ESMO 2023 was its usual chaotic wonderful self, with tens of thousands of attendees and great clinically relevant scientific presentations.
The increasing importance of immune checkpoint blockade in breast cancer was highlighted by several presentations. In triple negative breast cancer, we had the update of KEYNOTE 522 (Schmid P, LBA 18), demonstrating the benefit of pembrolizumab added neoadjuvantly (with 4-drug chemotherapy) and adjuvantly to complete one year of immunotherapy in virtually all triple negative breast cancers. This has changed the landscape of triple negative management since eligibility included all but small node-negative tumors. The updated 5y EFS analysis found a 9% absolute difference in favor of adding pembrolizumab (81% with pembrolizumab, 72% without), most of which was in distant relapse events. Those with pCR had a very good outcome (92% with pembrolizumab, 88% with chemotherapy alone), however at 5 years it is clear that the residual disease cohort remains an unmet need, with only 63% remaining event-free in spite of four chemotherapy drugs plus pembrolizumab for one year.
The new science related to the use of pembrolizumab was in high-risk hormone receptor positive, HER2-negative disease. Two relevant trials were presented. The first, CheckMate 7FL (Loi S, LBA 20) included approximately 500 patients with grade 3 disease (or grade 2 if ER-low), T1cN0 or higher, and randomized these patients to receive taxane/anthracycline chemotherapy with or without nivolumab given neoadjuvantly, again with completion of approximately one year of the immunotherapy adjuvantly (during which they also started endocrine therapy). CM-7FL found a difference of approximately 10% in pathologic complete response rate with the addition of the immune checkpoint inhibitor, from approximately 14% to approximately 24%. This was particularly true in the 1/3 of patients with PDL1-high tumors in whom the difference was approximately 24% (44% with nivolumab, 20% without). The difference was far smaller in PDL1-negative tumors, which were the majority and in whom there was only about 3% difference in pCR (14% vs 11%).
The other, larger trial was KEYNOTE-756 (Cardoso F, LBA 21), which had a similar design only the randomization was to pembrolizumab versus placebo, and eligibility was narrower and higher risk - all had to have grade 3 tumors, and T1/2 had to be node-positive. KN-756, which included over 1200 participants, has two primary endpoints, pCR and EFS. Only the pCR endpoint was presented, but also demonstrated a significant, nearly 9% improvement in pCR with the addition of pembrolizumab to chemotherapy, particularly in PDL1+ that, unlike in CM-7FL (which used different methodology), made up the majority of the tumors. Interestingly, the ER-low group, which comprised only 77 patients of the > 1200 enrolled, had a much higher 26% difference in pCR in favor of using pembrolizumab, again reminding us that this group, while molecularly heterogeneous, includes a majority of tumors that are non-luminal and are reasonably treated with chemotherapy plus immune checkpoint inhibition up front (although it is also reasonable to hedge your bets with adjuvant endocrine therapy given a significant minority are in fact luminal.
Unlike triple negative disease, the relationship of pCR to EFS in the setting of hormone receptor-positive HER2-negative cancer is far less clear, so while the KN-756 and CM-7FL presentations are intriguing, they are not practice-changing. We will need to await the EFS data from KN-756, which was powered for this endpoint), to see if there is a clinically meaningful benefit to adding immune checkpoint inhibitors to chemotherapy in high risk HR+ / HER2- early breast cancer.
Dr. Carey has no conflicts of interest to report.
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