Pembrolizumab Plus Neoadjuvant Chemo Promising for Early-Stage Breast Cancer

Findings from the I-SPY2 clinical trial suggest that combining pembrolizumab with neoadjuvant chemotherapy would be significantly better for patients with ERBB2-negative breast cancer than chemotherapy alone (JAMA Oncol. 2020 Feb 13. Epub ahead of print).

“Approximately 25% of patients with early-stage breast cancer who receive (neo)adjuvant chemotherapy experience a recurrence within 5 years. Improvements in therapy are greatly needed,” explained Rita Nanda, MD, The University of Chicago, Illinois, and co-investigators, who are evaluating whether pembrolizumab plus neoadjuvant chemotherapy could benefit patients with early-stage breast cancer in a phase 3 trial.

A total of 250 patients with high-risk, stage II/III breast cancer are currently involved in the phase 2, open-label, multi-center I-SPY2 study evaluating multiple investigational arms in parallel.

“Standard neoadjuvant chemotherapy serves as the common control arm; investigational agent(s) are added to this backbone. Patients with ERBB2 (formerly HER2)-negative breast cancer were eligible for randomization to pembrolizumab between November 2015 and November 2016,” Dr Nanda et al said.

Of the 250 patients in the study, 181 (median age, 47 years) were randomized to receive standard neoadjuvant chemotherapy and 69 (median age, 50 years; 40 with hormone receptor [HR]-positive and 29 with triple-negative disease) were randomized to receive 4 cycles of pembrolizumab plus weekly paclitaxel followed by adjuvant chemotherapy.

The primary end point of I-SPY2 is pathologic complete response (pCR), and secondary end points include residual cancer burden (RCB) and the event-free and distant recurrence-free survival rates at 3 years. Patients in investigational arms graduated when an 85% predictive probability of success in a hypothetical confirmatory phase 3 trial was observed.

According to the investigators, pembrolizumab graduated in all 3 biomarker signatures studied. As of March 2017, the final estimated pCR rates for pembrolizumab versus nonpembrolizumab, HR-positive/ERBB2-negative, and triple-negative cohorts were 44% versus 17%, 30% versus 13%, and 60% versus 22%, respectively.

Notably, RCB distribution was shifted to a lower disease burden with pembrolizumab in each cohort evaluated.

Furthermore, a pCR achievement seemed to prognosticate long-term outcomes in which patients with pCR following pembrolizumab plus chemotherapy had high event-free survival rates (93% at 3 years with 2.8 years’ median follow-up).

Documented adverse events included immune-related endocrinopathies, primarily thyroid abnormalities (13.0%) and adrenal insufficiency (8.7%).

“When added to standard neoadjuvant chemotherapy, pembrolizumab more than doubled the estimated pCR rates for both HR-positive/ERBB2-negative and triple-negative breast cancer, indicating that checkpoint blockade in women with early-stage, high-risk, ERBB2-negative breast cancer is highly likely to succeed in a phase 3 trial,” Dr Nanda and colleagues concluded.

“Pembrolizumab was the first of 10 agents to graduate in the HR-positive/ERBB2-negative signature,” they added.—Hina Porcelli