Abstract OT1-18-02: First-line chemo-immunotherapy with durvalumab, paclitaxel and carboplatin with or without anti-CD73 antibody oleclumab in advanced or metastatic triple-negative breast cancer: Preliminary results of the randomized phase II SYNERGY trial

Abstract Background: Metastatic triple-negative breast cancer (mTNBC) is the most aggressive and heterogeneous breast cancer subtype, with limited therapeutic options. Immune-checkpoint inhibitors (ICI) with chemotherapy are approved as first-line therapy in mTNBC for patients with PD-L1+tumors. The generation of immunosuppressive extracellular adenosine in the tumor microenvironment by the overexpression of ectoenzyme CD73 is a mechanism that could impair ICI and chemotherapy activity. The SYNERGY trial investigates if the addition of an anti-CD73 monoclonal antibody, oleclumab, increases the clinical benefit (CB) to the combination of chemotherapy with an anti-PD-L1 antibody, durvalumab, in previously untreated patients with advanced or mTNBC. Here we present data from a primary analysis including the first 68 evaluable patients. Methods: Patients with previously untreated inoperable locally advanced or mTNBC were randomized between carboplatin AUC 1.5 and paclitaxel 80 mg/m2 q1w x 12 in combination with durvalumab 1500 mg q4w with (Arm A) or without (Arm B) oleclumab 3000 mg q2w x5 followed by 3000 mg q4w according to the recommended phase 2 dose. Maintenance with immunotherapy was continued after chemotherapy. The primary hypothesis is that the addition of oleclumab increases the clinical benefit rate (CBR) at week 24 defined as complete response, partial response or stable disease according to RECIST 1.1. by 20% (1-sided α=0.1 and 80% power with 68 pts/arm; 150 pts to be enrolled). Patients were stratified by PD-L1 status and CD73 immunohistochemistry (IHC) expression assessed on baseline tumor tissue by a central lab. Using the Lan-Demets approach, the stopping boundary was z test < 0.074, p=0.464. Data from this primary analysis for safety and futility were reviewed by an independent data monitoring committee ( IDMC). Results: The 68th evaluable patient reached week 24 on the 2nd Apr 2021. Patients’ baseline characteristics were well balanced between both arms. Grade 3-4 adverse events (AE) occurred in 28/33 patients (84.9%) in Arm A and 21/35 patients (60.0%) in Arm B (p=0.03). Most common grade 3-4 AE were hematological toxicities with neutropenia (Arm A 17/33 [51.5%]; Arm B 12/35 [34.3%], and anemia (Arm A 5/33 [15.2%]; 1/35 [2.9%] in Arm B). There was no increase of immune-related AEs in the arm A with oleclumab. In Arm A, 15/33 patients (45%) met the CB criterion vs. 17/35 patients (49%) in Arm B. The futility boundary was crossed with z-value = -0.2574, p=0.69 (one-sided Fisher's exact). No significant difference in CBR was observed when patients were stratified according to PD-L1 status or CD73 IHC expression. Based on these results, the IDMC recommended to stop further recruitment. Patients under treatment are allowed to continue with durvalumab and oleclumab after being informed of these preliminary results. Of note, at the moment of interim analysis, long-lasting responses were observed with immunotherapy maintenance in both arms. Conclusion: The addition of oleclumab to the combination of chemotherapy by carboplatin and paclitaxel with durvalumab as first-line therapy for advanced or mTNBC did not significantly increase CBR at 6 months. Thus, in arm A the CBR was 45% in the overall population with long-lasting responses and an acceptable toxicity profile. Longer follow-up to evaluate the survival benefit is required. Further investigations evaluating the heterogeneity of this disease using blood and tissue samples collected during trial will shed light on the mechanisms associated with response and resistance to the trial regimens and help to define specific subgroups of patients with TNBC who could benefit from ICI and adenosine targeting agents. Citation Format: Veronique Debien, Christian Maurer, Philippe Aftimos, Florian Clatot, Delphine Loirat, Kevin Punie, François Ghiringhelli, Anhony Gonçalves, Donatienne Taylor, Tom Van den Mooter, Jean-Marc Ferrero, Hervé Bonnefoi, Jean-Luc Canon, François Duhoux, Renaud Poncin, Fernando Bazan, Nicolas Isambert, Philippe Barthelemy, Mariana Brandão, Paulus Kristanto, Michail Ignatiadis, Martine Piccart, Laurence Buisseret. First-line chemo-immunotherapy with durvalumab, paclitaxel and carboplatin with or without anti-CD73 antibody oleclumab in advanced or metastatic triple-negative breast cancer: Preliminary results of the randomized phase II SYNERGY trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-18-02.