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SAN ANTONIO -- Use of trastuzumab deruxtecan (T-DXd, Enhertu) in patients with localized, hormone receptor (HR)-positive, HER2-low breast cancer demonstrated evidence of clinical activity in the neoadjuvant setting, according to research presented here.

Investigators showed that among the 49 response-evaluable patients in the phase II clinical trial, objective response rates were 68% with the antibody-drug conjugate alone and 58% when used in combination with anastrozole, including two complete responses in each arm, reported Aditya Bardia, MD, MPH, of Massachusetts General Hospital and Harvard Medical School in Boston.

There was one pathologic complete response (pCR), the study's primary endpoint, though Bardia noted that surgical results were still pending for seven patients treated with T-DXd alone and nine patients treated with T-DXd plus anastrozole.

"The addition of endocrine therapy to T-DXd did not appear to enhance efficacy," Bardia said during a press briefing at the San Antonio Breast Cancer Symposium (SABCS). "But caution needs to be exerted in deriving strong conclusions given the small numbers."

"This is the first report of neoadjuvant T-DXd for patients with HR-positive, HER2-low breast cancer," he added. "And it provides the groundwork for future studies with antibody-drug conjugates for patients with early-stage breast cancer."

T-DXd has demonstrated impressive efficacy in metastatic HER2-low breast cancer, but its efficacy in localized HER2-low breast cancer is not known, Bardia noted.

"While neoadjuvant anthracycline/taxane-based combination chemotherapy is often utilized to treat high-risk localized hormone receptor-positive breast cancer, it can be associated with low [pCR] rates (which is slightly lower in HER2-low)," he said, along with "a radiological response rate of about 50%, dose reductions and interruptions, and significant toxicity -- including myelosuppression, peripheral neuropathy, cardiomyopathy, and risk of leukemia."

Bardia and colleagues designed an investigator-initiated clinical trial to evaluate T-DXd in patients with localized HR-positive/HER2-low breast cancer, and also to assess whether adding endocrine therapy would improve efficacy in this setting.

The 58 study participants (who had stage II-III disease) were randomly assigned 1:1 to neoadjuvant T-DXd as a single agent or in combination with anastrozole. The study's initial protocol called for patients to be treated with six cycles of T-DXd, but after half of patients had been enrolled, there was an amendment to the protocol increasing the number of cycles to eight. After surgery, patients could receive additional adjuvant therapy at the discretion of the provider.

In terms of residual cancer burden (RCB) after treatment with T-DXd alone, one patient with baseline stage III disease had RCB-0 (equating to a pCR) after eight cycles of treatment, while two patients had RCB-1 (minimal burden). Three patients had RCB-1 as the best response with T-DXd plus anastrozole.

Seventeen of 35 patients had a change in HER2 protein levels from baseline to surgery after T-DXd, as measured with immunohistochemistry, 88% of those being decreases in HER2 expression.

Carlos Arteaga, MD, SABCS co-director and director of the Simmons Comprehensive Cancer Center in Dallas, who served as moderator during the press briefing, asked Bardia whether it was possible too many patients with lower-grade tumors were enrolled in the study, "perhaps explaining the low RCB and pathologic complete response rate."

"We know that for tumors that are grade 1, the response rates to neoadjuvant chemotherapy are very low, and tumors that are grade 3 will be higher," Bardia said. "In this clinical trial, about one-third of patients who were enrolled had grade 3 tumors -- so there was a comparatively high proportion of patients who had grade 3 tumors, and I think that reflects investigator selection."

The toxicity profile was consistent with what was seen previously with T-DXd, with nausea the most common adverse event both with single-agent treatment and in combination, Bardia reported.

The rate of myelosuppression, including neutropenia, was low, he noted. One patient had grade 2 pneumonitis, and there were no reported cases of cardiomyopathy.

Three of the 58 patients (5%) had dose-reductions due to adverse events.

The investigators also evaluated the change in T-DXd gastrointestinal adverse events over time and found that the incidence of these events seemed to decrease over time as the study progressed, "possibly due to better supportive therapy," Bardia said.

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