In our last Science Spotlight, we summarized our take on the results of the DESTINY-Breast03 trial, an ongoing Phase III trial evaluating trastuzumab deruxtecan (T-DXd [Enhertu]) versus trastuzumab emtansine (T-DM1 [Kadcyla]) in previously treated patients with HER2+ metastatic breast cancer. In this week’s Science Spotlight, we continue our focus on the topic of T-DXd, except here in the HER2-low setting. HER2-low was a key topic of discussion at the 2022 SABCS and the subject of our recent Project LEAD Advanced Topic Session at SABCS.
The question now is whether the benefits and toxicities of T-DXd warrant moving this therapy to early breast cancer. NBCC believes there is insufficient evidence at this time to do so and there are many unasked, let alone unanswered, questions.
HER2-Low Breast Cancer and T-DXd
HER2-low breast cancer is a burgeoning area of research, especially given the positive results of the DESTINY-Breast04 trial which were presented at the 2022 ASCO annual meeting. We have described HER2-low breast cancer and how it is different from HER2+ breast cancer in a previous Science Spotlight, where we also summarized the results of the DESTINY-Breast04 trial. The outcomes of this trial resulted in the highly publicized FDA approval of T-DXd in metastatic HER2-low hormone receptor-positive [HR+] and triple-negative breast cancer [TNBC]. T-DXd is an antibody-drug conjugate (ADC) that combines the monoclonal antibody trastuzumab with deruxtecan, a highly potent chemotherapy. Despite the well-known toxicity of T-DXd, it comes as no surprise to NBCC that there is now a movement to advance T-DXd into earlier lines of treatment, including early-stage HER2 low breast cancer.
The TRIO-US B-12 TALENT Trial
The first data examining the use of T-DXd in early-stage HR+/HER2-low breast cancer were presented at SABCS from the TRIO-US B-12 TALENT trial. TALENT is an ongoing Phase II trial evaluating the clinical activity and toxicity of neoadjuvant (before surgery) T-DXd, either alone or in combination with endocrine therapy (anastrozole) in 58 patients with HR+/HER2-low early stage (stage 2 and 3) breast cancer who were randomly assigned to a group and received up to 8 cycles of treatment prior to surgery.
The primary endpoint of the trial is the pathologic complete response (pCR) rate in the breast and lymph nodes (defined as residual cancer burden index [RCBi] = 0) assessed following surgery. Secondary endpoints include the objective response rate[i] (ORR; both partial and complete tumor shrinkage measured by imaging prior to surgery), safety, and changes in tumor biomarkers such as the level of HER2 expression following treatment.
Outcomes reported were that one patient had experienced a pCR (RCB i= 0), though surgical outcomes were still pending for approximately 28% of patients at the time of this interim analysis. The ORR was 68% and 58% for patients treated with T-DXd alone and T-DXd with anastrozole, respectively. This suggests that the addition of endocrine therapy to T-DXd does not enhance response rates. However, the number of patients in either arm of this study (n=29) is too small to make broad conclusions. Notably, only two patients (8%) in each treatment group demonstrated a complete response (tumor not visible by imaging) prior to surgery. Most responses were partial responses (tumor shrinkage of at least 30% or more), though a number of these patients experienced 50% or more tumor shrinkage. The question remains however whether response rate in this context has any clinical benefit.
What about toxicity, an important consideration especially when thinking about the use of this drug in early-stage breast cancer? In this small cohort of patients, gastrointestinal side effects (nausea, diarrhea, and vomiting) were common, especially among the first 20 patients enrolled in the study. This toxicity decreased somewhat for patients enrolled later in the trial, which the investigators suggest may have been a result of better supportive therapy. However, one patient died from myocardial infarction following severe gastrointestinal toxicity. There was one case of grade 2 pneumonitis, a known side effect of T-DXd along with interstitial lung disease which can be fatal. This known toxicity may have been reduced given the limited exposure to T-DXd as this drug was given for only up to 8 cycles in the neoadjuvant setting.
In terms of biomarker outcomes, the investigators reported that immunohistochemistry-assessed HER2 scores changed following T-DXd treatment. Among the patients with evaluable post-surgery tissue samples, nearly 50 % demonstrated changes in the level of HER2 expression. Of these patients, the vast majority (88%) showed a decrease in HER2 expression. We do not know if any change in HER2 expression has any meaning for patients.
The Bottom Line
This is an ongoing Phase II trial with additional data pending. It will be important to examine all the data, especially as this data will likely inform decisions about whether a Phase III trial of this drug should take place, exposing many more patients with early-stage breast cancer to T-DXd and its side effects. Advocates should be asking, is the move of T-DXd to the high-risk early-stage breast cancer setting warranted? What is the benefit to patients and what are the risks, and do the potential benefits outweigh the known risks? If so, which patients should this highly toxic and risky medication be limited to? More than half of the patients included in the TALENT trial had stage 2 breast cancer. NBCC will be following this and other trials closely to keep advocates informed.
[i] The percentage of people in a study or treatment group who have a partial response or complete response to the treatment within a certain period of time. A partial response is a decrease in the size of a tumor or in the amount of cancer in the body, and a complete response is the disappearance of all signs of cancer in the body. In a clinical trial, measuring the objective response rate is one way to see how well a new treatment works. Also called ORR. (NCI Dictionary)