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

Abstract

Introduction: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: HER2; adverse event; interstitial lung disease; pneumonitis; trastuzumab deruxtecan.

Figure 1

Studies and patients included in the pooled analysis. The colored bar on each arrow indicates the time of patient enrollment and the gray is follow-up.^,,,,,,,,, All studies noted here are active but no longer recruiting, except for DESTINY-Gastric01 and DESTINY-CRC01, which were completed in 2020.^, Note that most patients were enrolled before the implementation of toxicity management guidelines. ILD, interstitial lung disease; NSCLC, non-small-cell lung cancer; Q, quarter. ^aOnly patients who received trastuzumab deruxtecan 5.4, 6.4, 7.4, or 8.0 mg/kg every 3 weeks are included.

Figure 2

Analysis of adjudicated drug-related ILD/pneumonitis events. (A) Kaplan–Meier analysis of time to first adjudicated drug-related ILD/pneumonitis event. Among 177 patients who had ILD/pneumonitis, 154 (87.0%) had a first ILD/pneumonitis event within 12 months of starting treatment. The median time to adjudicated ILD/pneumonitis onset among those with ILD/pneumonitis was 5.4 months (range, <0.1-46.8 months). The median treatment duration in all patients in the pool was 5.8 months (range, 0.7-56.3 months), and 24.1% of all patients remained on treatment for >12 months. Treatment discontinuations due to reasons other than ILD/pneumonitis were included as a competing event. (B) Multivariate stepwise Cox regression analysis, final model. Factors included in the final model were age group, sex, country, Eastern Cooperative Oncology Group performance status, baseline weight, presence of lung cancer or lung metastasis/lymphangitis carcinomatosis at baseline, prior chest/lung radiotherapy, presence of lung comorbidity, baseline renal function, baseline white blood cell count, baseline albumin category, number of prior lines of therapy in the locally advanced/metastatic setting, time since disease diagnosis category, time since the end date of the last anticancer therapy to the first infusion of trastuzumab deruxtecan category, dose category, and baseline SpO₂ category. Of these, seven factors were identified as factors of interest. HER2, human epidermal growth factor receptor 2; ILD, interstitial lung disease; q3w, every 3 weeks; Ref, reference; SpO₂, oxygen saturation. ^aHazard ratios are presented relative to the reference categories indicated. ^bIncludes asthma, chronic obstructive pulmonary disease, prior interstitial lung disease/pneumonitis, pulmonary fibrosis, pulmonary emphysema, and radiation pneumonitis. ^cDue to differences in data collection among the studies, some data were not collected for all patients; thus, the number of patients may not add up to the total population. ^dDetermined by Cockcroft–Gault formula.