Drug–related interstitial lung disease (ILD) occurred in less than 16% of patients with HER2-positive metastatic breast cancer following treatment with trastuzumab deruxtecan (T-DXd) at the approved dose (5.4 mg/kg), and the majority of these cases were Grade 1 or 2 according to findings presented at the ESMO Breast Cancer Virtual Congress 2021, held 5 to 8 May.
Lead author Charles A. Powell of the Pulmonary Critical Care and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, USA said that the phase II DESTINY-Breast01 study demonstrated strong efficacy of T-DXd in patients with pre-treated HER2-positive metastatic breast cancer. The study demonstrated an objective response rate of 61.4%, and median progression-free survival of 19.4 months.
In addition, a manageable safety profile was shown, which supported approval in the US, Japan, EU and UK for the treatment of patients with HER2-positive metastatic breast cancer that has progressed on ≥2 anti-HER2 therapies.
However, ILD remains an important identified risk with T-DXd. Dr. Powell and co-investigators set out to determine the occurrence of ILD in this patient population. They used data from patients with HER2-positive metastatic breast cancer treated with T-DXd monotherapy at 5.4 mg/kg every 3 weeks from August 2015 to June 2020; of these 61 patients participated in two phase I studies (DS8201-A-J101 [NCT02564900], DS8201-A-A104 [NCT03383692]) and 184 patients were in the phase II DESTINY-Breast01 study (NCT03248492).
Imaging and clinical data from baseline through the time of potential ILD case were retrospectively reviewed by an independent adjudication committee.
The investigators reported only ILD events that were adjudicated as drug related
This analysis included data from 245 patients with heavily pretreated HER2-positive metastatic breast cancer who received T-DXd for a median 9.7 months (range, 0.7 to 40.3 months).
During treatment, 38 (15.5%) patients experienced an ILD event that was adjudicated as drug related. Thirty (12.2%) were Grade 1 or 2 events. Grade 3 and Grade 4 ILD events were reported in one (0.4%) patient each. Six (2.4%) patients died due to a Grade 5 ILD event. Of patients with ILD, most (79%) experienced Grade 1 or 2 events.
Most of the ILD events occurred within the first 12 months of treatment. The median time to first ILD event was 5.6 (range, 1.1 to 20.8) months, with 97% of patients experiencing the first onset of ILD prior to 12 months. Forty-two percent of patients were treated for ≥12 months.
Time to event analysis for drug–related interstitial lung disease onset.
© Charles A. Powell.
The risk of patients having a new any grade ILD event beyond 12 months after treatment initiation was low, with a conditional probability of 1.8%.
In 27 of 44 (61.4%) events, the adjudication committee assessed the onset of ILD as being earlier than that reported by investigators (median difference, 52 days; range, 1 to 288 days). A summary on the use of steroids to manage ILD was also reported.
Prof. Harold Burstein of the Dana-Farber Cancer Institute and Harvard Medical School in Boston, MA, US who discussed the study findings said that ILD/ pneumonitis is an uncommon, but potentially serious side effects of many breast cancer treatments, including emerging therapies such as trastuzumab deruxtecan. Clinicians and patients need to be very aware of this risk. Risk factors are not well characterised. Prospective studies are needed to better define risks and screening. Patients with ILD/ pneumonitis should stop therapy. It will be particularly important to assess safety in early stage, curative treatment.
Conclusions
The investigators concluded that when T-DXd was administered at the approved dose (5.4mg/kg), most ILD events were low grade and occurred in the first 12 months. They added that the risk decreased after 12 months from the start of treatment, suggesting no cumulative toxicity.
It was noted that the adjudication committee assessed the onset of ILD as being earlier than the investigators in the majority of cases, which highlights the need for close monitoring that allows for earlier identification and effective management of ILD using updated guidelines.
They stated that additional follow-up is needed to confirm these findings.
Funding from AstraZeneca Pharmaceuticals LP was disclosed for this analysis. In March 2019, AstraZeneca and Daiichi Sankyo entered into a global development and commercialisation collaboration agreement for trastuzumab deruxtecan.
Reference
92O – Powell CA, Modi S, Iwata H, et al. Analysis of study drug–related interstitial lung disease (ILD) in patients (pts) with HER2+ metastatic breast cancer (mBC) treated with trastuzumab deruxtecan (T-DXd). ESMO Breast Cancer Virtual Congress 2021 (5-8 May).