medwireNews: A pooled analysis of nine early-phase trials of trastuzumab deruxtecan (T-DXd) monotherapy has identified an incidence of drug-related interstitial lung disease (ILD)/pneumonitis of 15.4%.
The majority of events were low grade and occurred within 12 months of receiving the first dose of T-DXd, note Charles Powell (Icahn School of Medicine at Mount Sinai, New York, USA) and co-authors, who also identified seven parameters “potentially associated” with the adverse event.
“The benefit–risk of T-DXd treatment is positive,” they say, but add that “some patients may be at increased risk of developing ILD/pneumonitis, and further investigation is needed to confirm ILD/pneumonitis risk factors.”
The team continues: “Close monitoring and proactive management of ILD/pneumonitis are warranted for all.”
The analysis included data on 1150 participants of four phase 1 and five phase 2 studies of single-agent T-DXd, including DESTINY-Breast01, DESTINY-Gastric01, DESTINY-CRC01, and DESTINY-Lung01, in which the antibody–drug conjugate was given at a dose of 5.4, 6.4, 7.4, or 8.0 mg/kg every 3 weeks.
Patients were aged a median of 60 years and had received a median of four prior treatment regimens (range, 1–27). Most (44.3%) had breast cancer, with gastric and lung cancer the next most common tumor types, at 25.6% and 17.7%, respectively. Forty-four percent of the participants were recruited from Japan and the rest from other countries.
As judged by an independent adjudication committee following a review of trial records, one or more T-DXd-related ILD/pneumonitis events occurred in 15.4% of patients. A total of 77.4% of the patients had events of grade 1 or 2, 1.3% of grade 3 or 4, and 2.2% of grade 5.
Most (87.0%) of the ILD/pneumonitis events happened in the first 12 months of T-DXd treatment, and the median time to onset of adjudicated ILD/pneumonitis was 5.4 months.
Powell and colleagues also report in ESMO Open that 47 of the 76 patients with a grade 1 event were rechallenged with T-DXd, and just three had recurrent ILD/pneumonitis, again grade 1 in all cases.
“Future research is warranted to better understand rechallenge with T-DXd,” they write.
Applying stepwise Cox regression, the team identified several baseline variables significantly associated with an increased risk for drug-related ILD/pneumonitis, namely:
- age less than 65 years;
- enrollment in Japan;
- T-DXd dose greater than 6.4 mg/kg;
- oxygen saturation less than 95%;
- moderate or severe renal impairment;
- presence of lung comorbidities (not including lung cancer); and
- time since initial cancer diagnosis of more than 4 years.
The researchers say that “the clinical relevance of some of these factors remains unclear,” but they believe the identified factors “are informative for clinicians on what to be aware of while treating patients with T-DXd.”
Powell et al add: “Future analyses of more homogeneous populations from randomized clinical trials will help confirm these findings and allow for further understanding of any relevant risk factors (e.g. specific to different tumor types).”
The team concludes that “[t]he monitoring, diagnosis, and management of ILD/pneumonitis is an area of continuing improvement,” and refers clinicians to guidelines updated in 2019 on the dosing and supportive care required during T-DXd treatment.
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