Abstract OT2-06-05: A randomized phase II study of peri-operative ipilimumab, nivolumab and cryoablation versus standard peri-operative care in women with residual triple negative early stage/resectable breast cancer after standard-of-care neoadjuvant chemotherapy

Abstract

Background: Triple negative breast cancer (TNBC) is a biologically distinct subtype with high risk of early relapse, particularly for patients who do not achieve a pathological complete response (pCR) after neoadjuvant chemotherapy (NAC), with an event free survival of < 60% at 3 years. Physical disruption of tumors with cryoablation (cryo) induces inflammation and releases antigens that can activate tumor-specific immune responses. In pre-clinical studies, the combination of cryo with checkpoint inhibition augmented tumor-specific immune responses and prevented cancer recurrence. In clinical studies, the combination of pre-operative ipilimumab (ipi)- +/- nivolumab (nivo)-mediated checkpoint blockade with cryo was safely administered in women with operable, early stage breast cancer and generated intra-tumoral and systemic immune responses (NCT01502592, NCT02833233). In this multi-center, randomized study, we evaluate the disease specific impact of peri-operative ipi, nivo and cryo versus standard care in women with residual TNBC after neoadjuvant taxane-based chemotherapy (NCT03546686). Methods:Eligible pts are aged ≥18 years, with ER, PR and HER2 negative operable tumors ≥ 1.0 cm after neoadjuvant taxane-based chemotherapy. Approximately 160 patients will be randomized to one of two arms: standard-of-care breast surgery (control arm) or ipi/nivo/cryo followed by standard-of-care breast surgery (intervention arm). Subjects randomized to the intervention arm will undergo percutaneous, ultrasound- (or MRI-) guided cryoablation with concurrent research core biopsy 7-10 days prior to surgery, and will receive a pre-operative infusion with ipilimumab at the dose of 1mg/kg IV, and nivolumab 240mg flat dose IV (1 to 5 days prior to cryoablation). After surgery, patients will receive three additional doses of nivolumab 240mg flat dose IV Q2 weeks. Adjuvant capecitabine is recommended for all participants and will be administered per standard-of-care at the treating physician's discretion. Patients will be stratified by prior platinum administration, prior anthracycline administration, and clinical nodal status (positive versus negative) at enrollment. The primary endpoint is 3-year Event Free Survival (EFS). Secondary end points include Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS), overall survival (OS) and safety. Exploratory correlative studies will be performed on tumor and serum to characterize the immunologic impact of the intervention and to explore predictors of efficacy and toxicity. Citation Format: McArthur HL, Comen EA, Solomon S, Rodine M, DiLauro Abaya C, Leal JHS, Patil S, Norton L. A randomized phase II study of peri-operative ipilimumab, nivolumab and cryoablation versus standard peri-operative care in women with residual triple negative early stage/resectable breast cancer after standard-of-care neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-06-05.

The Evolving Role of Cryosurgery in Breast Cancer Management: A Comprehensive Review

“…One of these trials focuses on the number of adverse events as the primary outcome of cryoablation, Nivolumab (anti-PD-L1), and Ipilimumab (anti-CTLA-4) treatment in patients with early-stage breast cancer [42]. Another phase II trial is investigating the impact of pre-operative cryoablation, Nivolumab, and Ipilimumab treatment in patients with triple-negative breast cancer after neoadjuvant chemotherapy [43].…”

Combination Immunotherapy Strategies in Breast Cancer

“…A pilot study utilizing cryoablation with ipilimumab demonstrated safety in women with operable breast cancer [106]. A phase II randomized study of perioperative ipilimumab, nivolumab, and cryoablation versus standard care in resectable TNBC following standard of care neoadjuvant therapy is ongoing [107]. The number of cryoablative treatments and timing for optimal outcome needs to be established; in one retrospective observational study of patients with metastatic breast cancer, multiple cryoablations were associated with greater median OS compared with single cryoablations (76 months vs 48 months, p = 0.0005) [108].…”