Pembrolizumab Doubles Pathologic Complete Response Rates When Added to Standard NACT


According to the researchers, these data suggest that checkpoint blockade in women with early-stage, high-risk, ERBB2-negative breast cancer is very likely to succeed in a phase III trial.

In the I-SPY2 study, published in JAMA Oncology, researchers found that pembrolizumab (Keytruda), when added to standard neoadjuvant chemotherapy (NACT), more than doubled the estimated pathologic complete response (pCR) rates for both HR-positive/ERBB2-negative and triple-negative breast cancer.

These data suggest that checkpoint blockade in women with early-stage, high-risk, ERBB2-negative breast cancer is very likely to succeed in a phase III trial. 

“The promising efficacy observed with single-agent checkpoint blockade for advanced ERBB2 (formerly HER2)-negative breast cancer, and the considerable benefits observed with PD-1 inhibitors combined with chemotherapy for lung cancer and other malignant diseases, led us to evaluate the efficacy of adding pembrolizumab to standard neoadjuvant chemotherapy in the I-SPY2 trial, with the hypothesis that immune-targeted agents would be more effective in the early-stage setting when the immune system is less likely to be compromised,” the authors wrote.

In this cohort of 250 women who were included in the final analysis, 181 were randomized to receive standard NACT as a control and 69 women (40 HR-positive and 29 triple-negative) were randomized to pembrolizumab every 3 weeks for 4 cycles concurrently with paclitaxel (Abraxane), followed by standard NACT. In all 3 biomarker signatures studied, pembrolizumab graduated.

The final estimated pCR rates, evaluated in March 2017, were 44% vs 17%, 30% vs 13% and 60% vs 22% for pembrolizumab vs control in the ERBB2-negative, HR-positive/ERBB2-negative, and triple-negative cohorts, respectively. Additionally, pembrolizumab shifted the residual cancer burden to a lower disease burden for each cohort evaluated.

Adverse events observed included immune-related endocrinopathies, notably thyroid abnormalities (13%) and adrenal insufficiency (8.7%). The researchers recommended that future work to characterize the risk factors for developing immune-related endocrinopathies is necessary to improve the therapeutic index of these agents. Moreover, achieving a pCR appeared predictive of long-term outcome, where patients with pCR following pembrolizumab plus chemotherapy experienced high event-free survival rates (93% at 3 years with 2.8 years’ median follow-up).

“It should be emphasized that the estimated pCR rates that are the reporting standard in I-SPY2 are different than pCR rates reported from the studies using a typical randomized clinical trial design,” the authors wrote. “The estimated pCR rate represents the mean of the final posterior probability distribution for pCR in a given subtype, using a model adjusting for subtype and time trend.” 

Within this study, actual rates of pCR were higher than the estimated rates, however this could be due to the adaptive randomization procedure that favors regimens and subtypes found to exhibit better response. The pCR rates observed between the experimental and control arms provided perspective on the possible impact of an individual therapy in a given subtype. However, researchers also suggested that it is important to consider that I-SPY2 is a phase II study designed to rapidly screen for agents that are likely to succeed in phase III trials and preliminary reports from the phase III KEYNOTE 522 study provide further validation of this approach. 

Notably, previous concerns that steroid pre-medications required for paclitaxel could interfere with the efficacy of pembrolizumab appeared to be unfounded. Furthermore, although steroid pre-medications were discontinued after 2 doses of weekly paclitaxel if no infusion reactions were shown, they were routinely used per physician discretion for infusion reactions and the management of immune-related adverse events. 

The concept of I-SPY2 is to accelerate drug development by “efficiently identifying effective agents and the signatures in which they are most effective.” The authors also indicated that, “future I-SPY2 arms will continue to build on the promise of checkpoint blockade for women with high-risk, early-stage breast cancer, and biomarker work to better select those who will benefit from immune checkpoint inhibition is ongoing.”


Nanda R, Liu MC, Yau C, et al. Effect of Pembrolizumab Plus Neoadjuvant Chemotherapy on Pathologic Complete Response in Women With Early-Stage Breast Cancer. JAMA Oncology. doi:10.1001/jamaoncol.2019.6650.

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