Results from the phase 2 SYNERGY trial suggest little or no benefit of adding oleclumab to durvalumab and chemotherapy for advanced frontline triple-negative breast cancer.
Results from the phase 2 SYNERGY trial (NCT03616886) that were presented at the 2022 European Society for Medical Oncology Congress (ESMO) did not demonstrate increased clinical benefit with the addition of oleclumab to durvalumab (Imfinzi) and chemotherapy vs durvalumab and chemotherapy alone as a first-line treatment for patients with advanced triple-negative breast cancer (TNBC).
There was a 24-week clinical benefit rate of 43% in patients with TNBC who were treated on the oleclumab arm as compared with a rate of 44% in patients treated with durvalumab and chemotherapy alone (P = .61). The rate of progressive disease was also higher in the oleclumab arm. Notably, more patients in the oleclumab arm achieved a complete response whereas more patients in the control group had a partial response.
“We have ongoing translation analysis that will shed light on the mechanism associated with response and resistance to the combination [of oleclumab, durvalumab, and chemotherapy], and we hope to identify predictive biomarkers of response,” lead study author Laurence Buisseret, MD, PhD, a medical oncologist at the Institut Jules Bordet of Hôpital Universitaire de Bruxelles in Brussels, Belgium, said in a presentation of the data.
Investigators have observed a survival benefit when PD-1/PD-L1 checkpoint inhibitors have been added to chemotherapy in frontline treatment of patients with TNBC. However, that benefit has only favored patients with PD-L1–positive tumors to date.
Previous results with mouse models showed that the inhibition of the adenosine pathway synergizes with PD-1/PD-L1 checkpoint inhibitors. Data from the phase 2 COAST (NCT03822351) and phase 2 NeoCOAST (NCT03794544) trials showed that the addition of the anti-CD73 monoclonal antibody oleclumab to the anti–PD-L1 monoclonal antibody durvalumab enhanced antitumor immune responses in patients with non–small cell lung cancer.
The SYNERGY trial evaluated the efficacy and safety of the oleclumab/durvalumab/chemotherapy triplet in adults with locally advanced or metastatic TNBC who had measurable disease by RECIST V1.1 criteria. Key inclusion criteria included no prior treatment in the metastatic setting, at least 6 months since the end of adjuvant treatment, an ECOG performance status of 0 or 1, and adequate organ function.
Patients were not permitted to have prior treatment with a checkpoint inhibitor or to have a major autoimmune disease.
Once enrolled, patients were randomly assigned to 3000 mg of oleclumab every 2 weeks for 5 cycles, then every 4 weeks, plus 1500 mg of durvalumab every 4 weeks. Patients in the control arm received 1500 mg of durvalumab every 4 weeks. Patients in both arms also received 80 mg/m2 of paclitaxel and carboplatin area under the curve 1.5 every week for 12 weeks. Stratification factors included baseline PD-L1 and CD73 expression per immunohistochemistry.
The primary end point of the trial was clinical benefit rate at week 24. Secondary end points included overall response rate, duration of response, progression-free survival (PFS), overall survival, and clinical benefit rate per PD-L1 and CD73 expression. Exploratory end points included response and PFS per RECIST v1.1 vs iRECIST v1.1.
The trial was powered to detect an increase in clinical benefit rate for 40% to 60% at week 24, and 136 evaluable patients were required. A formal interim analysis for futility for clinical benefit rate assessment at week 24 was possible for 68 patients, without stopping accrual after the 68th patient.
Notably, the futility boundary was crossed in the interim analysis and recruitment was stopped in June 2021 per the recommendation of the independent data monitoring committee. By the end of recruitment, 127 patients were randomly assigned and evaluable. Patients were allowed to continue treatment after being informed of the results of the interim analysis. The median follow-up for evaluable patients was 13.2 months (range, 1-39).
The median age of patients in the oleclumab arm (n = 63) and the control arm (n = 64) was 58 years (range, 47-67) and 55 years (range, 47-67), respectively. The majority of patients had an ECOG performance status of 0 (62.9% and 68.8% in the oleclumab and control arms, respectively), recurrent metastatic disease (73% and 62.5%), and a disease-free interval of more than 12 months (93.5% and 97.5%).
Prior chemotherapy in the early setting for patients in the oleclumab arm included taxane (84.8%), anthracycline (78.3%), and carboplatin (8.7%). Those rates were 92.5%, 82.5%, and 25%, respectively, in the control arm. In the oleclumab group, metastatic sites included liver (31.7%), bone (27%), lung (49.2%), lymph nodes (54.0%), and other (44.4%). Metastatic sites in the control group consisted of liver (31.3%), bone (18.8%), lung (42.2%), lymph nodes (59.4%), and other (51.6%).
In the oleclumab and control arms, the rates of baseline PD-L1 positivity were 52.4% and 56.3%, respectively. The rates of CD73 positivity were 27.0% and 32.8%, respectively.
In patients who were PD-L1 positive, the clinical benefit rate was higher in the oleclumab arm (n = 16 of 33) vs the control arm (n = 14 of 36; P = .29). In patients who were PD-L1 negative, the clinical benefit rate was higher in the control arm (n = 14 of 28) vs the oleclumab arm (n = 11 of 30; P = .90).
The clinical benefit rate for patients who were CD73 positive was higher in the control arm (n = 11 of 21) compared with the oleclumab arm (n = 4 of 17; P = .98). Patients who were CD73 negative experienced a higher clinical benefit rate in the oleclumab group (n = 23 of 46) vs the control group (n = 17 of 43; P = .22).
Patients treated in the control arm achieved a median PFS of 7.7 months compared with 6.0 months in the oleclumab arm. Nine patients in each arm remained on immunotherapy maintenance at data cutoff. Notably, 2 patients stopped treatment with oleclumab after the interim analysis.
Regarding safety, all patients in both arms experienced at least 1 adverse effect (AE) of any grade, and all patients reported at least any-grade AE during the first 12 weeks of treatment. The rates of grade 3/4 AEs in the oleclumab and control arms were 79.4% and 68.8%, respectively.
Grade 1/2 hematologic AEs occurred in 23.8% and 26.6% of patients in the oleclumab and control arms, respectively. The rates of grade 3/4 hematologic AEs were 60.3% and 46.9%, respectively. Rates of any-grade and grade 3/4 anemia, neutropenia, thrombocytopenia, and fatigue were similar across the 2 arms.
Grade 1/2 immune-mediated AEs (IMAEs) occurred in 73% of patients in the oleclumab group, compared with 68.8% of patients in the control group. The grade 3/4 rates of IMAEs were 15.9% and 12.5% in the oleclumab and control arms, respectively.
No toxicity-related deaths were reported. Four patients in the oleclumab arm and 5 patients in the control arm discontinued treatment due to AEs, including 2 patients in each arm prior to week 24.
"Optimal chemotherapy duration with immunotherapy needs to be further investigated, and we need to develop new therapeutic combinations for [patients with advanced TNBC],” Buisseret concluded.
Buisseret L, Loirat D, Aftimos P, et al. Primary endpoint results of SYNERGY, a randomized phase 2 trial, first-line chemo-immunotherapy trial of durvalumab, paclitaxel, and carboplatin with or without the anti-CD73 antibody oleclumab in patients with advanced or metastatic triple-negative breast cancer. Ann Oncol. 2022;33(suppl 7):LBA17. doi:10.1016/annonc/annonc1089