Trastuzumab Deruxtecan, With or Without Endocrine Therapy, Shows Promising Responses in Operable HR+, HER2-Low Breast Cancer

Neoadjuvant treatment with fam-trastuzumab deruxtecan-nxki (Enhertu) showed promising responses in patients with HER2-low, HR-positive localized breast cancer according to results from the phase 2 TRIO-US B-12 TALENT study (NCT04553770), which was presented at the 2022 San Antonio Breast Cancer Symposium. Moreover, the antibody drug conjugate demonstrated a promising safety profile and did not appear to have its efficacy impacted by the addition of endocrine therapy.

Among patients who received trastuzumab deruxtecan (n = 25), 68% (n = 17) achieved an objective response, 8% (n =2) achieved a complete response (CR), and 60% (n = 15) achieved partial response (PR).

Adding anastrozole (Arimidex) endocrine therapy did not appear to significantly influence the drug’s efficacy, but study authors caution that the small numbers mean strong conclusions are difficult to make. Among patients who received both neoadjuvant trastuzumab deruxtecan and anastrozole (n = 24), the objective response rate (ORR) was 58% (n = 14), the CR was 8% (n = 2), and the PR was 50% (n = 12). Imaging was used to determine efficacy in both cohorts.

Additionally, the study demonstrated that trastuzumab deruxtecan yielded dynamic changes in HER2 tissue expression; 48.6% of patients (n = 17) experienced a change in HER2 IHC expression after trastuzumab deruxtecan treatment. Among patients who experienced a change, 88.2% had a decrease in HER2 expression between baseline and surgery—this included a subset of patients with HER2 IHC-0 disease.

In terms of residual cancer burden (RCB), there was one patient with RCB-0, which, according to investigators, is equivalent to pathological CR, and there were 2 patients with RCB-1, which is “near” pCR.

“Neoadjuvant trastuzumab deruxtecan demonstrated preliminary evidence of clinical activity in HER2-low hormone receptor-positive localized breast cancer,” Aditya Bardia, MD, MPH, a medical oncologist with Massachusetts General Hospital in Boston, said in a presentation of the findings. “The toxicity profile was consistent with previous reports,” he added.

Trastuzumab deruxtecan has previously shown favorable results in the metastatic HER2-low setting, but evidence surrounding its efficacy in the localized setting is limited.

Currently, anthracycline-taxane based combinations are standard neoadjuvant treatment for patients in this setting, but this treatment is not associated with a high pathologic complete response rate (5%) and it’s radiological response rate is approximately 50%. Furthermore, this treatment is linked to significant toxicities, including myelosuppression, neuropathy, cardiomyopathy, and an increased risk of leukemia.

This investigator-initiated clinical trial was therefore designed to evaluate the efficacy of an antibody drug conjugate, trastuzumab deruxtecan, in the localized setting. Of note, because of the “cross-talk” known to exist between endocrine receptor and HER2, investigators also evaluated whether adding anastrozole endocrine therapy would boost responses.

Patients who were eligible to participate were men and women with HR+, HER2-low, operable, stage II-III breast cancer. Enrolled participants were randomly assigned 1:1 to receive either trastuzumab deruxtecan at a dose of 5.4 mg/kg (n = 29; Arm A) or trastuzumab deruxtecan at a dose of 5.4 mg/kg plus anastrozole, and a GnRH analog for men or premenopausal women. Treatment was originally intended to be 6 cycles, however, in February 2022, the design was amended to increase the number from 6 to 8 for newly enrolled participants, or for those who had not yet undergone surgery. Following surgery, patients were eligible for adjuvant therapy as per the discretion of the treating investigator.

Baseline tissues biopsies were collected before trastuzumab deruxtecan treatment, during treatment, and right before surgery.

Baseline characteristics were comparable between the 2 arms; the majority of patients overall (about 80%) had HER2-low disease, which was defined as IHC1+ and about 50% of patients had lymph node positive disease.

Ultimately, 58 patients were randomly assigned to a treatment arm. In Arm A (n = 29), 14 patients completed 6 cycles and 7 patients completed 8 cycles. Four patients are still receiving therapy, and 4 patients left the study prior to completing protocol-specified therapy—2 of which withdrew their consent, 1 of whom passed away because of myocardial infection after severe gastrointestinal toxicity, and 1 of whom developed grade 4 hypokalemia, which counted as discontinuation criteria.

In Arm B (n = 29), 13 patients completed 6 cycles and 8 patients completed 8 cycles. Five patients are still receiving therapy and 3 patients left the study prior to completing protocol-specified therapy—all of whom met discontinuation criteria, including one grade 1 hypokalemia, 1 small bowel obstruction leading to a dose hold for greater than 49 days, and 1 case of progressive disease, respectfully.

At data cutoff, among patients receiving 8 treatment cycles, 7 patients (24%) in treatment arm A and 9 patients (31%) in arm B still had pending surgical outcomes. An analysis of these patients is anticipated in the future.

In both cohorts, nausea represented the most frequently reported adverse event (AE). In the single-agent group, other common AEs included fatigue, diarrhea, alopecia, headache, vomiting, constipation, and anorexia. Hypokalemia, insomnia, decreased neutrophil counts, dehydration, decreases in white blood cells, edema, dysgeusia, breast pain, blurred vision, anemia, and alanine aminotransferase changes also occurred in this cohort.

In the endocrine therapy group, fatigue, vomiting, and alopecia were experienced by 40% of patients or more. Diarrhea, constipation, headaches, hot flashes, hypokalemia, gastroesophageal reflux disease, dehydration, and anorexia also occurred.

A total of 5.2% of patients (n = 3) needed to reduce their dose because of an AE. However, there were no reported cases of grade 3/4 pneumonitis, and no cases of cardiomyopathy or neuropathy.

According to study authors, the modest HER2 IHC concordance between the central and local labs underscores the need for better HER2 identification tools and standardized methods of analyzing tissue fixation conditions, processing methods, and types of antibodies. However, this study may lend itself to translational research evaluating novel methods of HER2 detection, predictive biomarkers, and mechanisms of resistance in this setting—potentially guiding future therapeutic strategies and combination approaches.

“This is the first report of neoadjuvant trastuzumab deruxtecan for patients with HR+, HER2-low breast cancer and provides groundwork for future studies with antibody-drug conjugates for patients with early-stage breast cancer,” Bardia concluded.

Reference

Hurvitz S, Wang LS, McAndrew NP, et al. TRIO-US B-12 TALENT: Neoadjuvant trastuzumab deruxtecan (T-DXd) with or without anastrozole for HER2-low, HR+ early-stage breast cancer. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.