ASCO 2025: Real-World Data Supports Rechallenging Trastuzumab Deruxtecan After ILD

Trastuzumab deruxtecan (T-DXd, Enhertu; AstraZeneca and Daiichi Sankyo) has become a pivotal therapy in the treatment of HER2-positive cancers, yet its use is associated with the risk of interstitial lung disease (ILD), a potentially serious and sometimes fatal complication. As the oncology community works to balance efficacy with safety, the question of whether and how to safely rechallenge patients with T-DXd after ILD remains critical.

At the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, Hope Rugo, MD, a medical oncologist, division chief of breast medical oncology, and a professor of medical oncology and therapeutics research at City of Hope in Duarte, California, presented data from a multi-institutional real-world study examining outcomes for patients rechallenged with T-DXd after experiencing ILD. In this interview with Pharmacy Times®, Rugo discusses key findings from the study, including criteria for rechallenge, the impact of steroids on recovery, and practical guidance for pharmacists and clinicians managing patients with ILD. The conversation offers valuable insights into navigating complex clinical decisions and optimizing outcomes for patients receiving T-DXd therapy.

Pharmacy Times: What were the specific criteria used to determine patient eligibility for rechallenge with T-DXd after experiencing ILD?

Hope Rugo, MD: A little background helps in understanding this question. ILD, or pneumonitis, is a known complication of some oncology drugs, though it occurs across many agents we use in cancer care. It’s generally rare, but T-DXd is somewhat unique in that, although the overall ILD rate isn’t very high—ranging from 11% to 15%—it is dose-related, and risk factors include race, ethnicity, renal function, and prior history of ILD, based on various trials. The key issue with ILD from T-DXd is the associated mortality risk, so many criteria have been developed to reduce the likelihood of serious ILD in patients receiving this therapy.

For patients with grade 1, asymptomatic ILD—meaning they have ground glass opacities seen on diagnostic chest CT imaging but no symptoms—the recommendation is to hold the drug, monitor for recovery by radiographic changes, and resume therapy only once the ILD has resolved completely. The timeframe for recovery has evolved as we’ve gained more experience, and there are recommendations to consider a half-milligram per kilogram dose of steroids to hasten improvement, which works well. Decisions about retreating are nuanced and depend on how well the cancer is controlled, how long you wait for recovery, and when you choose to repeat the CT. For patients with symptomatic ILD—grade 2 or higher—T-DXd is permanently discontinued, and they are treated with 1 mg/kg of steroids, with additional medications added if there isn’t a rapid response. We don’t fully understand why some patients develop asymptomatic ILD while others progress to symptomatic or higher-grade ILD. Importantly, in the large body of data on T-DXd, grade 4 ILD hasn’t really been observed. For patients who become very sick with ILD, mortality remains an unfortunate reality, though thankfully the rate is quite low—about 0.7% to 1.1%—except in specific cases like patients on steroids for brain metastases, where the higher mortality seemed related to infections.

A depiction of the overexpression of the HER2 protein. Image Credit: © Ayesha lateef - stock.adobe.com

So that’s the background. What data did we have before this study? The first insights on retreatment came from a pooled analysis of 9 prospective studies, presented at ESMO Breast 2024, and hopefully to be published soon. In that analysis, a portion of patients who had experienced grade 1 ILD were retreated—fewer than I had anticipated, likely due to patients being heavily pretreated or lacking good disease control by the time ILD was detected. Among those retreated, some remained on therapy for extended periods and had meaningful clinical benefit. Some developed recurrent ILD, but these were mostly grade 1, with 1 case of grade 2 that fully resolved. Patients with grade 1 ILD who were retreated, recovered, and then retreated again did well overall.

For the study we’re discussing today, our objective was to evaluate patients treated in real-world settings. Clinical trial populations are often healthier with fewer comorbidities, so we wanted to see what happens in everyday practice. This was a multi-institutional cohort study across 5 US centers, led by our senior fellow Kelsey Natsuhara, MD, who did the bulk of the work and, coincidentally, is welcoming her first child during ASCO, so I’m presenting the data on her behalf.

Pharmacy Times: What did you find in this real-world analysis?

Rugo: Across the 5 institutions, we reviewed data from 2017 to 2024 on patients treated with T-DXd for any reason. We identified 1476 patients overall, of whom 143 developed any grade of ILD. Sixty-five patients—about 45%—permanently discontinued T-DXd due to grade 2 or higher ILD. The mortality rate in this group was 0.5%, which was actually lower than what we’ve seen in clinical trials. Among the 59 patients with grade 1 ILD eligible for rechallenge, 75% (44 patients) were rechallenged. Interestingly, 18 of those 44 patients were rechallenged before CT imaging showed complete resolution—likely because patients and providers didn’t want to delay treatment too long. Twenty-six patients had radiographic improvement before rechallenge.

