Pembrolizumab Passes Phase II Test in HER2-Negative Breast Cancers

Adding the PD-1 inhibitor pembrolizumab (Keytruda) to standard neoadjuvant chemotherapy tripled the pathologic complete response (pCR) rate in multiple subtypes of HER2-negative breast cancer, according to results from the ongoing phase II I-SPY-2 clinical research program presented during the 2017 ASCO Annual Meeting.

Rita Nanda, MD

Adding the PD-1 inhibitor pembrolizumab (Keytruda) to standard neoadjuvant chemotherapy tripled the pathologic complete response (pCR) rate in multiple subtypes of HER2-negative breast cancer, according to results of a phase II trial.

Patients with triple-negative disease (TNBC) had a pCR rate of 60% with pembrolizumab and 20% with chemotherapy alone. In the hormone receptor (HR)-positive/HER2-negative subtype, pCR rates were 34% with pembrolizumab and 13% without. Across all HER2-negative subtypes, the addition of pembrolizumab led to a pCR rate of 46% versus 16% for chemotherapy alone.

The study is the first in the ongoing phase II I-SPY-2 clinical research program to suggest that a neoadjuvant regimen has a high probability of improving results in a phase III trial, Rita Nanda, MD, reported at the 2017 American Society of Clinical Oncology annual meeting in Chicago.

“Pembrolizumab for 4 cycles plus paclitaxel has graduated [to phase III eligibility] for all HER2-negative signatures studied,” said Nanda, assistant professor of medicine, and associate director, Breast Medical Oncology, University of Chicago Medicine. “Adrenal insufficiency was observed at a higher rate than previously reported in advanced cancer. The patients are doing well on replacement therapy, and follow-up of patient outcomes is ongoing.”

The pembrolizumab regimen is the latest to “graduate” to phase III status from the neoadjuvant I-SPY-2 standing platform of adaptive randomization. Multiple concurrent experimental arms are under evaluation at any given time.

A key feature of the trial is adaptive randomization, the process of assigning patients to treatment groups on the basis of results obtained in previously randomized patients. The overarching goals are to minimize the number of patients required to determine a regimen’s efficacy and to identify promising agents more efficiently.

Regimens “graduate” for efficacy in I-SPY-2 by achieving 85% predicted probability of success in a 1:1 randomized, 300-patient, phase III clinical trial, said Nanda.

I-SPY-2 eligibility criteria include breast tumors ≥2.5 cm, suitable for neoadjuvant chemotherapy, evaluation by breast MRI and biopsy, genomic assessment by MammaPrint, and adequate functional status, with an ECOG performance status of 2 or less. The primary endpoint is pCR, defined as no residual cancer in the breast or lymph nodes (ypT0/is and ypN0). Investigators use Bayesian modeling to generate predictive probability distributions of pCR rates by breast cancer subtype or “signature.”

Investigators evaluated pembrolizumab in patients with tumors representing 3 HER2-negative signatures: all HER2-negative subtypes, HR-positive/HER2-negative, and TNBC. Patients were randomized to weekly 80 mg/m2paclitaxel alone or with 200 mg of pembrolizumab every 3 weeks, followed by doxorubicin-cyclophosphamide. As pCR data became available in 1 of the HER2-negative groups, the results informed randomization in the other HER2-negative arms.

Nanda reported findings derived from 249 patients, including 69 randomized to pembrolizumab and 180 to the control arm. The methodology yielded estimated pCR rates that were approximately 3 times greater for treatment with pembrolizumab across all 3 signatures evaluated.

The results suggested a >99% probability that the pembrolizumab regimen was superior to the control regimen. The results further suggested that the pembrolizumab regimen had a 99% predictive probability of success in a randomized phase III trial for all HER2-negative signatures, a predictive probability >99% for the TNBC signature, and a predictive probability of 88% for the HR-positive/HER2-negative signature.

The most common adverse events (AEs; all grades) were fatigue (79.7% with pembrolizumab vs 81.1% without), nausea (73.9% vs 71.7%), peripheral sensory neuropathy (50.7% vs 59.4%), diarrhea (49.3% vs 37.8%), vomiting (34.8% vs 18.3%), and anemia (27.5% vs 18.9%). Among grade 3/4 AEs, only fatigue and nausea occurred more often with pembrolizumab (5.8% vs 4.3%) than with chemotherapy alone (0.6% vs 0.0%).

Most AEs of special interest (including immune-mediated toxicities) occurred more often with pembrolizumab: hypothyroidism (8.7% vs 0.6%), hyperthyroidism (4.3% vs 0.0%), adrenal insufficiency (8.7% vs 0.0%), hepatitis (2.9% vs 0.0%), pneumonitis (2.9% vs 1.1%), colitis (1.4% vs 0.8%), and pruritus (24.6% vs 11.1%). The only grade 3 to 5 AEs of special interest occurring in more than 1 patient with the pembrolizumab regimen were adrenal insufficiency (7.2%) and hepatitis (2.9%).


Nanda R, Liu MC, Yau C, et al. Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): results from the I-SPY 2.J Clin Oncol.2017;35(suppl; abstr 506).