medwireNews: Patients with HER2-positive metastatic breast cancer that is refractory or resistant to trastuzumab emtansine (T-DM1) have significantly better outcomes with trastuzumab deruxtecan (T-DXd) than a physician’s choice treatment, shows the phase 3 DESTINY-Breast02 trial.
“Overall, patients who received trastuzumab deruxtecan remained on treatment longer, had higher objective response rates [ORRs], and longer duration of response, progression-free survival [PFS], and overall survival [OS]” than those given capecitabine plus either trastuzumab or lapatinib, write the researchers in The Lancet.
They add that the study confirms “the favourable benefit–risk profile” of T-DXd in this patient population, as previously reported in the single-arm, phase 2 DESTINY-Breast01 trial, and supports “this drug as the preferred therapy for patients who received trastuzumab emtansine.”
The authors continue: “To our knowledge, this study is the first randomised trial to show a significant benefit of one antibody-drug conjugate treatment in patients who have progressed on another antibody-drug conjugate, providing an optimistic outlook for sequential antibody-drug conjugate treatments to improve disease outcomes in patients with HER2-positive metastatic breast cancer and other patient populations.”
DESTINY-Breast02 enrolled 608 patients with unresectable or metastatic HER2-positive breast cancer who had progressed on prior T-DM1 and randomly assigned them to receive either T-DXd at a 3-weekly dose of 5.4 mg/kg or treatment of physician’s choice, which was capecitabine plus trastuzumab or lapatinib on a 21-day schedule.
At a median follow-up of 21.5 months in the T-DXd group and 18.6 months in the control group, the primary endpoint of PFS by blinded independent review was significantly improved in the former, at a median of 17.8 versus 6.9 months, and a hazard ratio (HR) for progression or death of 0.36.
T-DXd was also associated with significantly better OS than treatment of physician’s choice, at medians of 39.2 and 26.5 months, respectively, and an HR for death of 0.66. The investigators describe the improvement as both “statistically significant and clinically meaningful.”
The ORR was also higher in the T-DXd than control arm, at 70% versus 29%, and the median duration of response was more than doubled, at 19.6 versus 8.3 months.
“The overall safety profile of trastuzumab deruxtecan in this study was consistent with the established safety of this drug, with no new safety signals observed,” say Ian Krop (Yale Cancer Center, New Haven, Connecticut, USA) and colleagues.
A total of 14% of patients receiving T-DXd discontinued treatment due to drug-related treatment-emergent adverse events (TEAEs) compared with 5% of those given treatment of physician’s choice. And there were four fatal drug-related TEAEs in the T-DXd group – two cases of pneumonitis and one each of acute myeloid leukemia and pneumonia – versus none in the control group.
Krop and team also report on the incidence of drug-related interstitial lung disease, “an important risk associated with trastuzumab deruxtecan treatment.” This occurred in 42 (10%) participants treated with T-DXd and just one (<1%) given physician’s choice of treatment. The majority (n=37) of cases in the T-DXd group were of grade 1 or 2, while three were of grade 3, and two were grade 5. The one case in the control group was of grade 3.
“Current management guidelines advise closely monitoring patients for signs and symptoms of interstitial lung disease or pneumonitis, immediately and actively managing all suspected events with corticosteroids, and delaying or stopping trastuzumab deruxtecan,” write the investigators.
“These revised guidelines might explain the numerically lower rates of grade 5 interstitial lung disease or pneumonitis events observed in DESTINY-Breast02 compared with DESTINY-Breast01,” they continue.
“Further research should be supported to explore the mechanisms of interstitial lung disease and better identify and describe the most at-risk patient groups.”
The author of a related commentary says that “the DESTINY Breast-02 trial showed robust activity of trastuzumab deruxtecan in patients with metastatic HER2-positive breast cancer who previously received trastuzumab emtansine.”
But Saranya Chumsri, from Mayo Clinic in Jacksonville, Florida, USA, adds: “Given rapid changes in the treatment landscape of patients with metastatic HER2-positive breast cancer, whether trastuzumab deruxtecan will be better than newer combination therapies remains unclear, since treatment of physician’s choice only included capecitabine plus trastuzumab or lapatinib in this trial.”
And she concludes that “[p]roper management, particularly with the treatment of interstitial lung disease and prophylactic antiemetics, is crucial to ensure patient safety and allow patients to continue this remarkable treatment.”
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Lancet 2023; doi:10.1016/S0140-6736(23)00620-7
Lancet 2023; doi:10.1016/S0140-6736(23)00732-8