Increases in rates of pathologic complete response (pCR) of approximately 2.3- to 3-fold were observed in molecularly defined subgroups of women with high-risk, early-stage breast cancer with the addition of the programmed cell death-1 (PD-1) inhibitor, pembrolizumab, to standard neoadjuvant chemotherapy, based on findings from the I-SPY2 study that was reported in JAMA Oncology.

An objective response rate (ORR) of 21.4% was achieved in women with metastatic programmed cell death-ligand 1 (PD-L1)–positive, triple-negative breast cancer treated with single-agent, pembrolizumab, according to results of a previous study.2

These results, as well as the finding that approximately one-quarter of women with early-stage breast cancer treated with neoadjuvant chemotherapy will experience a distant recurrence of disease by 5-year follow-up,3 provided support for evaluating the combination of standard neoadjuvant chemotherapy and immunotherapy in women with high-risk, nonmetastatic HER2-negative breast cancer.

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Evaluated as an arm of the adaptively-designed, randomized, open-label phase 2 I-SPY2 trial ( Identifier: NCT01042379), neoadjuvant therapy with pembrolizumab plus paclitaxel followed by doxorubicin and cyclophosphamide was compared with chemotherapy alone in women with stage II, III, or T4, any N, M0, HER2-negative breast cancer. Patients in both study arms subsequently underwent definitive surgery, and the primary study endpoint was pCR in biomarker-designated patient subgroups. Secondary study endpoints included 3-year event-free survival (EFS) and safety.

Of the 69 patients randomly assigned to receive the combination of pembrolizumab and chemotherapy, 40 had hormone receptor (HR)-positive disease. The control arm included 181 patients treated with standard chemotherapy alone.

In the pembrolizumab-containing arm, pCR rates were 44%, 30%, and 60% for patients with disease characterized as HR-negative and HER2-negative; HR-positive and HER2-negative; and triple-negative, respectively. In comparison, those receiving chemotherapy alone had response rates of 15% (HR-negative and HER2-negative), 13% (HR-positive and HER2-negative), and 22% (triple negative).

At a median follow-up of 2.8 years in the pembrolizumab-containing arm and 3.5 years in the chemotherapy-alone arm, the respective 3-year EFS rates were similar.

Regarding safety, the toxicity profiles of the 2 study arms mainly differed with respect to the frequency of immune-related adverse events, with rates of grade 3 or 4 hypothyroidism, adrenal insufficiency, hepatitis, and colitis observed in 1.4%, 7.2%, 2.9%, and 1.4% of patients, respectively, in those who received pembrolizumab. In contrast, these rates were 0%, 0%, 0%, and 0.6%, respectively, for those treated with chemotherapy alone.

In their concluding remarks, the study authors stated that these results provide support for the success of a hypothetical phase 3 trial of neoadjuvant immune checkpoint blockade plus chemotherapy in women with high-risk, early-stage, HER2-negative breast cancer.

Disclosure: Some of the study authors disclosed financial relationships with pharmaceutical companies and/or medical device companies. For a full list of disclosures, please refer to the original study.


  1. 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: An analysis of the ongoing phase 2 adaptively randomized I-SPY2 trial [published online February 13, 2020]. JAMA Oncol. doi: 10.1001/jamaoncol.2019.6650
  2. Adams S, Loi S, Toppmeyer D, et al. Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: Cohort B of the phase II KEYNOTE-086 study. Ann Oncol. 2019;30(3):405-411.
  3. Asselain B, Barlow W, Bartlett J, et al; Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials. Lancet Oncol. 2018;19(1):27-49.