Oral paclitaxel, carboplatin, and dostarlimab (OPE/Cb/D) without and with trastuzumab in early-stage, high-risk breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL.

person Kay T Yeung University of California, San Diego, La Jolla, CA info_outline Kay T Yeung, Kevin Kalinsky, Christina Yau, Amy Jo Chien, Judy Caroline Boughey, Erica Michelle Stringer-Reasor, Carla Isadora Falkson, Kathy S. Albain, Ingrid A. Mayer, Meghna S. Trivedi, Rita Nanda, Emily H. Douglas, Coral Oghenerukevwe Omene, Hope S. Rugo, Claudine Isaacs, Beverly Parker, Angela DeMichele, Douglas Yee, Laura Esserman

Authors person Kay T Yeung University of California, San Diego, La Jolla, CA info_outline Kay T Yeung, Kevin Kalinsky, Christina Yau, Amy Jo Chien, Judy Caroline Boughey, Erica Michelle Stringer-Reasor, Carla Isadora Falkson, Kathy S. Albain, Ingrid A. Mayer, Meghna S. Trivedi, Rita Nanda, Emily H. Douglas, Coral Oghenerukevwe Omene, Hope S. Rugo, Claudine Isaacs, Beverly Parker, Angela DeMichele, Douglas Yee, Laura Esserman Organizations University of California, San Diego, La Jolla, CA, Emory University Hospital, Atlanta, GA, University of California, San Francisco, San Francisco, CA, Mayo Clinic, Rochester, MN, University of Alabama at Birmingham, Birmingham, AL, University of Rochester Medical Center Department of Medical Oncology, Rochester, NY, Loyola University Medical Center, Maywood, IL, Vanderbilt University, Nashville, TN, Columbia University, New York, NY, University of Chicago, Chicago, IL, Wake Forest University School of Medicine, Winston-Salem, NC, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, University of California Comprehensive Cancer Center, San Francisco, CA, Lombardi Cancer Center, Georgetown University, Washington, DC, Living Beyond Breast Cancer, Naperville, IL, University of Pennsylvania, Philadelphia, PA, Masonic Cancer Center, Minneapolis, MN Abstract Disclosures Research Funding U.S. National Institutes of Health U.S. National Institutes of Health, U.S. National Institutes of Health, Quantum Leap Healthcare Collaborative Background: I-SPY 2 is a multicenter trial using response-adaptive randomization within biomarker subtypes including MammaPrint (MP) risk to evaluate novel neoadjuvant agents in high-risk breast cancer. Oral paclitaxel and encequidar (OPE) is an oral combination of paclitaxel (P) with a p-glycoprotein pump inhibitor, encequidar, to enhance gastrointestinal (GI) absorption. Dostarlimab (D) is an anti-PD-1 monoclonal antibody. Methods: Women with tumors ≥ 2.5cm and MP high-risk cancers were screened and treated starting Oct 5, 2020. Treatment included Oral Paclitaxel 205mg/m2 and encequidar 12.9 mg on days 1-3, Carboplatin (Cb) AUC 1.5 on day 1 weekly x 12, and Dostarlimab (D) 500 mg every 3 weeks x 4, followed by doxorubicin/ cyclophosphamide (AC) every 2-3 weeks x 4. The control arm was IV P weekly x 12 followed by AC every 2-3 weeks x 4. For patients with HER2+ disease, weekly Trastuzumab (T) was administered during the first 12 weeks. The arm was eligible for graduation [> 85% chance of success in a 300-person phase 3 neoadjuvant trial with a pathologic complete response (pCR) endpoint] in 10 predefined signatures. Results: 106 patients (44 HR+HER2-, 56 HR-HER2- (TN), 6 HER2+) received OPE/Cb/D ± T. The control arm included 388 historical controls (201 HR+HER2-, 156 TN, 31 HER2+). 22 patients (20 HR+, 2 HR-) in OPE/Cb/D were MP1 (MP high) and 84 patients (29 HR+, 55 HR-) were MP2 (MP ultra-high). OPE/Cb/D graduated in the TN signature and accrual was stopped. Conclusions: OPE/Cb/D graduated in the TN signature with a higher predicted pCR rate compared to control. OPE and D have been, individually, shown to have efficacy in other settings. The lower-than-expected pCR rate and lower irAEs with triplet therapy (taxane, platinum, immune checkpoint inhibitor [ICI]) in TN compared to prior IV chemo + ICI arms on I-SPY 2 suggests a possible interference of OPE with ICI. Changes in gut microbiome is being investigated as an explanation. Clinical trial information: NCT01042379. Estimated pCR rates after all patients completed surgery. Signature Estimated pCR rate (95% Probability Interval) Probability OPE/Cb/D Superior to Control Predictive Probability of Success in Phase 3 OPE/Cb/D Control HR-HER2- (TN) 0.49 (0.39-0.60) 0.29 (0.26-0.33) 0.97 0.79 HR- 0.49 (0.39-0.59) 0.31 (0.27-0.34) 0.89 0.62 HER2- 0.32 (0.26-0.39) 0.21 (0.19-0.29) 0.95 0.56 HR+ 0.18 (0.12-0.25) 0.16 (0.13-0.19) 0.50 0.20 MP2 0.49 (0.39-0.58) 0.30 (0.27-0.33) 0.89 0.60 Safety events for OPE/Cb/D versus control included increased rates of nausea (89%, 3.8% ≥ g3), diarrhea (76%; 7.5% ≥ g3), neutropenia (59.4%; 41.5% ≥ g3), anemia (35.8%), urinary tract infections (17.9% ≥ g2), febrile neutropenia (10.4%), immune-related adverse events (irAEs: hypothyroidism 12.3%, adrenal insufficiency 3.8%), but decreased rates of peripheral neuropathy (27.4% g1; 4.7% g2; 0% g3) and alopecia (28.3% ≥ g2).

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