The discussant of KEYNOTE-522 at the 2021 San Antonio Breast Cancer Symposium, Hope S. Rugo, MD, FASCO, Professor of Medicine and Director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Comprehensive Cancer Center, commented: “We are clearly making progress in the outcomes of patients with high-risk early triple-negative breast cancer by adding immunotherapy. The study showed an increase in pathologic complete responses and, most recently, a significant increase in event-free survival and distant recurrence–free survival with pembrolizumab.”

In the study population, about half the patients had lymph node involvement, three-quarters had stage II disease, and half were postmenopausal. Interestingly, in a previous prespecified exploratory analysis, the 3-year event-free survival benefit seen with pembrolizumab was independent of PD-L1 expression or achievement of pathologic complete response.

Unanswered Questions

“Overarching questions arise with regard to the association of pathologic complete response and event-free survival, and the discordance of PD-L1 in predicting the impact of checkpoint inhibitors in early vs late disease,” she continued. In the metastatic setting, PD-L1 is a good biomarker for response to checkpoint inhibition. “PD-L1 may be an imperfect marker, but it’s the best one we have at the present,” she said.

Hope S. Rugo, MD, FASCO

Pembrolizumab has been shown to have a greater impact on pathologic complete response in node-positive vs node-negative disease. It seems more likely this is related to a differential impact on disease stage, with a greater impact seen in higher-stage disease, she said. KEYNOTE-522 patients who achieved pathologic complete responses had relatively good event-free survival regardless of treatment arm, whereas patients without a pathologic complete response fared much better with pembrolizumab.

It is likely that a “shift” away from residual cancer burden, as one sees when pembrolizumab is given with chemotherapy, may be responsible for the improved event-free survival in the group not achieving a pathologic complete response. This may be somewhat responsible for the differential impact on pathologic complete response by nodal status, she added. 

Dr. Rugo posed other questions: What is the optimal chemotherapy backbone for immunotherapy? How should pembrolizumab be sequenced with other treatments after neoadjuvant therapy? What is the optimal duration of checkpoint inhibition in exceptional responders? Without a pathologic complete response, should pembrolizumab be combined with chemotherapy or olaparib [in the adjuvant setting] to optimize outcomes? 

“It’s still unclear whether everybody needs a checkpoint inhibitor…. In addition, we need to understand the balance of risk and toxicity,” she said. “There may be patients whose risk of immune toxicity is so high that we should not give them a checkpoint inhibitor, but this may take us a longer time to understand.” As for stopping treatment after an excellent response, Dr. Rugo acknowledged this is a tough question in clinical practice. “Sometimes toxicity gives us the answer. At some point, we need to stop therapy and understand what happens to those patients,” she said.

‘On the Right Path’

Although these questions will remain unanswered until more data come in, Dr. Rugo proposed “a potential roadmap” for the initial treatment of early-stage triple-negative breast cancer.  “For T1c node-negative disease, I believe in neoadjuvant treatment to optimize outcomes by understanding response, but patients should be treated with chemotherapy alone, as there are no data on checkpoint inhibitors in that setting,” she said. “For node-positive or T2 or greater disease, give pembrolizumab with a chemotherapy backbone that includes anthracyclines.” 

Paraphrasing Mark Twain, Dr. Rugo said: “The secret of making progress is to get started, and we’re clearly on the right path for triple-negative breast cancer.” 

DISCLOSURE: Dr. Rugo has served as a consultant or advisor to Puma Biotechnology, Napo, and Samsung; and has received institutional research funding from AstraZeneca, Ayala, Boehringer Ingelheim, Daiichi Sankyo, Genentech, Gilead, Lilly, Merck, Novartis, OBI Pharma, Pfizer, Polyphor, Sermonix, and Seattle Genetics.