Regorafenib and Avelumab Demonstrates Limited Benefit in All Comers With Biliary Tract Cancer

The combination of regorafenib and avelumab showed modest anti-tumor activity and survival rates in patients with heavily-pretreated biliary tract solid tumors.

The combination of regorafenib (Stivarga) and avelumab (Bavencio) showed modest anti-tumor activity and survival rates in patients with heavily-pretreated biliary tract solid tumors, according to cohort results from the phase 2 Regomune (NCT03475953) study presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

Certain subsets 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.

For non-randomized, multi-center Regomune study, 34 patients were enrolled and 33 were eligible to receive treatment. All patients were evaluated for safety and 29 were evaluated for efficacy. The patients included in the cohort had an ECOG performance status of 0 or 1, measurable disease, and who have 1 or more previous lines of systemic treatment.

The primary endpoint for the BTC cohort was the 6-month objective response rate (ORR). Secondary endpoints include best overall response, 6-moth progression-free rate, progression-free survival (PFS), overall survival (OS), and safety.

The cohort received regorafenib 160 mg/day for 3 weeks with 1 week off. Patients also received avelumab 10 mg/kg intravenously on day 15 of the first 28-day cycle and then once every 2 weeks. Treatment was continued until disease progression.

Of the patients enrolled, 1 patient did not receive treatment as they did not meet the eligibility criteria since they received previous treatment less than 3 weeks before treatment initiation. No patients were lost to follow-up. Twenty-eight patients discontinued intervention, 26 due to disease progression, 1 due to death, and 1 due to general/specific change in the patient condition.

More than 52.0% of the cohort was male, and 50.0% had an ECOG status 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%). One hundred percent of 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 1 (41.2%), but 35.3% of patients received 2 prior lines of treatment and 23.5% received more than 2 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 (95% CI, 6.6-12.4), the median PFS was 2.5 months (95% CI, 1.9-5.5), and the median OS was 11.9 months (95% CI, 6.2 to not assessable). Of the 34 patients, 10 patients (34.5%) had tumor shrinkage.

All patients experienced at least 1 adverse event (AEs) and 85% experienced a grade 3 or 4 AE. Serious AEs were observed in 62% of patients and 18% of patients withdrew from treatment due to AEs. An additional 18% of patients withdrew from regorafenib due to AEs and 3% withdrew from avelumab due to AEs. No grade 5 AEs were observed.

Fatigue was the most common grade 1 or 2 AE, occurring in 65% of patients. Grade 3-4 fatigue was seen in 15% of patients. Hypertension was the most common grade 3 or 4 AE and was observed in 18% of patients. Grade 1-2 hypertension was observed in 18% of patients. Other grade 1-2, and 3-4 AEs include palmar-plantar erythrodysesthesia (41%, 9%), AST and/r ALT increase (24%, 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 avelumab plus regorafenib 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 8.

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 (HR, 5.45; 95% CI, 1.68-NA). For patients with high PD-L1 expression, the median PFS was 5.45 months versus 2.8 months in those with low expression (HR, 2.28; 95% CI, 1.87-5.78).

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 (HR, 5.78; 95% CI, 2.00-NA). For patients with high expression of IDO1, the clinical benefit rate was 85.7% versus 7.14% for those with low 1DO1 expression (HR, 1.91; 95% CI, 1.84-5.45). According to investigators, further studies should evaluate this connection.

Cousin S, Bellera C, Guégan J, et al. Regomune: A phase II study of regorafenib + avelumab in solid tumors—results of the biliary tract cancer (BTC) cohort. J Clin Oncol. 2021; 39 (suppl 15; abstr 4096). doi: 10.1200/JCO.2021.39.15_suppl.4096.
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