More Data, More Benefit with T-DXd in Breast Cancer

The antibody–drug conjugate (ADC) trastuzumab deruxtecan (T-DXd; AstraZeneca/Daiichi Sankyo) continues to demonstrate impressive activity in patients with advanced HER2-positive breast cancer. In the phase II DESTINY-breast01 trial, the agent elicited a high overall response rate (ORR) and a long median progression-free survival (PFS)—as well as promising, but early, overall survival (OS) results. Findings were presented at the 2020 Virtual San Antonio Breast Cancer Symposium (SABCS) in December.

T-DXd combines the HER2-targeting monoclonal antibody trastuzumab and a cytotoxic payload—a topoisomerase I inhibitor derived from exatecan. At the 2019 SABCS meeting, researchers reported on 184 patients with previously treated advanced HER2-positive breast cancer at a median follow-up of 11.1 months. Patients had an ORR of 60.9%, a median duration of response (DoR) of 14.8 months, and a median PFS of 16.4 months—results that formed the basis of an FDA approval for third-line treatment.

At last month's meeting, researchers reported on those patients after about 9 more months. The ORR of 61.4% was similar, but the median DoR increased by 6 months, and the median PFS rose by 3 months. Median OS, which had not been reached previously, was nearly 25 months at 35% maturity. Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, NY, who presented the results, noted that with longer follow-up, she expects to see “a widening of the gap between median PFS and median [OS].”

Although no new toxicities were reported, all but one patient experienced side effects, and 61.4% of patients had adverse events classified as grade 3 or higher. Interstitial lung disease (ILD)—a serious side effect that can cause lung scarring—afflicted 15.2% of patients. “What we do recommend is that patients are monitored for respiratory symptoms” that may be indicative of ILD, Modi said.

Tiffany Traina, MD, also of MSKCC, agreed with Modi in her subsequent commentary, saying that “the risk of ILD really requires awareness, careful monitoring, and adherence to dose interruption and management guidelines to allow our patients the optimal risk–benefit balance.” However, she said that “these data confirm the ongoing and impressive activity of this antibody–drug conjugate.”

T-DXd is being tested in several randomized trials, including the phase III DESTINY-breast02 and DESTINY-breast03 trials, which are comparing it to therapies such as trastuzumab (Herceptin; Genentech) and ado-trastuzumab emtansine (T-DM1, Kadcyla; Genentech), among others. These trials “will further evaluate and hopefully confirm the benefit of this highly active [drug],” Traina said.

In addition, researchers are assessing the combination of T-DXd plus the PD-1 inhibitor nivolumab (Opdivo; Bristol Myers Squibb) based on preclinical research suggesting that it may have stronger antitumor activity than either agent alone. At SABCS, researchers presented data on 48 patients with previously treated advanced HER2-expressing breast cancer after a median follow-up of 6.9 months. Patients with HER2-positive disease had an ORR of 59.4% and a median PFS of 8.6 months; those with HER2-low cancer had an ORR of 37.5% and a median PFS of 6.3 months. Median DoR was not reached in either group. Adverse events of grade 3 and higher occurred in 43.8% of patients, evenly attributed to each drug. Five patients developed ILD.

“Acknowledging all the caveats of cross-trial comparisons, it's uncertain whether [immunotherapy] adds to trastuzumab deruxtecan benefit … although this is foundational work for us to learn from,” Traina said. “This combination strategy warrants additional study,” she added, noting her interest in whether it should be considered earlier in the course of treatment, or if its use could be guided by levels of biomarkers such as PD-L1 or tumor-infiltrating lymphocytes. –Catherine Caruso