal, Other, spin off (I have around 8% of stocks): Altum sequencing; Financial Interests, Personal, Ownership Interest, spin-off (10%): Stab Therapeutics; Financial Interests, Institutional, Coordinating PI: Daiichi Sankyo, AstraZeneca, Merck Sharp & Dohme Corp, BMS, Janssen-Cilag international NV, Novartis, Roche, Sanofi, Tesaro, Alkermes, Lilly, Takeda, Pfizer, PharmaMar, Cantargia; Financial Interests, Personal, Coordinating PI: Amgen; Financial Interests, Personal, Other, Member: AACR, ASCO, ESMO; Financial Interests, Personal, Other, Foundation Board Member: AECC; Financial Interests, Personal, Other, President. ASEICA (Spanish Association of Cancer Research): ASEICA; Financial Interests, Personal, Other, Foundation president: ONCOSUR; Financial Interests, Personal, Other, member: Small Lung Cancer Group; Non-Financial Interests, Personal, Other, Board member of this anti-cancer Charity: AECC; Non-Financial Interests, Personal, Member, Past-President: ASEICA (Spanish Cancer Research Association); Non-Financial Interests, Personal, Leadership Role, President: Oncosur Foundation. All other authors have declared no conflicts of interest.