Targeted Combo Flops as First-Line Treatment in Advanced Breast Cancer

PARIS — A novel combination failed to improve the clinical benefit rate (CBR) in advanced triple-negative breast cancer (TNBC) compared with chemoimmunotherapy, a randomized trial showed.

Adding the anti-CD73 antibody oleclumab to durvalumab (Imfinzi) and chemotherapy led to clinical benefit (response plus stable disease) in 43% of patients by 24 weeks as compared with 44% with durvalumab and chemotherapy. Analyses of CBR by PD-L1 and CD73 expression status also showed no significant difference between the treatment groups.

Durvalumab-chemotherapy without oleclumab had a numerically better progression-free survival (7.7 vs 6.0 months), reported Laurence Buisseret, MD, of Institut Jules Bordet in Brussels, at the European Society for Medical Oncology (ESMO) annual congress.

“The optimal chemotherapy duration with immunotherapy needs to be further investigated, and new therapeutic combination approaches are needed,” she said. “Ongoing translational research aims to better understand the mechanisms of response and to identify predictive biomarkers of response.”

The results contrasted with those from recent studies in unresectable/metastatic non-small cell lung cancer (NSCLC), wherein the addition of oleclumab boosted the CBR from less than 60% with durvalumab-chemotherapy to more than 80%. During a post-presentation discussion, Buisseret pointed out that NSCLC and TNBC have different molecular biology, emphasizing the need to identify biomarkers to guide the use of targeted therapies such as oleclumab.

Buisseret reported primary findings from the randomized phase II SYNERGY trial to evaluate chemoimmunotherapy with or without oleclumab as initial treatment for metastatic TNBC (mTNBC). The trial originated as part of an ongoing search for strategies to improve the efficacy of immunotherapy in mTNBC. One such strategy is to target immunosuppression in the tumor microenvironment, in this case, by focusing on adenosine.

“Tumors are proficient at converting ATP into immunosuppressive adenosine, which activates the A2 receptor on immune cells to induce several highly immunosuppressive functions,” she said. “Two enzymes that are key to degrading ATP into adenosine are CD39 and CD73. In breast cancer, CD73 is overexpressed in the TNBC subtype and is associated with worse outcome.”

In preclinical models, the combination of an adenosine-pathway inhibitor and a PD-1/L1 inhibitor enhanced immune response, Buisseret continued. In a preliminary clinical trial in patients with mTNBC, adding oleclumab to durvalumab and chemotherapy did not improve response, but the trial was underpowered to assess efficacy.

SYNERGY involved 127 patients with previously untreated locally advanced or metastatic TNBC and no prior exposure to an immune checkpoint inhibitor. All patients received paclitaxel-carboplatin chemotherapy and were randomized to durvalumab alone or with oleclumab. The primary endpoint was CBR at 24 weeks.

The study had an accrual target of 136 patients, which would provide statistical power to detect an improvement in CBR from 40% to 60% at 24 weeks. The trial ended early after an interim analysis met criteria for futility. At data cutoff, the study population had a median follow-up of 13.2 months.

When the trial ended, neither the objective response rate nor CBR differed significantly between treatment arms.

Biomarker status was not an inclusion criterion. Immunohistochemistry results showed that a little more than half of the patients had PD-L1 expression ≥1% (positive), whereas one-fourth to one-third of the patients tested positive for CD73.

An analysis of CBR by biomarker status showed no significant difference between groups with PD-L1-positive or negative tumors or CD73-positive or negative status (P=0.98 to P=0.22). The oleclumab regimen performed numerically better in patients with PD-L1-negative and CD73-positive tumors.

Adverse-event rates, overall and grade 3/4, were similar between the treatment arms.

“The trial is clearly negative. We also don’t see a signal with regards to CD73 expression and we don’t see a signal in progression-free survival,” said ESMO invited discussant Peter Schmid, MD, of University College London. “The addition of oleclumab in an unselected triple-negative breast cancer population clearly did not have a benefit and did not improve the efficacy of chemotherapy and a checkpoint inhibitor. The adenosine pathway is complex. There are several determinants and two receptors. There is overlap with other pathways. Unfortunately, we don’t have an optimal biomarker, so we can’t really select patients. Patient selection strategy at this point in time for clinical development is not quite clear. CD73 might not be optimal.”