Dr Yee on Neoadjuvant Datopotamab Deruxtecan Plus Durvalumab in Early-Stage Breast Cancer

Douglas Yee, MD, director, Masonic Cancer Center at the University of Minnesota, discusses the results from phase 2 I-SPY2.2 trial (NCT01042379) for combination of datopotamab deruxtecan (Dato-DXd) and durvalumab (Imfinzi) in the neoadjuvant setting for breast cancer.

Findings from the I-SPY2.2 trial presented at 

 by Rebecca A. Shatsky, MD, of the University of California, San Diego Medical Center, highlighted pathologic complete responses (pCR) achieved with this combination therapy. In this arm of the trial, 33% of patients (n = 106) were able to proceed to surgery without chemotherapy following 4 cycles of Dato-DXd plus durvalumab. Notably, 43%) of patients (n = 47) in the immune-positive subgroup achieved a pCR following 4 cycles with the combination, and the moddeled pCR rate for patients within this subgroup was 65% (95% CI, 47%-83%). This outcome successfully surpassed the prespecified goal of a 40% for this combination.

Yee notes that this patient cohort included some individuals with hormone receptor–positive disease, demonstrating the potential of this regimen to improve pCR rates across different breast cancer subtypes when used within a biomarker-defined population.

These results suggest Dato-DXd plus durvalumab may offer an effective alternative to traditional chemotherapy in the neoadjuvant setting, particularly for patients identified as immune-positive through predictive biomarkers, Yee explains. The trial's observed pCR rates in this subgroup highlight the importance of precision medicine in tailoring neoadjuvant treatments to individual patients' tumor biology, he adds.

Yee suggests that this combination therapy could lead to a shift away from conventional chemotherapy approaches, paving the way for more targeted therapies and less toxic treatment options in the neoadjuvant setting.

These results warrant further investigation in larger trials to confirm the efficacy and safety of this regimen and to explore its potential integration into standard treatment protocols for breast cancer, Yee concludes.

Videos

Douglas Yee, MD, discusses datopotamab deruxtecan and durvalumab in the neoadjuvant setting for early-stage breast cancer.

Douglas Yee, MD

Douglas Yee, MD, director and the John H. Kersey Chair in Cancer Research, Masonic Cancer Center, University of Minnesota, discusses the results from a cohort of the phase 2 I-SPY2.2 trial (NCT01042379) that evaluated neoadjuvant datopotamab deruxtecan (Dato-DXd) in patients with high-risk, early-stage breast cancer.

Results presented by Jane L. Meisel, MD, of Winship Cancer Institute of Emory University during the

 showed that the trial did not reach its prespecified pathologic complete response (pCR) threshold of 85% following 4 cycles of Dato-DXd. Overall, 32% of evaluable patients (n = 103) proceeded to surgery following treatment with Dato-DXd without requiring chemotherapy.

Although the study did not meet its primary end point, Yee explains strong efficacy signals were observed in patients in different subgroups within the overall population. A pCR rate of 31% was observed in patients with HER2-negative, immune-positive breast cancer (n = 46). Similarly, a pCR rate of 29% was recording in the HER2-negative, immune-negative, DNA repair deficiency–positive subgroup (n = 10). In patients with hormone receptor (HR)–negative, HER2-positive disease (n = 50), the pCR rate was 35%; conversely, those with HR-positive, HER2-negativie disease (n = 53) experienced a pCR rate of 6%.

Among all patients, Dato-DXd was well tolerated, Yee continues. No new safety signals were reported for the antibody-drug conjugate compared with prior data for Dato-DXd from the phase 3 TROPION-Breast01 trial (NCT05104866), and adverse effects did not lead to treatment discontinuation in any patients.

Despite not reaching the anticipated threshold, the pCRs observed still indicates a potential benefit for certain patient groups, Yee explains. Ongoing efforts will focus on better defining patient populations who would derive the most benefit from Dato-DXd in the neoadjuvant setting, he says. ADCs remain a promising therapeutic avenue for patients with breast cancer, and future research will help identify areas where these agents could have an earlier impact for patients, Yee concludes.

