Developing early endpoints in neoadjuvant breast cancer to support accelerated approval.

Abstract

e12755 Background: Pathologic complete response (pCR) is an early endpoint in neoadjuvant breast cancer considered in accelerated approval decisions by the FDA. However trial-level odds ratios of pCR and mature hazard ratios of disease free survival are only weakly associated in meta-analyses, resulting in approvals being delayed until survival evidence becomes available. We used data from the I-SPY 2 trial to develop early endpoints with better trial level correlations to support accelerated approvals. Methods: The I-SPY 2 trial treated 2117 patients with early stage high-risk breast cancer across 26 regimens between 2010 and 2022. When we separate the regimens into groups by subtype, there were 47 total experimental groups (19 HR+HER2-, 19 HR-HER2- and 9 HER2+). Each group is matched to concurrent control group enrolled within 90 days of the enrollment period, forming a experimental/control comparison. Treatment groups with less than 10 patients or insufficient follow-up were excluded, leaving 27 comparisons across 1577 patients. Hazard ratios for event free survival and negative log odds ratios for various early endpoints (e,g, pCR, RCB Class 0 or1) are computed for each experimental/control comparison. Novel early endpoints, including a binary subtype-specific RCB cutoffs, were developed on a training subset, with 5 comparisons held out for validation. The weighted trial-level correlation (R) was calculated overall and in HRHER2 subgroups. Subtype specific RCB cutoffs were chosen to optimize the overall and within subgroup weighted correlation, while maintaining C indices > .70 for individual survival association. More sophisticated models with RCB index as a continuous variable that incorporated baseline T stage, nodal status and response predictive subtypes were also explored. Results: Overall weighted correlations (R) for PCR, RCB 0/1 and Subtype Specific RCB cutoffs are shown in Table 1. Optimal cutoffs of RCB of 1.1 for HER2+, 1.7 for HR-HER2-, and 2.6 for HR+HER2- were identified giving a correlation of .70 overall in the training set and .54 in training and validation combined. The C index (C) was greater than 0.8 for all endpoints indicating good individual association. Preliminary results using more sophisticated models will be presented. Conclusions: Subtype-specific RCB cutoffs show a modest but clear improvement as an early endpoint over RCB-0/1 and pCR while maintaining a strong patient-level association with survival. External validation efforts are underway. Integrative approaches using continuous RCB improve trial level correlation and will be presented. Trial-level weighted correlation and individual C indices across all 3 subtypes and within each HRHER2 subtype separately. Measure OverallR,C HER2+R,C HR+HER2-R,C HR-HER2-R,C PCR .23, .84 .31, .80 .13, .84 .18, .87 RCB 0-1 .31, .83 .37, .80 .38, .85 .16, .85 Subtype Specific Cutpoint .54, .80 .37, .77 .40, .75 .54, .87 R = correlation; C = C index.