Ongoing Research Drives Further Questions in Early-Stage Breast Cancer Management

Erin Frances Cobain, MD

Although several advances have been made for the treatment of patients with early-stage breast cancer, further research is needed to delineate optimal disease management strategies using CDK4/6 inhibitors and neoadjuvant immunotherapy, according to Erin Frances Cobain, MD.

In an interview with OncLive^® following an OncLive Institutional Perspectives in Cancer (IPC) webinar on breast cancer which she chaired, Cobain highlighted key points presented at the meeting; this included unanswered questions regarding the optimal use of ribociclib in early-stage hormone receptor (HR)–positive, HER2-negative breast cancer, the role of immunotherapy in early-stage triple-negative breast cancer (TNBC), and how disease management strategies for metastatic disease may influence the early-stage treatment paradigm.

Cobain, who is an assistant professor and codirector of the Breast Cancer Clinical Research Team at the University of Michigan Rogel Cancer Center in Ann Arbor, provided further insights from this meeting in another article.

OncLive: Based on the presentation by Monika Burness, MD, how might the role of CDK4/6 inhibitors in early-stage HR-positive, HER2-negative disease continue to evolve as this drug class expands?

Cobain: Dr Burness spoke about the use of CDK4/6 inhibitors across the treatment settings, both in early-stage disease and metastatic disease. In early-stage HR-positive, HER2-negative breast cancer we have an FDA approval for the use of abemaciclib [Verzenio] as adjuvant CDK4/6 inhibitor therapy [in combination with endocrine therapy] knowing that it [induces] an improvement in event-free survival vs endocrine therapy alone.

We have now started to see the early data from the [phase 3] NATALEE clinical trial [NCT03701334] which examined ribociclib [(Kisqali) with endocrine therapy in patients with HR-positive, HER2-negative breast cancer]. Those data are currently under review. [Ribociclib] is not yet FDA approved [for this indication], but we all eagerly await more of the long-term follow-up data from NATALEE to determine whether [ribociclib] will also be a treatment option for these patients.

It would be interesting and potentially beneficial for patients to have 2 CDK4/6 inhibitors [available] in the early-stage treatment setting because the toxicity profiles of those 2 drugs are quite different. Some patients may have a difficult time tolerating 1 drug or the other, and the opportunity to have an alternative drug [that elicits] a similar clinical benefit would be a great advantage for patients. That’s something we’re eagerly awaiting and we anticipate more data from NATALEE.

Regarding the presentation by Margaret Gatti-Mays, MD, MPH, FACP, what questions arise pertaining to the use of adjuvant immunotherapy for patients with early-stage TNBC?

We’re eagerly awaiting more trial data on some important questions in that disease setting, mainly: What is the role for adjuvant immunotherapy? We’re now routinely using the [phase 3] KEYNOTE-522 trial [NCT03036488] regimen for patients with clinical stage II or III TNBC where we’re administering upfront chemotherapy and immunotherapy and continuing the immunotherapy in the adjuvant setting regardless of whether a patient has a pathologic complete response [pCR] or residual disease.

Right now, the benefit of that adjuvant immunotherapy component is not well understood. A [phase 3] clinical trial [NCT05812807] is now ongoing through the Alliance for Clinical Trials in Oncology for patients [who achieve] pCR [with chemotherapy plus pembrolizumab (Keytruda)], [who] we would anticipate having an excellent prognosis. [Patients have] the opportunity to be randomly assigned to either discontinue the immunotherapy and continue on observation or continue the immunotherapy. That’s an incredibly important clinical trial that will answer a question for us.

We also await data from trials such as the [phase 3] SWOG S1418 trial [NCT02954874], which assessed patients [with TNBC] who didn’t receive immunotherapy in the upfront treatment setting but were high risk due to residual disease and then received immunotherapy in the adjuvant setting. A critical scientific question is: Is it crucial for intact tumor to be present to generate the most robust immune response to the tumor? If that is the case, is the adjuvant immunotherapy not playing as important of a role as the neoadjuvant immunotherapy? That’s still an unknown and we need more trials to help us best understand that.

What is your main message for colleagues regarding future developments in early-stage breast cancer management?

[During this IPC], we covered a wide range of topics. We discussed CDK4/6 inhibitors in HR-positive, HER2-negative disease; early-stage triple-negative disease; and the use of antibody-drug conjugates [ADCs]. We also talked about therapies in HER2-positive metastatic breast cancer and how that treatment paradigm has changed, particularly for patients with brain metastases. We have therapies that can achieve good penetration of the blood-brain barrier as well as systemic treatments that improve outcomes in that setting.

One [idea] that unifies all the talks is that we spent most of our time discussing metastatic disease and figuring out how we use a lot of these therapies that have shown so much benefit in the metastatic setting. Where [these agents] fit in the early-stage treatment setting will be of critical importance as we move forward. Particularly regarding ADCs, we have not yet seen those drugs make their way into the early-stage treatment setting at least in a standard way. Several clinical trials are ongoing to answer that question, and that will be a critically important question to answer as we move forward.