I-SPY 2 Framework Could Represent the Future of Drug Development in Breast Cancer

Laura J. Esserman, MD, MBA

Traditional paradigms for clinical trials have limited accelerated progress in breast cancer treatment, leading investigators to place more emphasis on efficiencies in research. By moving away from adjuvant- to neoadjuvant-based protocols, such as I-SPY, investigators may be better able to develop effective treatments for patients in less time by refining the understanding of who will benefit from therapy, enabling strategies with multiple pathway targets, and testing approaches earlier in the disease course. This reimagined research model places emphasis on the importance of central institutional review boards, allows for targeted data collection with focused safety reporting, and should serve as the new gold standard for clinical trials, according to Laura J. Esserman, MD, MBA.¹

“It’s important to remember that trastuzumab [Herceptin] took 16 years to get from first trial to standard of care,” Esserman said in the Giants of Cancer Care^® lecture delivered at the 40th Annual Miami Breast Cancer Conference^®. “The decisions to test this drug in [patients with] HER2-positive [disease] was a difference between success and failure. We know that breast cancer subtypes differ in time to recurrence [and] rate of recurrence, and these molecular subtypes can provide new insight and open a way to think about rather than doing adjuvant studies, doing neoadjuvant studies.”

In the presentation, Esserman, who is the director of the University of California San Francisco (UCSF) Breast Care Center, the Alfred A. de Lorimier Endowed Chair in General Surgery, and professor of surgery and radiology at UCSF, in San Francisco, California, discussed future directions for I-SPY 2 (NCT01042379), an adaptive clinical trial platform designed to improve the way new treatments are evaluated in patients with high-risk breast cancer.

Since the launch of the trial in 2010,² investigators have made several discoveries that have pushed the needle forward. Among them include the fact that pathologic complete response (pCR) is a good surrogate for 3- and 5-year event-free survival and distant relapse-free survival, increasing confidence in neoadjuvant trial designs. Additionally, investigators have shown that there is value in evaluating residual cancer burden; prediction of treatment benefit can be improved by subtype; and biomarkers can be used for adaptation and graduation and lead to new ways to characterize tumors. Most notably, Esserman said the platform has evaluated 24 agents over 12 years, making advances that have improved response rates (ORR) from 19% at the trial outset to an estimated 60%.

“I started down this path with my colleague, Nola Hylton, PhD, [of UCSF,] 30 years ago, when she was developing the sequences for breast MRI and asked how I would [consider] using this tool,” Esserman said. “We started by looking at people who presented with locally advanced disease. All clinically advanced cancers certainly did not look the same, [and] the response to therapy was not the same. It was a clarion call that we had to design a framework for learning about risk and response and adaptively use it to improve outcomes.”

Because the trial is ongoing, process innovations are always being made, enabling investigators to not just manage, but learn how to get ahead of, challenges. One standing pillar that has remained consistent throughout the trial has been the weight placed on biomarkers.

“Biomarkers of response and non-response are really what are driving progress. We now have close to 100,000 specimens annotated with short- and long-term response,” Esserman said, crediting Laura van’t Veer, PhD, 2020 Giants of Cancer Care^® award winner for Diagnostics, Christina Yau, PhD, and Denise Wolf, PhD, all of UCSF, for spearheading the effort.3 The findings, which were published in Cancer Cell in June 2022, suggest that different biology may predict response to the same drugs in different receptor subtypes rather than the reverse.

“The power of platform trials is that you have this continuous learning platform to think about how you prevent metastatic disease, as well as complications,” Esserman said.

In the latest phase of the study, 2.2, with 39 active sites, investigators will focus on optimizing efficacy and safety considering past participant and current enrollee responses, with the goal of getting 90% of patients to pCR without standard therapy. Investigational agents will include selective estrogen receptor modulator metabolites, selective estrogen receptor degraders, and androgen receptor agonists and antagonists. Per the study design, patients will receive sequential blocks of treatment with built-in opportunities for escalation and de-escalation through assessment of functional tumor volume, mirroring care in real-world practice.

“This was our dream: to be able to run a trial where we can individualize therapy within the trial and still statistically work to identify and evaluate classes of agents but also strategies for patients, so we’re very excited about that,” Esserman concluded.

For more information on I-SPY 2, visit: https://www.ispytrials.org/i-spy-platform/i-spy2.

References

1. Esserman J. Novel strategies in neoadjuvant therapy: using biology and response to direct treatment. 40th Annual Miami Breast Cancer Conference®; March 2-5, 2023; Miami Beach, FL.
2. Wang H, Yee D. I-SPY 2: a neoadjuvant adaptive clinical trial designed to improve outcomes in high-risk breast cancer. Curr Breast Cancer Rep. 2019;11(4):303-310. doi:10.1007/s12609-019-00334-2
3. Wolf DM, Yau C, Wulfkuhle J, et al. Redefining breast cancer subtypes to guide treatment prioritization and maximize response: predictive biomarkers across 10 cancer therapies. Cancer Cell. 2022;40(6):609-623.e6. doi:10.1016/j.ccell.2022.05.005