Neoadjuvant pembrolizumab benefits patients with high-risk triple-negative breast cancer
SAN ANTONIO — The addition of pembrolizumab to neoadjuvant chemotherapy and as adjuvant therapy increased pathologic complete response among patients with high-risk triple-negative breast cancer, according to results of the KEYNOTE-522 trial presented at San Antonio Breast Cancer Symposium.
These included patients with stage IIIa or stage IIIb disease, as well as those with lymph node involvement.
“That is fantastic news for these very high-risk groups who, unfortunately, have a relatively poor prognosis,” Peter Schmid, MD, PhD, FRCP, clinical director of St. Bartholomew Breast Cancer Centre in London and lead of the Centre for Experimental Cancer Medicine at Barts Cancer Institute, told Healio. “We see a substantial benefit, with a difference in pathologic complete response of 20 [percentage points] among node-positive patients and up to 25 [percentage points] in patients with stage III disease. To me, that is a massive result.”
Triple-negative disease is the most aggressive breast cancer subtype. It accounts for about 15% of breast cancer cases and disproportionately affects young women.
Neoadjuvant chemotherapy followed by surgery offers the greatest chance for pathologic complete response.
Taxane- and anthracycline-based chemotherapy induce pathologic complete response rates of approximately 40%, and the addition of platinum agents can increase that rate to about 50%, according to study background. Meta-analyses have shown a strong association between pathologic complete response after neoadjuvant chemotherapy and improved long-term outcomes, including EFS (HR = 0.24) and OS (HR = 0.16).
“There continues to be a significant need for new regimens that can increase the pathologic complete response rate and increase long-term EFS for patients with triple-negative breast cancer,” Schmid said.
In the placebo-controlled KEYNOTE-522 trial — the first phase 3 trial to evaluate immunotherapy for early breast cancer — researchers evaluated the combination of the anti-PD-1 monoclonal antibody pembrolizumab (Keytruda, Merck) and chemotherapy followed by adjuvant pembrolizumab.
The analysis included 1,174 adults with previously untreated, nonmetastatic, centrally confirmed triple-negative breast cancer. All patients had stage T1c N1-2 or T2-4 N0-2 disease.
Researchers assigned 784 patients to 200 mg pembrolizumab every 3 weeks in combination with neoadjuvant chemotherapy (four cycles of paclitaxel and carboplatin, followed by four cycles of doxorubicin or epirubicin plus cyclophosphamide).
The other 390 patients chemotherapy plus placebo.
All patients underwent definitive surgery and received radiation therapy as indicated. After that, depending on randomization, they received adjuvant pembrolizumab or placebo. Adjuvant treatment continued for up to nine cycles, or until disease recurrence or unacceptable toxicity.
Pathologic complete response — defined as ypT0/Tis ypN0, meaning clearance of the cancer from the breast after chemotherapy — and EFS served as dual primary endpoints.
Secondary endpoints included OS, efficacy in the subset of patients with PD-L1-positive disease and additional measurements of pathologic complete response.
Schmid presented results of the definitive pathologic complete response analysis at this year’s European Society for Medical Oncology Congress.
That analysis included 602 evaluable patients and median follow-up of 15.5 months (range, 2.7-25).
Results revealed a statistically significant improvement in pathologic complete response rate with pembrolizumab plus chemotherapy in the entire population (64.8% vs. 51.2%; P = .00055), the subgroup of patients with PD-L1-positive disease (68.9% vs. 54.9%) and the subgroup of those with PD-L1-negative disease (45.3% vs. 30.3%).
In San Antonio, Schmid presented results of the first preplanned interim analysis for EFS. The analysis, also based on 15.5 months of follow-up, included 1,174 patients.
Results showed numerically superior 18-month EFS among patients assigned pembrolizumab (91.3% vs. 85.3%; HR = 0.63; 95% CI, 0.43-0.93). However, the difference did not reach statistical significance based on the precalculated boundary (P = .000051; HR < 0.4).
Schmid also presented pathologic complete response results based on multiple patient characteristics.
An analysis by disease stage showed the benefit with pembrolizumab persisted among patients with stage IIa (73.1% vs. 62.1%), stage IIb (86.2% vs. 48.4%), stage IIIa (66.7% vs. 42.1%) and stage IIIb (48.6% vs. 23.1%) disease.
Researchers observed an improvement in pathologic complete response with the pembrolizumab regimen among patients with node-negative disease (64.9% vs. 58.6%) and node-positive disease (64.8% vs. 44.1%).
“Who would’ve thought we would have achieved a 20 or 25 [percentage point] delta?” Schmid said. “If you had told me that a year ago, I would have said ‘wow.’ I still say ‘wow.’
“Think about what pathologic complete response means from a patient perspective,” Schmid added. “If you have to tell them that, unfortunately, there is still residual cancer left, unfortunately their recurrence risk is pretty high. Being able to give good news to this many more patients makes a huge difference.”
An analysis of pathologic complete response by PD-L1 expression level showed benefits among with pembrolizumab among patients with combined positive scores less than 1 (45.3% vs. 30.3%), 1 or higher (68.9% vs. 54.9%), 10 or higher (77.9% vs. 59.8%) and 20 or higher (81.7% vs. 62.5%).
“Everyone was intrigued by the results we showed at ESMO demonstrating benefit among patients with PD-L1-positive and PD-L1-negative disease,” Schmid told Healio. “We wanted to see if most of that benefit was driven by very inflamed tumors but, actually, you see a consistent benefit across all subsets. This gives us more confidence that what we see in PD-L1-negative tumors is, in fact, real, and PD-L1 staining doesn’t seem to make any difference in the early setting.”
An exploratory analysis showed the pathologic complete response benefit with pembrolizumab also persisted regardless of whether patients received full exposure to chemotherapy (69.7% vs. 55.3%) or less than full exposure (51.1% vs. 35.7%).
“We’re not impacting the delivery of full chemotherapy. We’re adding a checkpoint inhibitor, and that is an important point,” Schmid told Healio. “But if you are unable to give a full dose of chemotherapy because of side effects, optimal response, patient request or other factors, we still see a benefit for those patients from adding pembrolizumab, and that is an encouraging result.”
The pembrolizumab regimen also was associated with a higher rate of patients achieving residual cancer burden scores of 0 or 1.
Immune-mediated adverse event rates continued to appear consistent with known profiles of each regimen, and researchers observed no new safety concerns. The results continue to indicate this is a well-tolerated therapy, Schmid said.
“Our results suggest that adding pembrolizumab to neoadjuvant chemotherapy is beneficial for patients with the most aggressive disease and the highest unmet need,” Schmid said. “I think the results have the potential to be practice-changing.” – by Mark Leiser
Schmid P, et al. Abstract GS3-03. Presented at: San Antonio Breast Cancer Symposium; Dec. 10-14, 2019; San Antonio.
Disclosures: Merck Sharp & Dohme sponsored this study. Schmid reports research funding from Astellas, AstraZeneca, Genentech/Roche, Medivation, Novartis and OncoGenex Pharmaceuticals. He also reports honoraria or consultant fees from AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Merck, Novartis, Pfizer, Puma Biotechnology and Roche. Please see the abstract for all other authors’ relevant financial disclosures.