Regorafenib/Nivolumab Proof of Concept Suggested in Third-Line, Refractory HCC

Half of all patients with hepatocellular carcinoma (HCC) treated with the combination of regorafenib (Stivarga) and nivolumab (Opdivo) following progression on 2 lines of chemotherapy achieved disease control, according to initial results from a phase 2 proof-of-concept trial.¹

Study authors, led by Yasmina Ben Merabet, MD, of the Hepato-Biliary Center at the Paul-Brousse Hospital in Villejuif, France, suggested in a poster presented at the Digital Liver Cancer Summit 2021 that this disease control rate (DCR) was unexpected in these patients with advanced, pretreated HCC.

Patients with HCC who progress after more than 2 lines of chemotherapy have a very poor prognosis, but preclinical data are emerging to suggest that an angiogenic agent may enhance the activity of anti–PD-1 antibodies in HCC.

This was especially seen in the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin), which recently gained an FDA approval in the frontline treatment of patients with unresectable or metastatic HCC.² The approval was granted based on findings from the phase 3 IMbrave150 trial (NCT03434379), which demonstrated a significant benefit for overall survival (OS) compared with sorafenib (Nexavar).

The risk of death was reduced by 42% with the combination regimen compared with sorafenib, and at 12 months, the OS rate was 67.2% with atezolizumab/bevacizumab compared with 54.6% with sorafenib.³

However, this approach had not yet been investigated in a later-line setting for patients previously treated with 2 or more lines of chemotherapy.

The proof-of-concept phase 2 study sought to explore the potential for the combination of nivolumab and regorafenib in patients with HCC in the third-line setting or beyond.

The study included 10 patients with advanced or metastatic HCC who had progressed beyond a second line of oral chemotherapy, had good hepatic function (Child-Pugh score < 7), and an ECOG performance status of 0 or 1. Patients were also considered ineligible for atezolizumab and bevacizumab.

Patients were treated with 80 mg daily regorafenib for 3 out of 4 weeks of the first cycle followed by regorafenib in combination with 3 mg/kg intravenous nivolumab every 14 days until disease progression or unacceptable toxicity.

The primary end point of the study was safety and secondary end points were objective response rate (ORR), DCR, and time to response (TTR).

The included patients had a median age of 69.5 years (range, 62-72.5) and 80% were male. Most patients had an ECOG performance status of 0 (60%), although 1 patient had a score of 2 (10%). One-third of patients had liver cirrhosis, 20% had macrovascular invasion, and 80% had extrahepatic metastasis. Two-thirds of patients had Child-Pugh A5 disease and 80% had Barcelona Clinic Liver Cancer stage C disease. Alpha-fetoprotein (AFP) levels were below 400 ng/mL for 70% of patients.

Only 3 patients had received at least 3 prior lines of systemic therapy before inclusion in the study. Patients had a median time of 6 months (range, 4-7) to progression with first-line therapy and 8 months (range, 6-11) to progression with second-line therapy.

Patients received regorafenib/nivolumab for a median of 5 months (range, 4.5-8.5). The ORR was 30%, which consisted of all partial responses, and 2 other patients had disease control. The median time to response was 2.5 months (range, 2.1-3.3) and the median duration of disease control was 6 months (range, 5-7). AFP level decreases were observed in all responders after only 2 cycles of nivolumab.

Adverse events (AEs) were observed in all patients, but were mostly grade 1 or 2 and related to regorafenib treatment. However, 20% of patients experienced grade 3/4 events. Three patients interrupted treatment with regorafenib and/or nivolumab because of an AE, which included 2 who interrupted treatment with both agents and 1 who interrupted regorafenib treatment only. Two patients discontinued treatment with nivolumab because of AEs, 1 from a grade 3 cytolysis and 1 from a grade 2 rhizomelic pseudopolyarthritis requiring corticosteroids. Another patient discontinued regorafenib because of a grade 2 heart failure that was reversible.

The study serves as rationale for further clinical study of the combination of regorafenib and nivolumab in the treatment of patients with refractory HCC who have progressed on or after oral chemotherapy, the investigators concluded.

_REFERENCES

_{1. Merabet YB, Pascale A, Guettier C, et al. Safety and benefit of the combination of regorafenib and nivolumab in patients with hepatocellular carcinoma (HCC) in progression beyond two lines of oral chemotherapy. Presented at: EASL Digital Liver Cancer Summit 2021; February 5-6, 2021; Virtual. Abstract P-123.}

_{2. FDA approves atezolizumab plus bevacizumab for unresectable hepa-tocellular carcinoma. FDA. June 1, 2020. Accessed February 23, 2021. https://bit.ly/37GCqC6}

_{3. Finn RS, Qin S, Ikeda M, et al; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745}