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Evaluation of intra-tumoral (IT) SD-101 and pembrolizumab (Pb) in combination with paclitaxel (P) followed by AC in high-risk HER2-negative (HER2-) stage II/III breast cancer: Results from the I-SPY 2 trial.

Abstract

508
Background: I-SPY 2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint (MP) risk to evaluate novel agents as neoadjuvant therapy for women with high-risk breast cancer. SD-101 is an investigational Toll-like receptor 9 (TLR9) agonist CpG-C class oligodeoxynucleotide that stimulates the production of IFN-α and interleukin (IL)-12, functional maturation of plasmacytoid dendritic cells, and production of cytotoxic antibodies. IT SD-101 was combined with systemic anti-PD-1 antibody Pb to investigate the antitumor and immunologic activity of this novel immunotherapeutic strategy. Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only pts (pts) with HER2- disease were eligible for this treatment. Treatment included weekly P x 12 in combination with IT SD-101 2 mg/ml (1 ml for T2 tumors, 2 ml for >T3 tumors) weekly x 4, then q3 weeks x 2, and IV Pb q3 weeks x 4, followed by doxorubicin/cyclophosphamide (AC) q2-3 weeks x 4 (SD-101+Pembro 4). Pts in the control arm received weekly P x 12 followed by AC q2-3 weeks x 4. The I-SPY 2 methods have been previously published. This investigational arm was eligible for graduation (>85% chance of success in a 300-person phase 3 neoadjuvant trial) in 3 of 10 pre-defined signatures: HER2-, hormone receptor (HR)+/HER2- and HR-/HER2-. Results: 75 pts were randomized and evaluable in SD-101+Pembro 4 treatment arm. The control arm included 329 historical controls enrolled since April 2010. The study arm was stopped due to maximal patient accrual. Pt characteristics were balanced; 56% HR+, 44% HR-. The probability that SD-101+Pembro4 was superior to control exceeded 97% for all eligible tumor signatures, but did not reach the threshold for graduation in any of the signatures. However, it is notable that the rate of pCR/Residual Cancer Burden 1 (RCB1) in the HR+/HER2- signature was 51%. Preliminary safety events for SD-101+Pembro 4 include increased rates of fever, neutropenia, febrile neutropenia, transaminitis, and immune-related events, including adrenal insufficiency. Conclusions: The SD-101+Pembro 4 regimen was active but did not meet the pre-specified threshold for graduation in I-SPY 2. pCR/RCB 1 analysis suggests improved response in the HR+/HER-negative signature compared to control. The clinical significance of these findings needs to be weighed against the potential risk of immune-related toxicities. Clinical trial information: NCT01042379.
Signature
Estimated pCR rate

(95% prob interval)
Probability

SD-101+Pembro 4 Superior to Control
Predictive Probability of Success in Phase 3
SD-101+Pembro 4
Control
HER2–
0.34

(0.24-0.44)

N= 75
0.20

(0.16-0.24)

N= 329
>0.99
0.72
HR-/HER2-
0.44

(0.28-0.60)

N=29
0.28

(0.21-0.34)

N=147
0.97
0.71
HR+/HER2-
0.26

(0.14-0.37)

N=46
0.14

(0.09-0.18)

N=182
0.99
0.68

Information & Authors

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Published In

Journal of Clinical Oncology
Pages: 508

History

Published in print: May 20, 2021
Published online: May 28, 2021

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Amy Jo Chien
University of California, San Francisco, San Francisco, CA;
Hatem Hussein Soliman
H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL;
Cheryl Ann Ewing
University of California, San Francisco, San Francisco, CA;
Judy Caroline Boughey
Mayo Clinic, Rochester, MN;
Michael J. Campbell
University of California, San Francisco, San Francisco, CA;
Hope S. Rugo
University of California, San Francisco, San Francisco, CA;
Anne M. Wallace
University of California, San Diego, La Jolla, CA;
Kathy S. Albain
Loyola University Chicago Stritch School of Medicine, Maywood, IL;
Erica Michelle Stringer-Reasor
University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL;
An L Church
Masonic Cancer Center, University of Minnesota, Minneapolis, MN;
Kevin Kalinsky
Columbia University Medical Center, New York, NY;
Anthony D. Elias
University of Colorado, Anschutz Medical Center, Aurora, CO;
Zahi Ibrahim Mitri
Oregon Health and Science University, Portland, OR;
Amy Sanders Clark
University of Pennsylvania, Philadelphia, PA;
Rita Nanda
University of Chicago Medical Center, Chicago, IL;
Alexandra Thomas
Wake Forest Comprehensive Cancer Center, Winston-Salem, NC;
Christina Yau
University of California, San Francisco, San Francisco, CA;
I-SPY 2 Consortium
University of California, San Francisco, San Francisco, CA;
Donald A Berry
University of Texas, M.D. Anderson Cancer Center, Houston, TX;
Laura Esserman
University of California, San Francisco, San Francisco, CA;
University of California, San Francisco, San Francisco, CA; H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; Mayo Clinic, Rochester, MN; University of California, San Diego, La Jolla, CA; Loyola University Chicago Stritch School of Medicine, Maywood, IL; University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL; Masonic Cancer Center, University of Minnesota, Minneapolis, MN; Columbia University Medical Center, New York, NY; University of Colorado, Anschutz Medical Center, Aurora, CO; Oregon Health and Science University, Portland, OR; University of Pennsylvania, Philadelphia, PA; University of Chicago Medical Center, Chicago, IL; Wake Forest Comprehensive Cancer Center, Winston-Salem, NC; University of Texas, M.D. Anderson Cancer Center, Houston, TX

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Quantum Leap Healthcare Collaborative.

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Amy Jo Chien, Hatem Hussein Soliman, Cheryl Ann Ewing, Judy Caroline Boughey, Michael J. Campbell, Hope S. Rugo, Anne M. Wallace, Kathy S. Albain, Erica Michelle Stringer-Reasor, An L Church, Kevin Kalinsky, Anthony D. Elias, Zahi Ibrahim Mitri, Amy Sanders Clark, Rita Nanda, Alexandra Thomas, Christina Yau, I-SPY 2 Consortium, Donald A Berry, Laura Esserman
Journal of Clinical Oncology 2021 39:15_suppl, 508-508

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