The invited discussant of the DS8201-A-U105 trial, Rebecca A. Dent, MD, Head of the Department of Medical Oncology, Senior Consultant, and Chief of the Breast Medical Oncology Service at the National Cancer Center Singapore, said the results were reassuring in terms of safety and may pave the way for studying such combinations in other patient subsets.1 The combination makes sense, she said, based on the potential for synergy.
Rebecca A. Dent, MD
In DESTINY-Breast01, fam-trastuzumab deruxtecan-nxki (T-DXd) produced impressive results in 184 patients who had received a median of six prior regimens (as compared with 4.5 prior therapies in DS8201-A-U105).2 The confirmed response rate with the single agent was 61.4%, with 6.5% being complete responses, and median progression-free survival was 19.4 months. The goal of the current study was to determine whether the checkpoint inhibitor could enhance that efficacy.
However, the confirmed response rate, 65.6% in the HER2-positive cohort and 50.0% in the HER2-low subset, was similar to that seen in DESTINY-Breast01. “The waterfall plots look similar…, and the median progression-free survival was close to 11 or 12 months with the combination. The bottom line, as Dr. Hamilton said, is there was a negligible effect of immunotherapy added to this antibody-drug conjugate,” Dr. Dent commented. She added that nivolumab did not appear to increase toxicity, which is reassuring.
What Next?
Dr. Dent did not discount the possibility of greater efficacy down the line. “I would say, however, the combination is expected to affect the tumor microenvironment, with maybe little impact on the response rate. As we see with some of the other immunotherapy trials, it’s likely more realistic to expect a greater improvement in progression-free survival and overall survival,” she pointed out.
Dr. Dent also argued that other breast cancer subtypes, primarily triple-negative, are more immunogenic and perhaps, therefore, better targets for this combination. She also maintained the results would likely be more encouraging in earlier lines of treatment, “before immune escape sets in.”
“So, I wouldn’t say this trial is negative,” she concluded. “I think we need to evaluate this combination in a better context, potentially earlier and in different groups of patients” and in larger studies, which are currently ongoing.
DISCLOSURE: Dr. Dent has received honoraria from AstraZeneca, MSD, Pfizer, and Roche/Genentech; has served as a consultant or advisor to AstraZeneca, Eisai, Merck, Novartis, Pfizer, and Roche; and has been reimbursed for travel, accommodations, or other expenses by Amgen, Merck, Pfizer, and Roche.
REFERENCES
1. Hamilton EP, Shapiro CL, Boni V, et al: Primary analysis from DS8201-A-U105: A 2-part, open label, phase 1b trial assessing trastuzumab deruxtecan with nivolumab in patients with HER2-expressing advanced breast cancer. ESMO Breast Cancer Congress 2022. Abstract 162O. Presented May 3, 2022.
2. Modi S, Saura C, Yamashita T, et al: Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med 38:610-621, 2020.