Douglas Yee, MD, discusses neoadjuvant datopotamab deruxtecan in early-stage breast cancer

Dr Yee on Neoadjuvant Datopotamab Deruxtecan in High-Risk, Early-Stage Breast Cancer

Douglas Yee, MD, professor of medicine and pharmacology, Hematology, Oncology and Transplant, medical oncologist, University of Minnesota, discusses the categorization of patients with triple-negative breast cancer (TNBC).

The biggest unmet need in TNBC is the categorization of patients into relevant groups, says Yee. TNBC is currently categorized by gene expression profiling, but it is still not known whether those sub-categories can guide clinical decision. For example, before HER2 was discovered, patients with HER2-positive breast cancer were buried within the larger population of breast cancer, Yee says. Once HER2-directed strategies were discovered, the treatment approach for these patients changed, which subsequently altered outcomes.

Some patients with TNBC express the androgen receptor (AR), but to date, the clinical translation does not exist. Yee says that although AR is expressed, it does not necessarily mean that AR-positive patients should receive antiandrogens, but this is an evolving field.

Douglas Yee, MD, professor of medicine and pharmacology, Hematology, Oncology and Transplant, medical oncologist, University of Minnesota, discusses the categorization of patients with triple-negative breast cancer.

Dr. Yee Discusses the Categorization of Triple-Negative Breast Cancer

Douglas Yee, MD, professor of medicine and pharmacology, Hematology, Oncology and Transplant, medical oncologist, University of Minnesota, discusses neoadjuvant therapy for patients with triple-negative breast cancer (TNBC).

Adjuvant chemotherapy has proven to be effective for patients with TNBC, but Yee argues it is better to more effective in the neoadjuvant setting. There are very few patients, if any, who are at a low-enough risk to not require any therapy. The nature of the disease, Yee says, means there is nothing to target when it comes to treatment. Conventional chemotherapy remains the only viable option, and most, if not all, patients require therapy.

Douglas Yee, MD, professor of medicine and pharmacology, Hematology, Oncology and Transplant, medical oncologist, University of Minnesota, discusses neoadjuvant therapy for patients with triple-negative breast cancer.

Dr. Yee on Neoadjuvant Therapy for Triple-Negative Breast Cancer

Douglas Yee, MD, professor of medicine and pharmacology, Hematology, Oncology and Transplantation, Department of Medicine, medical oncologist, University of Minnesota, discusses the results of the phase II ADAPT trial, which examined T-DM1 in patients with HER2-positive, HR-positive early-stage breast cancer.

Pathological complete response (pCR) was the trial’s primary endpoint. The pCR rate was found to be clinically meaningful in patients who received T-DM1, especially when combined with endocrine therapy. The pCR rate was significantly lower with the combination of trastuzumab plus endocrine therapy, Yee adds.

The evidence that T-DM1 is an active agent in the neoadjuvant setting was shown in this study, Yee explains. However, it is uncertain what role T-DM1 will play in the adjuvant setting. As a first-line therapy for metastatic disease, T-DM1 was previously shown to be roughly equivalent to trastuzumab, a taxane, and pertuzumab.

Douglas Yee, MD, professor of medicine and pharmacology, Hematology, Oncology and Transplantation, Department of Medicine, medical oncologist, University of Minnesota, discusses the results of the phase II ADAPT trial, which examined T-DM1 in patients with HER2-positive, HR-positive early-stage breast cancer. 


Dr. Yee on Phase II ADAPT Trial Results for HER2+/HR+ Breast Cancer

Douglas Yee, MD, professor of medicine and pharmacology, Hematology, Oncology and Transplantation, Department of Medicine, medical oncologist, University of Minnesota, discusses the research that led to the FDA approval of neoadjuvant pertuzumab as part of a combination regimen for patients with HER2-positive breast cancer.

The NeoSphere trial was the major study that led to this approval, Yee says. The NeoSphere trial compared the efficacy of the doublets trastuzumab/docetaxel, pertuzumab/docetaxel, and pertuzumab/trastuzumab, as well as the triplet pertuzumab/trastuzumab/docetaxel. 

In this study, the pathologic complete response rate was statistically increased. Data showed that the triplet of pertuzumab, trastuzumab and docetaxel demonstrated higher efficacy over the other regimens.

Moreover, the ongoing AFFINITY trial, which is examining chemotherapy and trastuzumab with or without pertuzumab in the adjuvant setting, may impact the use of pertuzumab as an adjuvant treatment for HER2-positive breast cancer.