ASCO 2017: I-SPY 2 Trial: Combination of Pembrolizumab Plus Standard Neoadjuvant Therapy in High-Risk Breast Cancer

Key Points

  • In patients with triple-negative breast cancer, an absolute increase in the estimated pathologic complete response rate of 40% was observed in the pembrolizumab arm.
  • In patients with HER2-negative breast cancer, an absolute increase in the estimated pathologic complete response rate of 30% was observed in the pembrolizumab arm.
  • In patients with hormone receptor–positive/HER2-negative breast cancer, an absolute increase in the estimated pathologic complete response rate of 21% was observed in the pembrolizumab arm.

At the 2017 ASCO Annual Meeting, results were presented from the phase II I-SPY 2 trial investigating pembrolizumab (Keytruda) in combination with standard therapy (paclitaxel followed by doxorubicin and cyclophosphamide) as a neoadjuvant treatment for patients with locally advanced triple-negative breast cancer or hormone receptor–positive/HER2-negative breast cancer (Abstract 506).  

Findings showed that the addition of pembrolizumab increased the estimated pathologic complete response rate nearly threefold in patients with triple-negative breast cancer (60% vs 20%) and in patients with hormone receptor–positive/HER2-negative breast cancer (34% vs 13%) compared to standard therapy. Overall, based on Bayesian predictive probability of success in a confirmatory phase III trial, pembrolizumab has graduated from the I-SPY 2 TRIAL for all signatures in which it was tested (triple-negative breast cancer, all HER2-negative, and hormone receptor–positive/HER2-negative).

“Pembrolizumab in combination with standard therapy tripled the rate of pathologic complete responses in HER2-negative patients in the I-SPY 2 Trial,” said Laura J. Esserman, MD, MBA, Professor of Surgery and Radiology and Director of the Carol Franc Buck Breast Care Center at UCSF Helen Diller Family Comprehensive Cancer Center, and the overall principal investigator for the I-SPY trials. “The regimen indicates a new and important treatment pathway and gives us well-grounded hope for new options for patients with these aggressive breast cancers—and that’s potentially very good news.” 

More Details About I-SPY 2

The I-SPY 2 trial (NCT01042379) is a standing phase II randomized, controlled, multicenter trial for women with newly diagnosed, locally advanced breast cancer (stage II/III), and is designed to screen promising new treatments and identify which therapies are most effective in specific patient subgroups based on molecular characteristics (biomarker signatures). The primary endpoint is to determine whether the combination of certain therapies increases the probability of pathologic complete response in the breast and the lymph nodes at the time of surgery. The data presented at ASCO from the I-SPY 2 trial were based on results observed in patients at high risk of relapse using upfront tumor profiling (including hormone receptor status, HER2 status, and the MammaPrint 70-gene signature test).

Patients were treated with weekly standard chemotherapy (paclitaxel) for 12 weeks, with or without pembrolizumab, followed by doxorubicin and cyclophosphamide every 3 weeks for four cycles. Sixty-nine patients were adaptively randomized to receive pembrolizumab in the trial from December 2015 until it graduated in November 2016. In total, 46 patients have undergone surgery; the other 23 have on-therapy magnetic resonance imaging assessments.

Major Findings

In patients with triple-negative breast cancer, an absolute increase in the estimated pathologic complete response rate of 40% was observed in the pembrolizumab arm (based on the estimated pathologic complete response rate of 60% with pembrolizumab plus standard therapy compared to 20% with standard therapy alone). In patients with HER2-negative breast cancer, an absolute increase in the estimated pathologic complete response rate of 30% was observed in the pembrolizumab arm (based on the estimated pathologic complete response rate of 46% with pembrolizumab plus standard therapy compared to 16% with standard therapy alone). In patients with hormone receptor–positive/HER2-negative breast cancer, an absolute increase in the estimated pathologic complete response rate of 21% was observed in the pembrolizumab arm (based on the estimated pathologic complete response rate of 34% with pembrolizumab plus standard therapy compared to 13% with standard therapy alone). The Bayesian model estimated pathologic complete response rates appropriately adjusted to characteristics of the I-SPY 2 population, including MammaPrint status.

The safety profile of pembrolizumab was consistent with that observed in previously reported studies across tumors. In the pembrolizumab arm, grade 3­ to 5 treatment-related adverse events include diarrhea (n = 5), febrile neutropenia (n = 5), fatigue (n = 4), anemia (n = 3), nausea (n = 3), neutropenia without fever (n = 1), peripheral motor neuropathy (n = 1), peripheral sensory neuropathy (n = 1), and vomiting (n = 1). Immune-mediated adverse events of grade 3 to 5 include adrenal insufficiency (n = 5), hepatitis (n = 2), colitis (n = 1), and hypothyroidism (n = 1). Five of six patients presented with adrenal insufficiency after completion of doxorubicin/cyclophosphamide (21–24 weeks after starting pembrolizumab), and one presented during pembrolizumab treatment (5 weeks after starting pembrolizumab).

“Not all breast cancers are the same—and there has continued to be a significant gap in the treatment options available for patients with certain subtypes, particularly triple-negative breast cancer,” said Rita Nanda, MD, a medical oncologist at The University of Chicago. “The results observed in this trial are not only encouraging, but demonstrate the potential for treatment combinations that can make a difference in patient outcomes.”

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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