Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies.

This pooled analysis of nine phase I and II trastuzumab deruxtecan (T-DXd) monotherapy studies described drug-related interstitial lung disease (ILD)/pneumonitis in patients treated with T-DXd. Patients who received T-DXd across nine studies were included. Investigator-assessed ILD/pneumonitis events were retrospectively reviewed by an independent adjudication committee; events adjudicated as drug-related ILD/pneumonitis are summarized. The analysis included 1150 patients (breast cancer, 44.3%; gastric cancer, 25.6%; lung cancer, 17.7%; colorectal cancer, 9.3%; other cancer, 3.0%). Median treatment duration was 5.8 (range, 0.7-56.3) months, with a median of 4 (range, 1-27) prior lines of therapy. The overall incidence of adjudicated drug-related ILD/pneumonitis was 15.4% (grade 5, 2.2%). Most patients with ILD/pneumonitis experienced low-grade events (grade 1 or 2, 77.4%); 87.0% had their first event within 12 months [median, 5.4 (range, <0.1-46.8) months] of their first dose of T-DXd. Based on data review, adjudicated ILD/pneumonitis onset occurred earlier than identified by investigators for 53.2% of events [median difference in onset date, 43 (range, 1-499) days]. Stepwise Cox regression identified several baseline factors potentially associated with increased risk of adjudicated drug-related ILD/pneumonitis: age <65 years, enrollment in Japan, T-DXd dose >6.4 mg/kg, oxygen saturation <95%, moderate/severe renal impairment, presence of lung comorbidities, and time since initial diagnosis >4 years. In this pooled analysis of heavily treated patients, the incidence of ILD/pneumonitis was 15.4%, with most being low grade and occurring in the first 12 months of treatment. The benefit-risk of T-DXd treatment is positive; however, some patients may be at increased risk of developing ILD/pneumonitis, and further investigation is needed to confirm ILD/pneumonitis risk factors. Close monitoring and proactive management of ILD/pneumonitis are warranted for all.

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Disclosure All authors received nonfinancial support (assistance with manuscript preparation) from ArticulateScience, LLC, funded by AstraZeneca. Additional disclosures are as follows: CAP reports personal fees from Daiichi Sankyo, AstraZeneca, and Voluntis, outside of the submitted work. SM reports consulting or advisory roles for Daiichi Sankyo, MacroGenics, and AstraZeneca; speakers bureau involvement with Genentech, Daiichi Sankyo, AstraZeneca, and Seagen; travel fees from Genentech and Daiichi Sankyo; honoraria from Novartis; and research funding from Roche/Genentech, Novartis, Seagen, Synta, and Daiichi Sankyo. HI reports grants from Daiichi Sankyo, Novartis, AstraZeneca, Pfizer, Eli Lilly Japan, Chugai, Eisai, Kyowa Kirin, Merck Sharp & Dohme (MSD), GSK, Nippon Kayaku, and Bayer; and personal fees from Daiichi Sankyo, Novartis, AstraZeneca, Pfizer, Eli Lilly Japan, Chugai, Eisai, and Kyowa Kirin. ST reports grants and personal fees from Daiichi Sankyo, Eisai, Novartis, Taiho, MSD, Chugai, Bayer, and AstraZeneca. EFS reports consulting or advisory roles for Lilly, AstraZeneca, Boehringer Ingelheim, Roche/Genentech, Bristol Myers Squibb, Merck KGaA, MSD Oncology, Takeda, and Bayer; and research funding from Boehringer Ingelheim, Bayer, Roche/Genentech, AstraZeneca, and Bristol Myers Squibb. SS reports personal fees from Amgen, Roche/Genentech, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Merck KGaA, Seagen, Checkmab, and AstraZeneca. DYC reports personal fees from Novartis, Pfizer, Eli Lilly, Roche, AstraZeneca, Sanofi, Amgen, and Daiichi Sankyo; and travel fees from Pfizer, Daiichi Sankyo, and Eisai. EM and NS are employees of AstraZeneca and may own stock or stock options in that company. AQ, JS, and CT are employees of Daiichi Sankyo and may own stock or stock options in that company. DRC reports personal fees from Daiichi Sankyo.