Efficacy Without Excess Is Reshaping Breast Cancer Trials

Breast cancer oncologist Douglas K. Marks, MD, medical director of the Clinical Trials Office at Perlmutter Cancer Center at NYU Langone Hospital—Long Island, oversees a broad trial portfolio for breast cancer and other solid tumors while leading and collaborating on several of his own studies. As the lead accruer for breast cancer trials at both the Long Island and Manhattan sites, he works with oncologists and researchers to connect patients with innovative trials, not only at NYU Langone but also at other academic medical centers nationally and worldwide.

In this Q&A, Dr. Marks highlights select metastatic and early-stage breast cancer trials with the potential to refine or redefine current treatment paradigms.

Physician Focus: Perlmutter Cancer Center has a robust metastatic breast cancer trial portfolio. Which studies do you see as most likely to impact practice?

Dr. Marks: Of the 21 trials we currently have active for stage 4 patients, I would be happy to highlight two which we recently activated and are particularly noteworthy.

The first trial, sponsored by Avenzo, is evaluating a novel combination of a selective CDK2 and a selective CDK4 inhibitor in patients previously treated with standard therapy. CDK4 inhibition is typically delivered as a combined CDK4/6 agent, but CDK6 blockade is associated with certain toxicities. By avoiding CDK6 inhibition, the trial aims to maintain efficacy while improving tolerability.

Another trial, sponsored by Pfizer, is assessing a selective CDK4 inhibitor as first-line therapy for metastatic breast cancer, directly comparing it with a traditional CDK4/6 inhibitor. The goal is to determine whether focusing solely on CDK4 inhibition can achieve similar or superior outcomes with fewer CDK6-related adverse effects.

CDK inhibition has been transformative in breast cancer, but we’ve reached a plateau. These trials are asking: How do we optimize CDK inhibition to maximize benefit and improve quality of life?

Physician Focus: What’s one study you’re particularly enthusiastic about for patients with stage 2 or 3 disease?

Dr. Marks: S2206 is particularly compelling. This randomized phase 3 study is investigating the addition of the immunotherapy durvalumab to neoadjuvant chemotherapy in patients with ER-positive, HER2-negative breast cancer, and an ultra-high-risk MammaPrint score. We know immunotherapy doesn’t work for everyone with ER-positive, HER2-negative disease, but there is some evidence that a high MammaPrint score may help identify that subset of patients who will respond. In general, patients who respond to immunotherapy can have durable responses.

We have FDA-approved immunotherapy for patients with triple-negative breast cancer, but there are currently no FDA-approved immunotherapies for patients with ER-positive breast cancer. If S2206 supports the phase 2 data, it could introduce immunotherapy into ER-positive breast cancer and represent a landmark trial that changes frontline therapy.

Physician Focus: Can you tell us about some of the most promising trials available for patients with low-risk breast cancer?

Dr. Marks: Two studies I’d like to mention include ADEPT and ATEMPT 2.0, which focus on patients with stage 1 HER2-positive invasive breast cancer. These trials aim to increase the amount of targeted biologic therapy we can provide while reducing the amount of chemotherapy patients receive. It’s not withholding therapy, it’s treating smarter.

ADEPT is a phase 2, single arm, open-label trial in which patients receive an adjuvant regimen of the HER2-directed therapies trastuzumab and pertuzumab, administered as subcutaneous injections, in combination with endocrine therapy, but without the “backbone” of chemotherapy.

ATEMPT 2.0 is a randomized phase 2 trial comparing adjuvant trastuzumab emtansine (T-DM1) followed by subcutaneous trastuzumab to paclitaxel in combination with subcutaneous trastuzumab. T-DM1, an antibody-drug conjugate, is designed to deliver chemotherapy directly to cells that overexpress the HER2 protein, potentially improving precision and reducing systemic toxicity. The primary end point for both trials is invasive-disease-free survival.

We’re trying to tune the therapy, optimized for patients who are quite low risk, to de-escalate treatment toxicity while maintaining that very high cure rate.

Physician Focus: How has precision oncology changed trial design and patient selection?

Dr. Marks: In breast cancer, we’ve been at the forefront of biomarker-driven treatment. Some of the first examples of targeted therapies in cancer were hormone therapies in breast cancer. Now, precision medicine is even helping us target our studies to the patient subgroup most likely to benefit.

For example, previously, in the phase 1 setting, we would only evaluate safety and dosage of a new medication or combination. Earlier, patients with a mixture of cancer types might be enrolled with the hope of a signal of benefit, with treatment effectiveness traditionally evaluated in the phase 2 setting. Now, we’re using biomarker targets even in phase 1 to choose patients who are most likely to benefit, often within specific cancer types.

In oncology, we’re working to meet patients with personalized care. The only way we can provide it is by evolving treatment to the very specific patient situations we encounter in the clinic every day, and that’s accomplished through clinical trials; precision oncology starts at precision trial design.

If you need assistance finding a study or if you have any questions, please email: CancerTrials@NYULangone.org.