Adding the Novel Drug Oleclumab to Imfinzi and Chemotherapy Fails to Improve TNBC Outcomes

There was no clinical benefit observed by adding the novel drug oleclumab to Imfinzi (durvalumab) and chemotherapy for frontline, advanced triple-negative breast cancer treatment, according to findings from the phase 2 SYNERGY clinical trial.

The findings showed that the 24-week clinical benefit rate (percentage of patients whose disease shrinks, disappears or stabilizes) for patients in the oleclumab group was 43% compared with 44% in the control group.

Patients in the control group received Imfinzi plus chemotherapy without the addition of oleclumab.

More patients in the oleclumab group achieved a complete response (complete disappearance of cancer), while more patients in the control group had a partial response (cancer shrinking as a result of treatment). Additionally, the rate of progressive disease was higher in the oleclumab group.

“We have ongoing translation analysis that will shed light on the mechanism associated with response and resistance to the combination (of oleclumab, [Imfinzi] and chemotherapy), and we hope to identify predictive biomarkers of response,” lead study author Dr. Laurence Buisseret, a medical oncologist at the Institut Jules Bordet of Hôpital Universitaire de Bruxelles in Brussels, Belgium, said in a presentation of the data at the European Society of Medical Oncology 2022 Congress.

Oleclumab Plus Immunotherapy Previously Showed Promise

Oleclumab works by binding to CD73, an enzyme found on tumor cells, and stops the production of immunosuppressive adenosine, which helps cancer cells escape the immune system.

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 Imfinzi enhanced antitumor immune responses in patients with non–small cell lung cancer.

Investigators have observed a survival benefit when PD-1/PD-L1 checkpoint inhibitors have been added to chemotherapy in frontline treatment of patients with triple-negative breast cancer. However, that benefit has only favored patients with tumors that express high levels of PD-L1, the protein that checkpoint inhibitors like Imfinzi and Keytruda (pembrolizumab) target.

SYNERGY Trial

The SYNERGY trial evaluated the efficacy and safety of the oleclumab/Imfinzi/chemotherapy triplet in adults with locally advanced or metastatic triple-negative breast cancer who had measurable disease.

To be eligible for participation in the trial, patients must have: no prior treatment in the metastatic setting, at least six months since the end of adjuvant treatment, an ECOG performance status of 0 or 1 (indicating that their disease has little to no impact on their daily functioning) and adequate organ function.

According to the National Cancer Institute, adjuvant therapy is additional cancer treatment administered following the initial treatment to lower the risk that the disease returns.

Patients were not permitted to have prior treatment with a checkpoint inhibitor or to have a major autoimmune disease.

The main goal of the trial was clinical benefit rate at week 24. Moreover, the investigators aimed to assess overall response rate (percentage of patients whose disease shrunk or disappeared as a result of treatment), duration of response, progression-free survival (time from treatment until disease worsens), overall survival (time from treatment until death by any cause) and clinical benefit rate per PD-L1 and CD73 expression.

In the oleclumab and control groups, the rates of baseline PD-L1 positivity were 52.4% and 56.3%, respectively. The rates of CD73 positivity were 27% and 32.8%, respectively.

In patients who were PD-L1 positive, the clinical benefit rate was higher in the oleclumab groups (16 of 33 patients experienced benefit) compared to the control group (14 of 36 patients experienced benefit). However, the difference in clinical benefit was not statistically significant between these two groups, meaning that the researchers could not be sure that it was the difference in treatment regimens — not chance — that one group outperformed the other.

In patients who were PD-L1 negative, the clinical benefit rate was higher in the control group (14 or 28 patients benefitted) versus the oleclumab group (11 of 30 patients benefitted).

The clinical benefit rate for patients who were CD73 positive was higher in the control group (11 of 21 patients) compared with the oleclumab group (4 of 17 patients). Patients who were CD73 negative experienced a higher clinical benefit rate in the oleclumab group (23 of 46) versus the control group (17 of 43).

None of the differences in clinical benefit were found to be statistically significant.

Patients treated in the control group achieved a median progression-free survival of 7.7 months compared with six months in the oleclumab group. Nine patients in each group remained on immunotherapy maintenance at data cutoff.

Notably, two patients stopped treatment with oleclumab after the interim analysis.

Side Effects

Regarding side effects, all patients in both groups experienced at least one side effect of any severity, and all patients reported at least one any-severity side effect during the first 12 weeks of treatment. The rates of serious or severe side effects in the oleclumab and control groups were 79.4% and 68.8%, respectively.

Mild to moderate blood-related side effects occurred in 23.8% and 26.6% of patients in the oleclumab and control groups, respectively. The rates of serious or severe blood-related side effects were 60.3% and 46.9%, respectively. Rates of any-severity and serious or severe anemia, neutropenia (decrease in neutrophils, a type of white blood cell), thrombocytopenia (decrease in thrombocytes, a type of white blood cell) and fatigue were similar across the two groups.

Mild to moderate immune-related side effects occurred in 73% of patients in the oleclumab group, compared with 68.8% of patients in the control group. The serious or severe rates of immune-related side effects were 15.9% and 12.5% in the oleclumab and control groups, respectively.

No toxicity-related deaths were reported. Four patients in the oleclumab group and five patients in the control group discontinued treatment due to side effects, including two patients in each group 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 triple-negative breast cancer),” Buisseret concluded.

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