267MO - Pooled analysis of trastuzumab deruxtecan (T-DXd) retreatment (RTx) after recovery from grade (Gr) 1 interstitial lung disease/pneumonitis (ILD)

Background

T-DXd, an approved therapy for multiple cancers, carries a risk of interstitial lung disease/pneumonitis (ILD) which may have fatal outcomes if not appropriately identified and managed. Management guidelines require interrupting T-DXd for all ILD grades, even if asymptomatic, but patients (pts) with Gr 1 ILD may be retreated upon complete radiographic recovery. In this retrospective analysis of T-DXd trials, we examined RTx duration and recurrence of ILD (rILD).

Methods

Data were pooled from 9 clinical trials of pts with HER2-altered breast, gastric, colorectal, and non-small cell lung cancer who received ≥1 dose of T-DXd (5.4-8.0 mg/kg) monotherapy. T-DXd RTx duration and rILD were assessed in pts following Gr 1 first ILD (fILD); defined as complete recovery from investigator (inv)-assessed Gr 1 drug-related ILD, confirmed by an independent adjudication committee (AC).

Results

Overall, 9.0% (193/2145) of pooled pts had Gr 1 fILD, 50.3% (97/193) of whom received steroids. Per inv assessment or treatment dose discontinuation requirements (per protocol/label), 76.7% (148/193) of Gr 1 fILD pts were not eligible for T-DXd RTx. Following Gr 1 fILD, 23.3% (45/193) of pts were retreated with T-DXd. Median RTx duration was 85 d (range, 1-848 d); 31.1% (14/45) of pts were retreated with a 1-level reduced dose vs their original T-DXd dose; 17.8% (8/45) received T-DXd RTx for ≥1 year. Of those retreated: 2 pts (4.4% [2/45]) had RTx before Gr 1 fILD was confirmed resolved, per AC, and events progressed to Gr 2 and Gr 3 (1 each), and 33.3% (15/45) had rILD (median time to rILD was 64 d [range, 22-391 d]). All pts with rILD received the same T-DXd dose level as their original dose: 40.0% (6/15) of rILD events were AC-assessed ILD Gr 1; 60.0% (9/15) Gr 2; no Gr ≥3 events. At the data cutoff from each trial, per inv assessment, 20.0% (3/15) of rILD cases were ongoing; 53.3% (8/15) of pts recovered without sequalae; 6.7% (1/15) recovered with sequalae; 20.0% (3/15) did not recover.

Conclusions

This is the first pooled analysis of T-DXd RTx data after Gr 1 fILD recovery which shows clinically meaningful extension of treatment duration with RTx. All rILD events were of low grade and generally manageable using existing treatment guidelines.

Clinical trial identification

NCT02564900; NCT03248492; NCT03523585; NCT03529110; NCT03734029; NCT03329690; NCT04014075; NCT03505710; NCT04644237.

Editorial acknowledgement

Under the guidance of authors, assistance in medical writing and editorial support was provided by Vishal Gor, PhD, and Toinette Labuschagné, MSc, of ApotheCom.

Legal entity responsible for the study

Daiichi Sankyo, Inc., and AstraZeneca.

Funding

This study was funded by Daiichi Sankyo, Inc., and AstraZeneca. Medical writing support (ApotheCom) was funded by Daiichi Sankyo, Inc.

