I-SPY2.2: A Personalized Medicine Trial for Neoadjuvant Breast Cancer Treatment

The ISPY2.2 trial (NCT01042379) presented as a late-breaking abstract at the 2024 ASCO Annual Meeting explores a new approach to treating high-risk breast cancer in the neoadjuvant setting. It uses a platform design to test multiple treatment combinations efficiently.

Patients are classified into 6 tumor response predictive subtypes (RPS) based on factors like immune response, DNA repair, and hormone receptor status. The trial tests a new drug combination of datopotamab deruxtecan (Dato-DXd) and durvalumab (Imfinzi) followed by standard chemotherapy regimens if needed. MRI testing during treatment helps predict response and allows some patients to skip to surgery early. For the applicable patients, the most effective taxane-based chemotherapy for is chosen based on the patient's RPS.

The primary goal is to achieve a complete disappearance of the tumor (pathologic complete response, pCR) after treatment.

A total of 106 patients received Dato-DXd plus durvalumab between September 2022 and August 2023. Early analysis suggests the combination is particularly effective for patients in the RPS S3 subtype, with an estimated pCR rate of 72%. Based on these results, Dato-DXd plus durvalumab qualifies for further investigation in a larger confirmatory trial.

Here, Rebecca Shatsky, MD, breast medical oncologist at the University of California San Diego, explains the study's findings and how the I-SPY2.2 trial demonstrates the potential of personalized medicine for neoadjuvant breast cancer treatment.

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0:05 | The efficacy findings in in ISPY2.2, the newest version of the trial, are always a little bit complicated because again, we're not allowing every patient that goes on trial to immediately go to the to surgery early after just the upfront combination therapy. So for this trial, the novel agents that we investigated were 4 cycles of datapotamab deruxtecan combined with 4 cycles of durvalumab. So for those patients that we predicted would have benefit, they went on and about 33% of all patients who went on this arm of the trial, so there was 106 patients, 33% were able to just do 4 cycles of datapotamab deruxtecan and durvalumab and skip traditional chemotherapy, which includes skipping the toxicities of a taxane-based therapy, meaning neuropathy, and the potential use of an anthracycline, which could cause leukemia or cardiotoxicity.

1:04 | For triple-negative patients that we had go on this first phase of the trial, we saw about, in our most conservative estimate, we saw about a 33% chance of pathologic complete response. However, ISPY utilizes a very complicated Bayesian covariant analysis modeling system where we can model if we had allowed all patients to go to surgery after just, you know, datapotamab deruxtecan and durvalumab alone, what percentage of patients would have achieved a pathologic complete response if we allowed them to, and for triple-negative patients, that was 43%. And for the subgroup that we've identified by our own biomarkers, which is our immune responsive subgroup, and that includes both hormone positive and triple-negative patients that had sort of this immune biomarker that suggests sensitivity to immunotherapy, what we modeled in that group is that their pathologic complete response rate would be 65%. And so we find that really valuable data because we've identified this subgroup of people who we can deescalate therapy on to avoid potential toxicities with overtreating them. But at the same time, of course, in the trial, we don't want to undertreat anybody, so we allow patients if they're not likely to achieve a pathologic complete response, to move on to, you know, additional blocks of therapy based on the standard of care.