Immuno-Oncology Resource Center
Immuno-Oncology Resource Center
February 13, 2020
3 min read

Pembrolizumab plus neoadjuvant chemotherapy linked to higher pathologic complete response rates in breast cancer

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Rita Nanda, MD
Rita Nanda

The addition of pembrolizumab to standard neoadjuvant chemotherapy significantly increased estimated pathologic complete response rates among women with early-stage breast cancer at high risk for recurrence, according to an analysis of the ongoing phase 2 I-SPY2 trial published in JAMA Oncology.

These data led researchers to conclude that the combination has a “high likelihood to succeed” in future phase 3 trials.

“We decided to conduct this study after the promising efficacy of pembrolizumab (Keytruda, Merck) monotherapy observed in advanced triple-negative breast cancer in the KEYNOTE-012 trial,” Rita Nanda, MD, associate professor of medicine at University of Chicago, told Healio. “I-SPY2 has multiple concurrently enrolling arms. One arm of the trial studied the addition of four cycles of pembrolizumab to paclitaxel followed by adjuvant chemotherapy. We found that the addition of four cycles of pembrolizumab to standard neoadjuvant chemotherapy more than doubled the likelihood of achieving a pathologic complete response among women with triple-negative breast cancer and among women with hormone receptor-positive, [70-gene (MammaPrint, Agendia) status] high-risk breast cancer.”

These findings led to two randomized phase 3 trials: KEYNOTE-522 in early-stage triple-negative breast cancer and KEYNOTE-756 in hormone receptor-positive breast cancer.

“KEYNOTE-522 found that adding pembrolizumab to standard neoadjuvant chemotherapy significantly improved pathologic complete response rates in triple-negative breast cancer,” Nanda told Healio. “KEYNOTE-756 in high-risk hormone receptor-positive breast cancer is actively enrolling patients, so it will be interesting to follow this trial and see if the pembrolizumab I-SPY2 arm successfully predicts the outcome of this study.”

The open-label, multicenter, adaptively randomized phase 2 I-SPY2 trial, which began in 2010, uses standard neoadjuvant chemotherapy (paclitaxel followed by doxorubicin and cyclophosphamide) as the control treatment, compared with 11 other agents and combinations. The concept of I-SPY2 is to efficiently identify effective agents and signatures in which they are most effective, in order to accelerate drug development, according to researchers.

The current data set included 250 women randomly assigned to standard neoadjuvant chemotherapy (n = 181; median age, 47 years) or four cycles of pembrolizumab in combination with weekly paclitaxel followed by adjuvant chemotherapy (n = 69; median age, 50 years). The pembrolizumab group included 40 women with hormone receptor-positive breast cancer and 29 women with triple-negative breast cancer.

Pathologic complete response served as the primary endpoint. Secondary endpoints included residual disease burden and 3-year EFS.

Pembrolizumab reached the predefined graduation threshold of an 85% or greater predictive probability of success in a hypothetical confirmatory phase 3 trial for all three biomarker signatures studied, according to the researchers.


Results showed final estimated pathologic complete response rates of 44% in the pembrolizumab group vs. 17% in the control group among women with HER2-negative breast cancer, 30% vs. 13% among women with hormone receptor-positive/HER2-negative disease, and 60% vs. 22% among women with triple-negative disease.

Moreover, researchers observed lower residual disease burden for each cohort evaluated in the pembrolizumab group.

Results of an exploratory analysis that included 66 women in the pembrolizumab group and 172 women in the control group showed women with pathologic complete response in the pembrolizumab group achieved a 3-year EFS rate of 93% with median follow-up of 2.8 years.

Pembrolizumab exhibited a safety profile consistent with that observed in prior studies.

“The story of how I-SPY2, with only 69 patients in the investigational arm, was able to accurately predict the outcome of an almost 1,200-patient randomized phase 3 study is quite remarkable and a win for the concept of an adaptive trial design as far as its ability to predict the future success of a randomized phase 3 trial,” Nanda told Healio. “In fact, of the 69 women [randomly assigned] to pembrolizumab, only 29 were triple-negative. This means the benefit of pembrolizumab for early-stage triple-negative breast cancer was actually predicted by the response of just 29 [women with triple-negative disease].” – by Jennifer Southall

For more information:

Rita Nanda, MD, can be reached at University of Chicago, 900 E. 57th St., Suite 8118, Chicago, IL 60637; email:

Disclosures: Nanda reports grants from Quantum Leap for this study; grants from AstraZeneca, Celgene, Corcept Therapeutics, Genentech/Roche, Immunomedics, Merck, OBI Pharma, Odonate Therapeutics, Pfizer and Seattle Genetics outside the study; and personal fees from Aduro, AstraZeneca, Athenex, Celgene, Daiichi Sankyo, G1 Therapeutics, Genentech, MacroGenics, Merck, Novartis, Pfizer, Puma and Syndax. Please see the study for all other authors’ relevant financial disclosures.