Disclosure

H.S. Rugo: Financial Interests, Personal, Other, Consultancy/advisory support: NAPO, Mylan/Viatris, Daiichi Sankyo, Eisai; Financial Interests, Institutional, Invited Speaker: Novartis, Lilly, Pfizer, OBI Pharma, F. Hoffmann-La Roche AG/Genentech, Inc., Daiichi, AstraZeneca, Gilead Sciences, Inc., Merck; Financial Interests, Institutional, Research Grant: Stemline Therapeutics, Ambryx; Non-Financial Interests, Advisory Role, I advise a number of companies without compensation: various. E. Tokunaga: Financial Interests, Personal, Invited Speaker: AstraZeneca, Eli Lilly, Daiichi Sankyo. H. Iwata: Financial Interests, Personal, Advisory Board: Chugai, Daiichi Sankyo, AstraZeneca, Lilly, Sanofi; Financial Interests, Personal, Invited Speaker: Chugai, Daiichi Sankyo, AstraZeneca, Lilly, Pfizer, Sanofi, Taiho; Financial Interests, Personal and Institutional, Invited Speaker: Chugai, Daiichi Sankyo, AstraZeneca, MSD, Amgen, Sanofi, Lilly, Novartis, Bayer, Pfizer, Kyowa Hakko Kirin, Behringer, Nihon Kayaku. V. Petry: Other, Institutional, Invited Speaker: Novartis, MSD; Other, Institutional, Invited Speaker, Congress Sponsorship: Pfizer, AstraZeneca; Other, Institutional, Invited Speaker, Member Advisory Board: Daiichi Sankyo. E.F. Smit: Financial Interests, Institutional, Advisory Board: AstraZeneca, Daiichi Sankyo, MSD, Boehringer Ingelheim, Roche, Eli Lilly, Takeda, Sanofi, Janssen, BMS; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Merck Seranno; Financial Interests, Institutional, Other, DSMB member: DSI; Financial Interests, Institutional, Invited Speaker: Pfizer, AZ, Genmab, DSI, Sanofi. Y. Goto: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Guardant Health Inc., Illumina, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho, Johnson and Johnson, D3bio; Financial Interests, Personal, Invited Speaker: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, MSD, Merck, Novartis, Ono Pharmaceutical, Pfizer, Taiho, Thermo Fisher; Financial Interests, Personal, Other, Travel Grant: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Guardant Health, Preferred Network; Financial Interests, Personal and Institutional, Invited Speaker: Chugai, Novartis, Pfizer; Financial Interests, Institutional, Research Grant: Prefered Network; Non-Financial Interests, Member of Board of Directors: Cancer Net Japan, JAMT. D. Kim: Financial Interests, Personal, Invited Speaker: Korean Cancer Association, Korean Society of Medical Oncology, Korean Association for Lung Cancer, Japan Cancer Association; Financial Interests, Personal, Other, Scientific Advisor: Health Insurance Review & Assessment Service, Korea; Financial Interests, Personal, Invited Speaker, Medical writing assistance: Amgen, AstraZeneca, Boehringer-Ingelheim, BMS, Chong Keun Dang, Daiichi Sankyo, GSK, Pfizer, MSD, Merck, Novartis, Roche, Takeda, Yuhan; Financial Interests, Institutional, Invited Speaker, Clinical Trial Funding: Alpha Biopharma, Amgen, AstraZeneca/MedImmune, Boehringer-Ingelheim, Daiichi Sankyo, Hanmi, Janssen, Merus, MIrati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan, Chong Keun Dang, Bridge BioTherapeutics, GSK; Financial Interests, Institutional, Research Grant, Laboratory research funding to my institution: InnoN, IMBDx; Non-Financial Interests, Advisory Role: Amgen, BMS / ONO Pharmaceuticals, Daiichi Sankyo, Janssen, GSK, Pfizer, AstraZeneca, SK Biopharm, Takeda, Yuhan; Non-Financial Interests, Member of Board of Directors: Korean Society of Medical Oncology, Korean Association for Lung Cancer, Asian Thoracic Oncology Research Group; Non-Financial Interests, Advisory Role, Member of Scientific Advisory Board: NoveltyNobility; Other, Clinical trial research funding to my institution: Asian Thoracic Oncology Research Group. K. Shitara: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Takeda, Ono, MSD, Novartis, Daiichi