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Effective early detection and optimal management are critical in preventing high-grade interstitial lung disease, a treatment-related adverse effect of fam-trastuzumab deruxtecan-nxki in patients with HER2-positive metastatic breast cancer.
Effective early detection and optimal management are critical in preventing high-grade interstitial lung disease (ILD), a treatment-related adverse effect of fam-trastuzumab deruxtecan-nxki (Enhertu) in patients with HER2-positive metastatic breast cancer, according to retrospective data from a pooled analysis presented during the ESMO Breast Cancer Virtual Congress 2021.1
Data also showed that the risk of all-grade ILD decreases over time, suggesting that this patient population does not experience cumulative toxicity. Furthermore, toxicity management guidelines for ILD have been updated and implemented across the program since December 2019, in an effort to lower the rates of high-grade ILD through early detection.
Overall, the clinical findings support the positive benefit-risk profile of trastuzumab deruxtecan, said lead study author Charles A. Powell, MD, in a presentation during the meeting.
“Trastuzumab deruxtecan has shown significant and unprecedented clinical activity in HER2-positive metastatic breast cancer,” said Powell, director of the Mount Sinai-National Jewish Health Respiratory Institute, and professor of medicine, pulmonary, critical care and sleep medicine at Mount Sinai. “The analysis from this breast cancer cohort highlights the need for earlier detection of ILD and management consistent with the current guidelines.”
In December 2019, the FDA granted an accelerated approval to fam-trastuzumab deruxtecan-nxki for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior anti–HER2-based regimens in the metastatic setting.
The regulatory decision was based on findings from the phase 2 DESTINY-Breast01 trial, updated data of which showed that trastuzumab deruxtecan induced a confirmed objective response rate of 61.4%, a median duration of response of 20.8 months (95% CI, 15.0–not estimable [NE]) and a median progression-free survival of 19.4 months (95% CI, 14.1–NE).2
Because ILD has been identified as a special AE of interest in patients receiving trastuzumab deruxtecan, investigators looked to further characterize ILD in heavily pretreated patients with metastatic breast cancer.
The analysis specifically included patients with HER2-positive metastatic breast cancer who received the 5.4-mg/kg dose of trastuzumab deruxtecan every 3 weeks in 2 phase 1 studies, as well as in the phase 2 DESTINY-Breast01 trial, between August 2015 and June 8, 2020, which was the data cutoff date.
All potential ILD cases were retrospectively reviewed by an independent adjudication committee through imaging and clinical data; the committee assessed whether the reported event was a case of ILD and whether it was related to trastuzumab deruxtecan. Events that were adjudicated as related to treatment were reported, Powell said, adding that ILD cases with fatal outcomes were assessed to determine whether the cause of death was linked to treatment-related ILD.
Investigators also utilized a multivariate stepwise Cox regression model to evaluate the link between baseline factors and time to occurrence of the outcome; the stepwise variable selection entry criterion was P <.05 and the remain criterion was P <.10.
Heavily pretreated patients, with a median 7 (range, 2-27) prior lines of therapy, were pooled from the single-arm phase 1 DS8201-A-J101 (NCT02564900; n = 50) and DS8201-A-A104 (NCT03383692; n = 11) studies, as well as the phase 2 DESTINY-Breast01 study (NCT03248492; n = 184).
To identify ILD, Powell said that the ILD adjudication committee was established in November 2017, Kubo guidelines were added to clinical protocols in the first quarter of 2018, and an ILD awareness campaign, designed to educate on ILD identification and management, was initiated in June 2019.
All patients were enrolled prior to implementation of the updated toxicity management guidelines in December 2019 across all trastuzumab deruxtecan clinical trials, Powell emphasized. Regarding baseline characteristics of the overall analysis population (N = 245), the median age was 56.0 years (range, 28-96), 23.7% of patients were from Japan, and 57.1% had an ECOG performance status of 0.
Study drug–related ILD was identified via the adjudication committee in 38 patients (15.5%) overall; of these, 79% had grade 1/2 events. In a Kaplan-Meier analysis of time to first ILD events, it was found that 97% of ILD events occurred in the first 12 months of trastuzumab deruxtecan and 42% of patients were on treatment for at least 1 year (median, 9.7 months; range, 0.7-40.3 months).
The median time to first ILD event was 5.6 months (range, 1.1-20.8 months).
Investigators identified ILD onset (n = 44) earlier or at the same time as the adjudication committee in 38.6% of cases. However, investigators identified onset of the AE later than the adjudication committee in 61.4% of cases (n = 27), with a median difference of 52.0 days (range, 1-288).
“This highlights an opportunity for more timely detection of ILD,” Powell said.
Systemic steroid use was also assessed and was used in patients who experienced grade 2 or higher ILD (n = 24), 58.3% (n = 14) were treated with steroids. Six events led to grade 5; 3 of these cases were treated with steroids.
“This means that 40% of grade 2 through 4 events were not treated with steroids as per the management guidelines, and half of the events leading to death were not treated with steroids,” Powell said. “However, it’s important to note that 43 of the 44 adjudicated ILD events occurred prior to December 15, 2019, when the updated toxicity management guidelines were implemented in clinical trials.”
The median time from adjudicated all-grade ILD onset to the start of steroid treatment was 25.0 days (range, 1-87).
The updated toxicity management guidelines state that all patients who experience ILD are required to stop treatment. Those with grade 1 ILD may restart once ILD has resolved, but those with grade 2 to 4 ILD must discontinue trastuzumab deruxtecan, Powell explained.
Select patient characteristics were also assessed as potential factors of interest associated with developing ILD through the stepwise multivariate Cox regression model. These included patients treated in Japan (n = 58; non-Japan, n = 187) and moderate/severe renal impairment at baseline (n = 30; no impairment, n = 118). However, these risk factors need to be confirmed in larger, randomized, controlled trials, Powell noted.
In a pooled analysis that Powell presented at the 2021 AACR Annual Meeting, investigators evaluated ILD across multiple tumor types of trastuzumab deruxtecan trials.3
Most patients included in the analysis experienced ILD that was either grade 1 (4.6%; n = 40) or grade 2 (7.7%; n = 68) in severity (78%; n = 108/139). A total 1.0% (n = 9), 0.1% (n = 1), and 2.4% (n = 21) experienced grade 3, 4, or 5 ILD, respectively.
Two of the trials, the phase 2 DESTINY-Lung01 (NCT03505710) and DESTINY-Gastric-02 (NCT04014075), both enrolled patients following the implementation of the updated toxicity management guidelines (n = 160 combined). Of these, any-grade, grade 3 or higher, and grade 5 ILD events were observed in 11 (6.9%), 3 (1.9%), and 2 (1.3%) patients, respectively.
“By looking at the rates of ILD by year of enrollment, these data suggest potentially lower incidence of high-grade ILD events after implementation of the guidelines,” Powell said. “Although this difference may be partly due to a shorter treatment duration, these findings are suggestive of a difference after introduction of the new guidelines, but they need to be confirmed in ongoing studies.”
Powell added that the analysis presented at the ESMO Breast Cancer Virtual Congress 2021 is exploratory and hypothesis generating in nature. Phase 3 randomized, controlled trials of trastuzumab deruxtecan in breast cancer are ongoing, Powell concluded.