Of the 44 rechallenged patients, 12 (27%) developed recurrent ILD, mostly grade 1. Two had grade 2 or grade 3 ILD. Of the 8 patients who had recurrent ILD, 3 were rechallenged a second time, and they did not experience further ILD recurrence. The primary reasons for not rechallenging were disease progression, concerns about ILD, and, in 1 case, patient choice due to side effects.

Interestingly, 19 patients who had grade 2 ILD were rechallenged. They stayed on T-DXd for a median of 91 days, with 16% developing recurrent ILD—1 with grade 2, 1 with grade 3, and 1 with grade 4. This suggests a potentially higher risk of symptomatic ILD when rechallenging after grade 2 events, though the numbers are small, so we have to be cautious. Sometimes, if there’s uncertainty about whether the ILD was drug-related—perhaps a patient had pneumonia, a viral infection, or asthma—you might opt to rechallenge, but it’s important to proceed carefully.

Steroid use made a significant difference: patients treated with steroids for grade 1 ILD showed radiographic improvement in a median of 29 days, compared to 82 days for those without steroids—a statistically significant difference. I routinely treat with 0.5 mg/kg of steroids to promote faster recovery. The median time to ILD improvement after rechallenge was about 39 days, while patients who weren’t rechallenged took longer, though this could be confounded by lack of follow-up CT scans, as they typically moved on to different treatments.

Most patients who were rechallenged had breast cancer, and the median time to rechallenge was 42 days. Some received interim therapy, but most were rechallenged at the same T-DXd dose, even while still tapering steroids. After rechallenge, patients remained on T-DXd for a median of 215 days—almost a year—which is remarkable. Only 27% developed recurrent ILD, and most of those events were grade 1. Three patients with recurrent grade 1 ILD were rechallenged again, and 2 of them continued T-DXd for 63 and 211 days; 1 patient is still on therapy as of May 2025. Notably, none of the patients rechallenged after grade 2 ILD developed grade 5 ILD, and even those who developed grade 3 or 4 ILD after rechallenge recovered. Overall, this real-world data shows that rechallenge after grade 1 ILD is safe in a diverse patient population and can result in prolonged clinical benefit. Steroid use promotes faster radiographic improvement, and the recurrence of ILD after rechallenge is uncommon and mostly low grade. Importantly, no patients in this cohort died from ILD after rechallenge, which is very encouraging and supports using this approach to maximize the benefit of T-DXd in eligible patients.

Pharmacy Times: Based on your findings, what recommendations would you make for clinical practice regarding rechallenging patients with T-DXdafter ILD?

Rugo: [These] data [are] very informative for clinical practice. The key takeaway is that ILD or pneumonitis is a real toxicity associated with T-DXd, particularly in breast cancer patients treated at standard dosing. In clinical trials, the rate is around 11% to 12%, sometimes a bit lower, and most cases are grade 1 or 2, which is encouraging. The only way to detect asymptomatic ILD is through diagnostic CT scans—specifically, proper diagnostic CTs, not fused PET/CTs or non-diagnostic scans. For average-risk patients, I recommend CT scans at 9 weeks, then again at 12 weeks, continuing this pattern for the first year since 89% of ILD cases occur within the first year. After that, scans can be spaced out based on tumor staging. However, it’s crucial to remember that rare cases of significant ILD, including grade 5, can occur even beyond the first year, so we shouldn’t stop monitoring.

For higher-risk patients—such as older individuals, those heavily pretreated, those with prior ILD from other drugs, or with renal insufficiency—I recommend an initial CT at 6 weeks to catch early changes. For patients with grade 1 ILD, I hold the next T-DXd dose, treat with 0.5 mg/kg of steroids, and taper after a week, usually maintaining steroids until a 3-week follow-up CT. In all our cases, we’ve been able to retreat once ILD resolves. Sometimes, we see fleeting ground glass opacities that shift location and are hard to characterize; in those cases, as long as there’s significant improvement from baseline, we’ve safely resumed therapy.

For recurrent ILD, the guideline is to dose-reduce when retreating. For grade 2 ILD, the current recommendation is not to rechallenge. However, if it’s unclear whether the ILD was drug-related or due to an infection or underlying airway disease, you can cautiously consider rechallenge following the same protocols. Personally, if a patient was symptomatic, I’m unsure it was drug-related, and they’ve fully recovered, I might consider rechallenging at a reduced dose to maximize safety. For patients with uncomplicated grade 1 ILD that resolves, we can feel confident about rechallenging, as this often results in meaningful clinical benefit for patients.