Immunotherapy, Novel Agents May Reshape the Early Breast Cancer Landscape

Heather McArthur, MD, focused on current and future strategies for treating early-stage breast cancer.

Heather McArthur, MD, shed light on advancements in early breast cancer treatment, with a particular focus on immunotherapy and its evolving role. The discussion delved into current FDA approvals, promising clinical trials, and the considerations for patient selection and managing immune-related adverse effects.

In a conversation with CancerNetwork® during the 2025 International Congress on the Future of Breast Cancer East hosted by Physicians Education Resource LLC®, McArthur highlighted the current FDA approval of pembrolizumab for early-stage triple-negative breast cancer.1,2 She also discussed the challenging yet promising future of combining immunotherapy with other standard treatments. A key challenge lies in the inability to co-administer CDK4/6 inhibitors with immunotherapy due to the risk of lung and liver toxicity.

The conversation also explored the evolving role of CDK4/6 inhibitors in the adjuvant setting for hormone receptor (HR)–positive, HER2-negative early breast cancer, emphasizing patient selection and duration of therapy. Looking ahead, McArthur expressed excitement about combination strategies involving antibody drug conjugates (ADCs) with immunotherapy for triple-negative disease in both neoadjuvant and high-risk residual disease settings. She also highlighted the potential for de-escalation strategies, where patients achieving a complete response with neoadjuvant therapy might forego additional treatment.

McArthur is the clinical director of Breast Cancer and Komen Distinguished Chair in Clinical Breast Cancer Research at the University of Texas Southwestern Medical Center.

What are the top line topics you discussed during your presentation today?

Today, we talked about innovation in immune therapy for the treatment of early-stage breast cancer. We talked about the current FDA approval for pembrolizumab for early-stage triple-negative breast cancer. We talked about promising clinical trials in estrogen receptor (ER)–positive high-risk early-stage breast cancer, and I presented data from our investigator-initiated trial in HER2–positive disease.

For HR-positive, HER2-negative early breast cancer, what are your thoughts on the evolving role of CDK4/6 inhibitors in the adjuvant setting, particularly concerning patient selection and duration of therapy?

Adjuvant CDK4/6 inhibitors have become a cornerstone of treatment for high-risk HR-positive disease, particularly those patients who have received prior chemotherapy. It will be challenging if the ongoing anticipated immunotherapy results from phase 3 KEYNOTE-756 [NCT03725059] trial, which demonstrated the 8.5% improvement in [pathological complete response with] neoadjuvant therapy with the addition of pembrolizumab, if that translates into an event-free survival [EFS] benefit and becomes another standard of care.3 The reason why that is complicated is that we cannot co-administer CDK4/6 inhibitors together with immune therapy because of the risk for lung and liver toxicity. That is a potential clinical challenge that we’ll be facing in the not-too-distant future.

How do you foresee immunotherapy’s role expanding into early breast cancer, particularly for high-risk triple-negative or HER2-positive subtypes? What are the key considerations for patient selection and managing immune-related adverse events?

We outlined a number of ongoing studies, particularly studies that are combining immune therapy with a promising new category of ADCs. We talked about studies that are ongoing, looking at patients who have high-risk residual disease after neoadjuvant therapy, being [randomly assigned] to the current standard of care, which is adjuvant immune therapy alone, vs immune therapy with one of these promising novel ADCs. There are studies that are moving even earlier in the course of disease, looking at ADCs with immune therapy going head-to-head against the FDA-approved phase 3 KEYNOTE-522 trial [NCT03036488] regimen, or part of the KEYNOTE-522 regimen.4

Looking 5 to 10 years out, what do you believe will be the most transformative advancements in early breast cancer treatment, and what research avenues do you think are most critical to get there?

That’s a difficult question to answer because the landscape has evolved so rapidly over the last few years, and so it would be anticipated that in 10 years, it will be dramatically transformed and hard to understand with the pace of drug development and novel technologies, exactly what will succeed in the next era.

Most eminently, I’m excited about combination strategies with ADCs together with immune therapy for the treatment of triple-negative disease, both in the neoadjuvant setting and in the high-risk residual disease setting. I’m also excited about so-called de-escalation strategies. If patients who achieve a complete response with neoadjuvant therapy, can they forego any additional therapy? Do they need to complete a year of therapy? I’m excited about those strategies as well.

In the HER2-positive space, we’re also seeing a lot of excitement around ADC strategies. Those successes from the metastatic setting have also moved into the curative intent setting. There will be a big ADC story there. I would also advocate for further exploration of immune therapy for HER2-positive disease. In the HR-positive space, there are a lot of exciting drugs that are in development, [including] a lot of exciting oral selective estrogen receptor degrader [SERD] combination strategies and oral medications. There’s a lot going on in that space, and it will be nice to have more oral options for our patients who are high-risk so that maybe they can forego chemotherapy as well.

What do you hope others will take away from this conversation?

I hope that people take away that there’s a huge amount of hope right now for both providers and patients, that we have had unprecedented drug approvals in recent years in all spaces. The whole field has transformed as a result; it’s a direct reflection of successful clinical trials. Enrollment in clinical trials is the way that we further advance the field. I would encourage people to continue to enroll their patients in clinical trials.

References

1. FDA approves pembrolizumab for high-risk early-stage triple-negative breast cancer. News release. FDA. July 26, 2021. Accessed July 14, 2025. https://tinyurl.com/4xm5y295
2. McArthur H. Immunotherapy for high-risk early-stage breast cancer: who benefits? Presented at the 2025 International Congress on the Future of Breast Cancer East; July 11-12, 2025, New York, NY.
3. Cardoso F, O'Shaughnessy J, Liu Z, et al. Pembrolizumab and chemotherapy in high-risk, early-stage, ER+/HER2- breast cancer: a randomized phase 3 trial. Nat Med. 2025;31(2):442-448. doi:10.1038/s41591-024-03415-7
4. Schmid P, Cortes J, Dent R, et al. Overall survival with pembrolizumab in early-stage triple-negative breast cancer. N Engl J Med. 2024;391(21):1981-1991. doi:10.1056/NEJMoa2409932