348P - First findings from SYNERGY, a phase I/II trial testing the addition of the anti-CD73 oleclumab (O) to the anti-PD-L1 durvalumab (D) and chemotherapy (ChT) as first line therapy for patients (pts) with metastatic triple-negative breast cancer (mTNBC)

Background

Immunotherapy with PD-(L)1 blocking agents combined with ChT improve prognosis in mTNBC, but responses are limited to a proportion of pts and most will experience disease progression. The adenosine pathway has been demonstrated to limit anti-tumor activity in TNBC, making CD73, the adenosine generating enzyme, an attractive target to enhance the efficacy of immunotherapy in this disease.

Methods

Pts with locally-advanced unresectable or mTNBC were enrolled to the phase I, dose-finding part consisting of O, starting at 3000mg (as previously defined for use with D alone) every 2 weeks (q2w) x 5, followed by maintenance q4w, given with D 1500mg q4w plus paclitaxel 80mg/m² and carboplatin AUC 2, both q1w x 12, until disease progression, limiting toxicity or withdrawal of consent. The incidence of dose-limiting toxicities (DLT), i.e. any adverse event (AE) ≥ G3 occurring up to 28 days after 1^st O infusion, was used to find its recommended phase II dose (RP2D) in combination with D + ChT, within a de-escalation 3+3 design. Phase II is recruiting in Belgium and France, and openly randomizes pts 1:1 to arm A (O + D + ChT) or arm B (D + ChT). The primary aim is to improve the clinical benefit rate at week 24 [complete response (CR) + partial response (PR) + stable disease (SD) rates, per RECIST] of arm A vs. arm B, from 40% to 60% (1-sided α=0.1 and 80% power with 68 pts/arm; 150 pts to be enrolled).

Results

At the end of the DLT period, 0 of 6 pts experienced any DLT, thus the RP2D for O is 3000mg (no dose de-escalation needed). Yet, outside the DLT period, 5 pts experienced ≥ G3 neutropenia. There were no serious immune-related AE. Four pts had a clinical benefit at week 24. Table: 348P

Key phase I data

Conclusions

At 3000mg, O with D and ChT is safe and shows signs of activity. Given the high incidence of ChT-related myelotoxicity, carboplatin was reduced from AUC 2 to 1.5 upon start of phase II.

Clinical trial identification

EudraCT: 2017-004651-23; Sponsor Protocol Number: IJB-SYNERGY-012017; NCT03616886.

Editorial acknowledgement

Legal entity responsible for the study

Institut Jules Bordet.

Funding

AstraZeneca.

Disclosure

D. Eiger: Research grant/Funding (self), Research grant/Funding (institution), Funding provided for his ESMO Fellowship (2018-2019): Novartis; Research grant/Funding (institution): Roche; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Servier. C. Maurer: Travel/Accommodation/Expenses: Mundipharma; Travel/Accommodation/Expenses: Amgen; Travel/Accommodation/Expenses: Servier Deutschland GmbH. M. Brandao: Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Servier. P.G. Aftimos: Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Amgen; Advisory/Consultancy, Research grant/Funding (institution): Synthon; Advisory/Consultancy: Boehringer-Ingelheim; Advisory/Consultancy: Macrogenics; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Novartis; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Radius; Research grant/Funding (institution): Servier. K. Punie: Honoraria (institution), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (institution), Travel/Accommodation/Expenses: Novartis; Honoraria (institution), Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: Pharma Mar; Honoraria (institution), Travel/Accommodation/Expenses: Roche; Research grant/Funding (institution): Sanofi; Honoraria (institution): Vifor Pharma. J-L. Canon: Advisory/Consultancy, Research grant/Funding (institution): Amgen; Advisory/Consultancy, Research grant/Funding (institution): Roche; Research grant/Funding (institution): Novartis. F. Duhoux: Advisory/Consultancy, Speaker Bureau/Expert testimony: Amgen. E. de Azambuja: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy: Seattle Genetics; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Servier. M. Ignatiadis: Officer/Board of Directors: EORTC; Advisory/Consultancy: Celgene; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Tesaro; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Menarini Silicon Biosystems; Research grant/Funding (institution): Janssen Diagnostics; Research grant/Funding (institution): Pfizer. M. Piccart: Advisory/Consultancy, Leadership role, Scientific Board: Oncolytics; Leadership role, Research grant/Funding (institution), Scientific Board: Radius; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy: Camel-IDS; Advisory/Consultancy: Crescendo Biologics; Advisory/Consultancy: Debiopharm; Advisory/Consultancy: G1 Therapeutics; Advisory/Consultancy, Research grant/Funding (institution): Roche/GNE; Advisory/Consultancy: Huya; Advisory/Consultancy: Immunomedics; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Advisory/Consultancy: Menarini; Advisory/Consultancy, Research grant/Funding (institution): MSD; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Odonate; Advisory/Consultancy: Periphagen; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: Seattle Genetics; Research grant/Funding (institution): Servier; Research grant/Funding (institution): Synthon. L. Buisseret: Travel/Accommodation/Expenses: Roche; Speaker Bureau/Expert testimony: BMS. All other authors have declared no conflicts of interest.