Effect of Pembrolizumab Plus Neoadjuvant Chemotherapy on Pathologic Complete Response in Women With Early-Stage Breast Cancer

Abstract

IMPORTANCEApproximately 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.OBJECTIVE To determine if pembrolizumab plus neoadjuvant chemotherapy (NACT) in early-stage breast cancer is likely to be successful in a 300-patient, confirmatory randomized phase 3 neoadjuvant clinical trial. DESIGN, SETTING, AND PARTICIPANTSThe I-SPY2 study is an ongoing open-label, multicenter, adaptively randomized phase 2 platform trial for high-risk, stage II/III breast cancer, evaluating multiple investigational arms in parallel. Standard NACT 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.INTERVENTIONS Participants were randomized to receive taxane-and anthracycline-based NACT with or without pembrolizumab, followed by definitive surgery. MAIN OUTCOMES AND MEASURESThe primary end point was pathologic complete response (pCR). Secondary end points were residual cancer burden (RCB) and 3-year event-free and distant recurrence-free survival. Investigational arms graduated when demonstrating an 85% predictive probability of success in a hypothetical confirmatory phase 3 trial. RESULTSOf the 250 women included in the final analysis, 181 were randomized to the standard NACT control group (median [range] age, 47 [24.77] years). Sixty-nine women (median [range] age, 50 [27-71] years) were randomized to 4 cycles of pembrolizumab in combination with weekly paclitaxel followed by AC; 40 hormone receptor (HR)-positive and 29 triple-negative. Pembrolizumab graduated in all 3 biomarker signatures studied. Final estimated pCR rates, evaluated in March 2017, were 44% vs 17%, 30% vs 13%, and 60% vs 22% for pembrolizumab vs control in the ERBB2-negative, HR-positive/ERBB2-negative, and triple-negative cohorts, respectively. Pembrolizumab shifted the RCB distribution to a lower disease burden for each cohort evaluated. Adverse events included immune-related endocrinopathies, notably thyroid abnormalities (13.0%) and adrenal insufficiency (8.7%). Achieving a pCR appeared predictive of long-term outcome, where patients with pCR following pembrolizumab plus chemotherapy had high event-free survival rates (93% at 3 years with 2.8 years' median follow-up).CONCLUSIONS AND RELEVANCE When added to standard neoadjuvant chemotherapy, pembrolizumab more than doubled the estimated pCR rates for both HR-positive/ERBB2negative 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. Pembrolizumab was the first of 10 agents to graduate in the HR-positive/ERBB2-negative signature.

Role of Immunotherapy in Triple-Negative Breast Cancer

“…The combination of ICIs with chemotherapy in earlystage TNBC has also demonstrated preliminary success (Table 3). Among patients with stage II-III disease, the I-SPY 2 trial (ClinicalTrials.gov identifier: NCT01042379) initially revealed that pembrolizumab added to neoadjuvant paclitaxel followed by doxorubicin and cyclophosphamide nearly tripled the estimated pathologic complete response (pCR) rates from 22% to 60%, 31 perhaps related to the known immunostimulatory effects of anthracyclines to increase intratumoral immune effectors, 32 as well as antigen uptake and processing. 33 However, the GeparNuevo trial (NCT02685059), which included earlier-stage T1b and higher disease, demonstrated that the addition of durvalumab to neoadjuvant nab-paclitaxel followed by epirubicin and cyclophosphamide did not significantly improve pCR rates in the overall trial and only improved pCR rates when durvalumab was started 2 weeks before chemotherapy, which was a subgroup analysis underpowered for significance testing.…”

ICON: A randomized phase IIb study evaluating immunogenic chemotherapy combined with ipilimumab and nivolumab in patients with metastatic hormone receptor positive breast cancer

“…Based on this study, atezolizumab has been approved by the FDA and EMA in combination with taxanes for metastatic TNBC. Further, in early studies of preoperative therapy, the combination of PD-1 blockade and chemotherapy has produced a substantial increase in response rates, compared to chemotherapy alone, for both ER+/HER-2 negative and triple negative BC patients [9,10]. Our study rationale is in line with these ndings, combining checkpoint blockade with a carefully selected chemotherapy regimen, as 1 st / 2 nd line metastatic treatment.…”

“…Immunotherapy with PD-1 and CTLA-4 inhibitors has shown remarkable clinical e cacy against several cancer forms [1][2][3][4][5][6] and now show activity in breast cancer [7][8][9][10]. This includes durable responses in metastatic breast cancer (mBC) patients, amid minimal adverse effects.…”

Early Triple Negative Breast Cancer: Conventional Treatment and Emerging Therapeutic Landscapes

“…The I-SPY 2 phase II trial evaluated the addition of pembrolizumab to standard NACT, showing a 40% improvement in the probability of pCR compared to the control arm (60% vs. 22%) [97]. Furthermore, in the phase Ib Keynote-173 trial, a multicohort study assessing the safety and the efficacy of pembrolizumab combined with various schedules and doses of platinum and taxanes followed by AC as NACT, the pCR rate across all cohorts ranged from 60% to 80%, with the best response registered in the subgroup of patients treated with pembrolizumab added to nab-paclitaxel plus carboplatin [98].…”