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.
Evaluated as an arm of the adaptively-designed, randomized, open-label phase 2 I-SPY2 trial (ClinicalTrials.gov 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.
- 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
- 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.
- 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.