Sankyo, Amgen, Guardant Health Japan Corp, Astellas Pharma Inc., Astellas, Bayer, AstraZeneca, Zymeworks Biopharmaceuticals Inc., ALX Oncology Inc; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Janssen, AstraZeneca, Eli Lilly, Astellas, Ono Pharmaceutical; Financial Interests, Institutional, Research Grant: Astellas, Ono, Daiichi Sankyo, Taiho, Chugai, MSD, Eisai, Amgen, PRA Health Sciences. S. Modi: Financial Interests, Personal, Advisory Board, and invited speaker: Genentech, Daiichi Sankyo, AstraZeneca; Financial Interests, Personal, Invited Speaker, and invited speaker: Seagen, Gilead; Financial Interests, Institutional, Sponsor/Funding: Genentech, Daiichi Sankyo, AstraZeneca, Seagen, DualityBio, Nuvation; Financial Interests, Personal, Advisory Board: DualityBio. J. Cortés: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Lilly, MSD, LEUKO, Bioasis, Clovis oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Jazz Pharmaceuticals, AbbVie, Scorpion Therapeutics, Biocon; Financial Interests, Personal, Invited Speaker: Roche, Novartis, Eisai, Pfizer, Lilly, MSD, Daiichi Sankyo; Financial Interests, Personal, Other, Consulting/advisor: Expres2ion Biotechnologies; Financial Interests, Personal, Other, consulting: Bridgebio; Financial Interests, Personal, Stocks/Shares: MAJ3 Capital; Financial Interests, Personal, Stocks/Shares, (relative): Leuko; Financial Interests, Institutional, Research Grant: Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, Guardant health, MSD, Pfizer, Piqur Therapeutics, Queen Mary University of London; Other, Travel cost and expenses: Roche, Novartis, Eisai, Daiichi Sankyo, Pfizer, Gilead, AstraZeneca, Stemline Therapeutics; Other, travel cost and expenses: MSD. I. Krop: Financial Interests, Personal, Advisory Board: Genentech/Roche, AstraZeneca, Daiichi Sankyo, Macrogenics, Seagen; Financial Interests, Personal, Other, DSMB member: Novartis; Financial Interests, Personal, Other, DSMC member: Merck; Financial Interests, Personal, Full or part-time Employment, Spouse: PureTech; Financial Interests, Personal, Officer, I am CSO in this non-profit: Translational Breast Cancer Research COnsortium; Financial Interests, Personal, Stocks/Shares, Spouse: PureTech; Financial Interests, Institutional, Invited Speaker: Pfizer, Macrogenics, Genentech, Roche. P.A. Jänne: Financial Interests, Personal, Advisory Board, Consulting fees for advice on drug development: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Eli Lilly, Voronoi, Daiichi Sankyo, Novartis, Sanofi, Takeda Oncology, Mirati Therapeutics, Trasncenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Eisai, Allorion Therapeutics, Accutar Biotech, AbbVie, Duality Biologics; Financial Interests, Personal, Advisory Board, Consulting fees for advice on diagnostic development: Biocartis; Financial Interests, Personal, Advisory Board, Consulting fee for advice on drug development: Merus, Frontier Medicines; Financial Interests, Personal, Advisory Board, Consulting fees for advice on drug development: Hongyun Biotechnology; Financial Interests, Personal, Stocks/Shares: Gatekeeper Pharmaceuticals, Allorion Therapeutics; Financial Interests, Personal, Royalties, I receive post-marketing royalties from being an inventor on a DFCI owned patent on EGFR mutations licensed to Lab Corp: Lab Corp; Financial Interests, Institutional, Research Grant, Sponsored research agreement with my institution: AstraZeneca, Daiichi Sankyo, PUMA, Eli Lilly, Boehringer Ingelheim, Revolution Medicines, Takeda Oncology. Y. Cheng, C. Taitt, F. Cheng: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. C.A. Powell: Financial Interests, Personal, Advisory Role: Daiichi Sankyo, Seagen, Silverback Therapeutics, Aptar; Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb. All other authors have declared no conflicts of interest.