ISPY2: A Unique, Flexible Breast Cancer Trial for Modern Times

Posted in Lombardi Stories  |  Tagged breast cancer, breast cancer research, cancer, clinical trials, hormone receptor positive breast cancer, triple-negative breast cancer

(August 16, 2024) — The ISPY2 breast cancer clinical trial, a unique phase 2 study that offers a broad range of treatment options for patients with locally advanced breast cancer, is enrolling people through Georgetown’s Lombardi Comprehensive Cancer Center, a part of the MedStar Georgetown Cancer Institute. The trial is offered at MedStar Georgetown University Hospital and MedStar Washington Hospital Center.

The innovative design of this platform trial allows a number of potential therapies to be tested at the same time, with investigational drugs added or dropped from further testing without having to halt enrollment.

Clinicians closely track response markers for treatments, so that positive findings can springboard a therapy to a definitive trial to prove — with a high degree of certainty — if a new therapy tested in ISPY2 is better than the current standard of care. Over the 15 years of its existence, ISPY2 has enrolled over 2,500 patients and tested 25 new therapies. The trial has evolved to treat breast cancer based on more than the traditional subtypes by virtue of its nimble trial design.

“The ultimate goal of ISPY2 is to provide each individual patient with the most personalized therapy that can be offered,” says Georgetown professor Claudine Isaacs, MD, associate director for clinical research at Georgetown Lombardi. “Women in the trial have the possibility of getting novel agents as clinicians tailor therapy and follow patients very closely with tools that aren’t normally available in standard clinical practice.”

As part of the ISPY2 standard protocol, clinicians use serial MRIs scans over a period of weeks or months to serve as biomarkers of response to treatment. These serial scans provide a sense of whether the tumor is shrinking or not in response to the therapy, thereby allowing patients to either stop a treatment sooner if it does not seem to be effective, or to skip additional treatments if a maximal response has already been achieved.

For example, triple-negative breast cancer is a more aggressive, difficult-to-treat subtype. In a best-case scenario, clinicians want to see a quick response to treatment — if the tumor has shrunk by more than 65% at a six-week time point, that signals the possibility that patients might have a complete response to just 12 weeks of treatment and could go straight to surgery and avoid the toxicities of the other standard chemotherapies. However, if there’s not an early response, doctors don’t want patients to continue with a suboptimal therapy; they want to provide patients with a potentially better option. Often the initial treatment involves novel targeted therapies, one of which is currently composed of just antibodies. In some cases, doctors are seeing excellent responses that avoid the toxicities of standard chemotherapy.

Several cancer treatments first tested in ISPY2 have gone on to demonstrate superiority to standard therapy and earned FDA approval. One such example is pembrolizumab (Keytruda), shown to extend survival in women with advanced triple-negative breast cancer.

Most recently, two separate phase 3 clinical trials released positive results of adding either pembrolizumab or durvalumab (Imfinzi), both immunotherapy agents, to chemotherapy to treat high-risk hormone receptor positive breast cancer. The trials based their protocols on results from ISPY2 studies that were the first to show a benefit of using immunotherapy in this subtype of breast cancer.

Also, based on this outcome, clinicians in ISPY2 subsequently identified a signature to predict which patients with hormone receptor positive cancers could benefit; recent findings from ISPY2 show that 80% of people with the immune positive signature saw a complete disappearance of the tumor or had just a tiny bit of tumor left.

ISPY2 is expected to continue for many years with various study arms, including one for patients who have hormone receptor positive breast cancer where endocrine therapy, as opposed to chemotherapy, might be more appropriate. There are also arms that are looking at novel hormone therapies.

“ISPY2 is continuously evolving and learning from today’s patients to inform what is done tomorrow will happen in a hopefully much shorter timeline than with traditional clinical trials,” Isaacs said.