Laura J. Esserman, MD, MBA, Alfred A. de Lorimier Endowed Chair in General Surgery, professor, Departments of Surgery and Radiology, affiliate faculty, Institute for Health Policy Studies, University of California San Francisco (UCSF); director, UCSF Breast Care Center; co-leader, Breast Oncology Program, Helen Diller Family Comprehensive Cancer Center, discusses the rationale and design for the phase 2 I-SPY2 trial (NCT01042379).

I-SPY2 is a platform trial investigating the efficacy of combining several novel agents with standard chemotherapy in patients with breast cancer, with the goal of identifying optimal treatment strategies for different subsets based on molecular characteristics. This trial uses pathologic complete response as an early surrogate efficacy end point.

The aim of I-SPY2 is to determine therapies and treatment sequencing that will provide better outcomes to patients with breast cancer, such as those that are more effective and less toxic, Esserman says. This ongoing trial allows the opportunity to continually add new agents for investigation through 3 blocks of treatment categories—Blocks A, B, and C, Esserman explains.

Block A consists of the experimental regimens ARX788 with or without cemiplimab-rwlc (Libtayo), VSV-IFNβ-NIS plus cemiplimab, and datopotamab deruxtecan (DS-1062a) with or without durvalumab (Imfinzi). If patients are predicted to achieve CR with these agents, they’ll proceed to surgery, Esserman says. If they do not achieve a CR at 6 weeks, they will be assigned to Block B and receive the best available standard chemotherapy for their response predictive subtype, Esserman says. If patients have persistent disease after Block B, they will receive doxorubicin plus cyclophosphamide in Block C and proceed to surgery if they are predicted to have CR with this combination.

This trial uses MRI, functional tumor volume, and biopsy to predict which patients will have CRs to each block of therapy, Esserman adds. I-SPY2 follows standards that help investigators decide whether a patient will likely achieve a sufficient response based on their tumor type, Esserman says. This trial required all patients to have a biopsy at enrollment, allowing for molecular profiling that has helped to recategorize the breast cancer tumor types, Esserman explains.

For example, high-risk, hormone receptor–positive disease is heterogenous, as some tumors in this category have an immune phenotype that responds to treatment like a basal cancer would; others are not as responsive to the same treatments, Esserman notes. This trial has created a framework for assigning patients to the optimal therapies for their disease type, which will advance the breast cancer treatment landscape as this research evolves, Esserman concludes.

Videos

Laura J. Esserman, MD, MBA, discusses the rationale and design for the phase 2 I-SPY2 trial. 

Dr. Esserman on the I-SPY2 Trial in Breast Cancer

Laura J. Esserman, MD, MBA, professor, University of California, San Francisco Helen Diller Comprehensive Cancer Center, 2018 Giant of Cancer Care

 for Cancer Diagnostics, discusses the elements of the I-SPY 2 trial in breast cancer.

There are 4 key elements of the I-SPY 2 trial, explains Esserman. First, drugs are being tested in earlier settings where there is a better potential for cure. Second, the order of therapy has been rearranged, in which efficacy is being evaluated using pathologic complete response. Previously, patients underwent surgery and went on to receive further treatment; that can impede the understanding of which drugs work well for which patients, she explains.

Third, imaging and biomarker guidance is incorporated into the trial. Investigators are using MRI imaging to evaluate a patient’s response to therapy. In addition to standard biomarkers, investigators are accounting for emerging markers of tumor biology to figure out how to best tailor therapy to each patient. The last element of the I-SPY 2 trial has reformed the historical clinical trial design by way of an adaptive trial design to enhance efficiency, says Esserman. Now, investigators do not have to rewrite a new protocol every time a new agent is brought into the trial.

Laura J. Esserman, MD, MBA, professor, University of California, San Francisco Helen Diller Comprehensive Cancer Center, 2018 Giant of Cancer Care® for Cancer Diagnostics, discusses the elements of the I-SPY 2 trial in breast cancer.

Dr. Esserman on the Elements of the I-SPY 2 Trial in Breast Cancer

 for Cancer Diagnostics, discusses the I-SPY 2 trial in breast cancer.

The I-SPY trials are neoadjuvant breast cancer trials designed for patients who are at a very high risk for early recurrence. Esserman explains that these trials aim to accelerate the pace of learning which agents are going to work for certain tumors. The I-SPY 2 trial (NCT01042379) is currently investigating neoadjuvant and personalized adaptive novel agents for the treatment of patients with breast cancer.

These trials are attempting to move the testing of new agents into the early-stage high-risk neoadjuvant setting. Esserman says that these trials test agents in the neoadjuvant setting, because that is where they can have the highest potential impact, or possibly cure patients.

Laura J. Esserman, MD, MBA, professor, University of California, San Francisco Helen Diller Comprehensive Cancer Center, 2018 Giant of Cancer Care® for Cancer Diagnostics, discusses the I-SPY 2 trial in breast cancer.

Laura J. Esserman, MD, MBA

Articles

Dr. Esserman on the I-SPY2 Trial in Breast Cancer

Dr. Esserman on the Elements of the I-SPY 2 Trial in Breast Cancer

Dr. Esserman Discusses the I-SPY 2 Trial in Breast Cancer