A phase I/II randomized clinical trial called SYNERGY has evaluated the addition of the anti-CD73 antibody oleclumab to standard chemo-immunotherapy for patients with previously untreated locally advanced or metastatic triple-negative breast cancer (TNBC). The study, published on November 2, 2023 in Nature Communications, was conducted at 16 centers in Belgium and France.
The trial was designed and sponsored by the Institut Jules Bordet in Brussels, with support from AstraZeneca/MedImmune, which provided the study drugs (durvalumab and oleclumab) and funding. The primary purpose was to determine if targeting the immunosuppressive adenosine pathway with oleclumab could enhance the antitumor activity of standard chemo-immunotherapy in TNBC.
SYNERGY consisted of a phase I dose-finding portion followed by a randomized phase II part. In phase I, 6 patients were treated to determine the recommended phase II dose of oleclumab in combination with durvalumab (anti-PD-L1) and weekly carboplatin/paclitaxel chemotherapy. For phase II, 127 women were randomized 1:1 to receive 12 weeks of carboplatin/paclitaxel plus durvalumab with (arm A) or without (arm B) oleclumab, followed by maintenance immunotherapy.
Eligible patients had previously untreated, inoperable locally advanced or metastatic TNBC, were at least 18 years old, had ECOG performance status 0-1, and at least one measurable lesion. Key exclusion criteria included untreated brain metastases and autoimmune disorders. Patients were stratified by PD-L1 and CD73 status assessed centrally on baseline tumor samples.
The median age was 58 years in arm A and 55 years in arm B. About 27-38% had de novo metastatic disease, while the rest had recurrent metastatic TNBC. Approximately 60% of tumors were PD-L1 positive and 30% were CD73 positive at baseline. Other baseline characteristics were generally well-balanced between arms.
The primary endpoint was clinical benefit rate (CBR) at 24 weeks, defined as complete response, partial response, or stable disease. After a median follow-up of 16.5 months, the CBR was 43% in arm A and 44% in arm B (p=0.61), failing to meet the primary endpoint. Objective response rates were similar at 63-64% in both arms.
Median progression-free survival was 5.9 months with oleclumab versus 7.0 months without (p=0.90). Overall survival showed a non-significant trend favoring oleclumab (25.1 vs 19.3 months, p=0.62). Subgroup analyses suggested greater benefit in PD-L1 positive tumors, but the interaction was not statistically significant.
The safety profile was manageable in both arms, with slightly higher rates of neutropenia in the oleclumab arm (52.4% vs 42.2% grade 3-4). Immune-related adverse events occurred in 15.9% with oleclumab versus 12.5% without during the combination phase, decreasing to 6.4% vs 0% during maintenance.
A subset of 28 patients (22% overall) had durable responses lasting at least 12 months, with 6 patients progression-free for over 2 years at data cutoff. Long-term responders were more likely to have de novo metastatic disease. Interestingly, some long-term responses occurred in PD-L1 negative tumors.
Key limitations include the open-label design, investigator-assessed responses, and limited power for survival endpoints due to early trial termination after a negative interim analysis. There were also some imbalances in baseline characteristics between arms.
The authors concluded that adding oleclumab to standard chemo-immunotherapy did not improve outcomes in unselected patients with advanced TNBC. However, the trial provides additional evidence that chemo-immunotherapy can produce durable responses in a subset of patients, highlighting the heterogeneity of TNBC and need for better predictive biomarkers.
While disappointing overall, these results are unlikely to change current clinical practice, as chemo-immunotherapy remains standard first-line treatment for PD-L1 positive advanced TNBC. However, the identification of long-term responders, including some with PD-L1 negative disease, supports ongoing research to optimize patient selection and treatment duration for immunotherapy in TNBC.
The translational analyses from tumor biopsies collected in this trial may provide insights to guide future combination strategies targeting the adenosine pathway or other immunosuppressive mechanisms. Additional research is clearly needed to improve outcomes for patients with this aggressive breast cancer subtype who do not benefit from current chemo-immunotherapy approaches.
References
Buisseret L, Loirat D, Aftimos P, et al. Paclitaxel plus carboplatin and durvalumab with or without oleclumab for women with previously untreated locally advanced or metastatic triple-negative breast cancer: the randomized SYNERGY phase I/II trial [published correction appears in Nat Commun. 2023 Dec 12;14(1):8223. doi: 10.1038/s41467-023-44071-8]. Nat Commun. 2023;14(1):7018. Published 2023 Nov 2. doi:10.1038/s41467-023-42744-y
