Giuseppe Curigliano, MD, PhD
Invited discussant Giuseppe Curigliano, MD, PhD, Associate Professor of Medical Oncology at the University of Milan, Italy, and Head of the Division of Early Drug Development at the European Institute of Oncology, said the “clear” findings of KEYNOTE-5221 are “practice-changing.” However, the ideal patient for neoadjuvant pembrolizumab plus chemotherapy remains to be determined.
Joining Other Informative Trials
Although KEYNOTE-522 is by far the largest phase III trial evaluating checkpoint inhibitors as neoadjuvant therapy in triple-negative breast cancer, several smaller trials have also been informative. In IMpassion031, atezolizumab resulted in a clear increase in pathologic complete response, but event-free survival data have not been reported.2 With -NeoTRIPaPD-L1, also evaluating atezolizumab, the primary endpoint of event-free survival is not mature.3 The GeparNuevo trial showed a “borderline” increase in pathologic complete response but a “very impressive” improvement in invasive disease–free survival and other clinical endpoints at 3 years, as recently reported at the 2021 ASCO Annual Meeting,4 although the study is underpowered for that endpoint, noted Dr. Curigliano.
The mature KEYNOTE-522 results are consistent with GeparNuevo, showing a statistically significant and clinically meaningful 7.7% improvement in event-free survival. “No doubt, this is a clinically meaningful improvement, and for this patient population, I believe this is quite important,” Dr. Curigliano commented.
The addition of pembrolizumab to chemotherapy especially benefited patients with residual disease, “who have the worst prognosis” and “most importantly” prevented distant disease progression and distant recurrences, he said. In addition, though early, “it is interesting to observe a 3% difference in overall survival.”
Dr. Curigliano did caution, however, that “toxicity should be taken into account.” Side effects led to treatment discontinuation in 27.7% of the pembrolizumab/chemotherapy arm; immune-related adverse events, especially endocrine abnormalities, were not uncommon and can be concerning to young patients with early breast cancer, as they can be irreversible and may affect fertility, he noted.
Who Is Most Likely to Benefit?
Dr. Curigliano asked this question: “Should we give pembrolizumab plus chemotherapy, then adjuvant pembrolizumab, to all patients? According to this analysis, the answer is yes, but I believe we need to identify those patients with the most benefit,” he said.
Doing so is the challenge. Tumor burden has not correlated with pathologic complete response for either pembrolizumab or atezolizumab, where rates are similar with node-positive and node-negative disease. Although the addition of either checkpoint inhibitor clearly boosts pathologic complete response rates, PD-L1 status has not been predictive of benefit, although by combined positive score, the rates in -KEYNOTE-522 were highest among patients with a score higher than 20 (81.7%). “We may need to identify patients who are more PD-L1–enriched,” Dr. Curigliano suggested.
Other studies have suggested looking at dynamic changes in the tumor microenvironment, especially increasing immunogenesis, as well as immune signatures that reflect upregulation of genes involved in immune response, one being CD274, encoding for PD-L1. The use of circulating tumor DNA and the role of tumor-infiltrating lymphocytes could also be evaluated as a means of selecting patients for escalation and de-escalation of treatment (ie, checkpoint inhibitor alone or with chemotherapy), he added.
Other Key Questions
Two other important questions are whether immunotherapy is needed at all in the adjuvant setting for patients who achieve pathologic complete response and how checkpoint inhibitors can be integrated into the “expanding arsenal.” The growing armamentarium now includes olaparib for patients with residual disease and BRCA-mutated tumors, capecitabine (the standard of care) and, perhaps at some point, sacituzumab govitecan-hziy.
Finally, there is the question of global accessibility, emphasized Dr. Curigliano. Limited-income countries will undoubtedly not be able to afford pembrolizumab. Studies should attempt to identify those patients who will benefit most and to define the ideal “immunogram” of patients with breast cancer.
DISCLOSURE: Dr. Curigliano has received honoraria from Ellipses Pharma; has served as a consultant or advisor to AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Foundation Medicine, GSK, Lilly, Novartis, Pfizer, Roche/Genentech, Samsung, and Seattle Genetics; has participated in a speakers bureau for Daiichi Sankyo, Foundation Medicine, Lilly, Novartis, Pfizer, Roche/Genentech, Samsung, and Seagen; has received institutional research funding from Merck; and has been reimbursed for travel, accommodations, or other expenses by Pfizer and Roche/Genentech.
REFERENCES
1.Schmid P, Cortes J, Dent R, et al: KEYNOTE-522: Phase 3 study of neoadjuvant pembrolizumab plus chemotherapy versus placebo plus chemotherapy, followed by adjuvant pembrolizumab versus placebo for early-stage triple-negative breast cancer. ESMO Virtual Plenary. Abstract VP7-2021. Presented July 15, 2021.
2. Mittendorf EA, Zhang H, Barrios CH, et al: Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): A randomised, double-blind, phase 3 trial. Lancet 396:1090-1100, 2020.
3. Gianni L, Huang C, Egle D, et al: Pathologic complete response to neoadjuvant treatment with or without atezolizumab in triple-negative, early high-risk and locally advanced breast cancer. NeoTRIPaPD-L1 Michelangelo randomized study. 2019 San Antonio Breast Cancer Symposium. Abstract GS3-04. Presented December 12, 2019.
4. Loibl S, Schneeweiss A, Huober JB, et al: Durvalumab improves long-term outcome in TNBC: Results from the phase II randomized GeparNuevo study investigating neoadjuvant durvalumab in addition to an anthracycline/taxane based neoadjuvant chemotherapy in early triple-negative breast cancer (TNBC). 2021 ASCO Annual Meeting. Abstract 506. Presented June 7, 2021.
