First-line durvalumab plus chemotherapy with or without oleclumab for locally advanced or metastatic triple-negative breast cancer: SYNERGY overall survival and circulating tumor DNA analysis.

Abstract

1097 Background: SYNERGY (NCT03616886) is a randomized, investigator-initiated, phase I/II trial testing if targeting the immunosuppressive adenosine pathway with the anti-CD73 antibody oleclumab, plus the anti-PD-L1 durvalumab and chemotherapy, enhances antitumor activity in untreated locally advanced or metastatic triple-negative breast cancer (TNBC). Here, we report the overall survival (OS) and circulating tumor DNA (ctDNA) analysis. Methods: 133 patients received weekly carboplatin and paclitaxel x12 plus durvalumab, with (arm A) or without (arm B) oleclumab (6 in phase I, 63 in arm A, 64 in arm B). Maintenance with durvalumab +/- oleclumab was continued until disease progression or unacceptable toxicity. The primary endpoint was clinical benefit rate at week 24 (previously reported, Nat Commun. 2023;14(1):7018). Secondary endpoints included OS and progression-free survival (PFS). Exploratory endpoint included ctDNA analysis. Circulating cell free DNA (cfDNA) was extracted from 343 plasma samples collected at baseline (n = 128), week 3 (n = 122), and week 13 (n = 93). For ctDNA detection, we performed low-coverage genome-wide sequencing of cfDNA from the above-mentioned samples and from 55 plasma samples from healthy donors to correct a possible batch effect. Results: Data cut-off was September 13, 2024, with a median follow-up of 21.7 months. Median OS was not significantly different between arms: 25.1 vs. 20.9 months in arm A vs. B, respectively; HR 0.97 (95%CI 0.63-1.50, p = 0.90). The updated median PFS showed similar PFS: 4.8 vs. 5.4 months in arm A vs. B, respectively; HR 1.22, (95%CI 0.84-1.78, p = 0.29). Among the 343 plasma samples analyzed, ctDNA detection declined from 77% at baseline to 46% at week 3, to 18% at week 13. At any timepoint, CtDNA detection was significantly associated with worse PFS and OS (Table). Twelve patients across both arms exhibited exceptional long responses, without progressive disease and still receiving the study treatment at data cutoff; all exceptional responders evaluable for ctDNA analysis had ctDNA clearance. Conclusions: Theaddition of oleclumab to chemo-immunotherapy did not improve PFS or OS in advanced TNBC. However, a subgroup of patients experienced exceptional long-lasting response, indicating potential benefit in selected cases. CtDNA detection was strongly associated with poorer outcomes at all timepoints, underscoring its potential as a biomarker in this disease/setting. Clinical trial information: NCT03616886 . Timepoint ctDNA detection mPFS (95% CI)* P value mOS (95% CI)* P value Baseline Yes 4.6 (4.2-5.4) 0.002 19.3 (16.6-25.9) 0.007 No 9.2 (5.7-16.4) 37.5 (22.5-NE) Week 3 Yes 3.9 (2.7-4.7) <.001 18.1 (12.8-26.5) 0.003 No 5.7 (4.6-9.3) 25.7 (19.0-NE) Week 13 Yes 0.7 (0.4-2.4) <.001 8.4 (7.3-24.2) <.001 No 3.7 (3.4-6.2) 25.6 (22.1-34.5) *PFS and OS for Week 3 and 13 estimated from this time point.