Two-Drug Combo Shows Modest Benefit in Biliary Tract Cancer

In patients with advanced, heavily pretreated biliary tract solid tumors, Stivarga (regorafenib) plus Bavencio (avelumab) had minor anti-tumor activity, according to data from a cohort of patients enrolled in a phase 2 trial.

The study results, which were presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, also demonstrated that certain subgroups of patients were found to have a higher chance of deriving benefit from the combination, warranting further research.

Patients with advanced-stage biliary tract cancer (BTC), tend to have a poor prognosis with no available treatment option after failure of first-line treatment with cisplatin/gemcitabine chemotherapy. Immune checkpoint inhibitors alone have only shown modest results. However, research suggests that targeting vascular endothelial growth factor (VEGF) and its receptor (VEGFR) may help immune checkpoint inhibition in this patient population.

Thirty-four patients were enrolled onto the REGOMUNE study, and 33 were eligible to receive treatment. All patients were evaluated for safety and 29 were evaluated for how effective the drug regimen was at attacking cancer. The patients included in the cohort were highly functioning, had measurable disease, and had one or more previous lines of systemic treatment.

The primary endpoint for the BTC group was the six-month objective response rate (ORR), defined as how much patients’ tumors shrunk. Secondary endpoints include best overall response (the percentage of patients whose cancer responds to and shrinks from treatment), six-moth progression-free rate, progression-free survival (PFS; how long patients live without their disease getting worse), overall survival (OS) and safety.

The cohort received Stivarga at 160 mg/day for three weeks with one week off. Patients also received Bavencio at 10 mg/kg intravenously on day 15 of the first 28-day cycle and then once every two weeks. Treatment was continued until disease progression.

Of the patients enrolled, one patient did not receive treatment as they did not meet the eligibility criteria since they received previous treatment less than three weeks before treatment initiation. No patients were lost to follow-up. Twenty-eight patients discontinued intervention, 26 due to disease progression, one due to death and one due to general/specific change in the patient condition.

More than 52% of the cohort was male, and 50% had an ECOG status (which measures how functional a patient is) of 1. The majority of patients (76.5%) had intra-hepatic tumor location, 20.6% had extra-haptic tumor location and 2.9% had gallbladder tumor location.

Additionally, 82.4% had multiple metastatic sites, the majority of which (79.4%) were in the liver. Other metastatic sites included the lungs (58.8%), peritoneum (41.2%), lymph node (52.9%), and other (32.4%). All patients received platinum-based and gemcitabine-based chemotherapy. Additionally, 38.2% received topoisomerase 1 or 2 inhibitors, and 8.8% received taxanes. The most common number of prior treatment lines was one (41.2%), but 35.3% of patients received two prior lines of treatment and 23.5% received more than two prior lines of treatment.

Objective responses were determined by the percentages of complete responses (CRs), partial responses (PRs), stable disease (SD), and progressive disease (PD) observed by imaging tumor assessment. No patients in the cohort achieved a CR. PRs were seen in 13.8% of patients, SD was seen in 37.9% of patients, and progressive disease in 48.3% of patients.

At a median follow-up of 9.8 months, the average PFS was 2.5 months, and the average OS was 11.9 months. Of the 34 patients, 10 patients (34.5%) had tumor shrinkage.

All patients experienced at least one side effect and 85% experienced a severe (grade 3 or 4) side effect. Serious side effects were observed in 62% of patients and 18% of patients withdrew from treatment due to side effects. An additional 18% of patients withdrew from Stivarga due to side effects and 3% withdrew from Bavencio due to side effects. No treatment-related deaths were observed.

Fatigue was the most common mild or moderate side effect, occurring in 65% of patients. Serious or severe fatigue was seen in 15% of patients. Hypertension was the most common serious or severe side effect and was observed in 18% of patients. Mild to moderate hypertension was observed in 18% of patients. Other mild to moderate, and serious or severe side effects included hand-foot syndrome (41%, 9%), alkaline phosphatase and/or gamma-glutamyl transferase increase (21%, 9%), thrombocytopenia (21%, 9%) and maculopapular rash (15%, 12%).

In an exploratory analysis, investigators sought to show how Bavencio plus Stivarga impacted the tumor microenvironment and to find predictive biomarkers of response. Baseline tumor samples were available for 27 patients out of 34, and C2D1 samples were available for eight.

The analysis showed that high PD-L1 expression correlated with a better durable clinical benefit rate and PFS. For patients with high PD-L1 expression, the PFS was 46.15% versus 7.14% in those with low PD-L1 expression at baseline. For patients with high PD-L1 expression, the average PFS was 5.45 months versus 2.8 months in those with low expression.

In addition to PD-L1 expression, better PFS and improved clinical response benefit was linked to having high expression of indoleamine 2,3 dioxygenase 1 (IDO1). The PFS for this population was 5.78 months compared with 1.91 months for those with low IDO1 expression. For patients with high expression of IDO1, the clinical benefit rate was 85.7% versus 7.14% for those with low 1DO1 expression. Further studies, according to the study authors, should evaluate this connection.

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