Regorafenib Then Nivolumab Sequence Is Tolerable After First-Line HCC Treatment

The sequence of regorafenib (Stivarga) followed by nivolumab (Opdivo) was found to be safe for patients with hepatocellular carcinoma (HCC) who progressed on and tolerated first-line sorafenib (Nexavar), according to early data from the ongoing phase 1/2a GOING trial (NCT04170556).¹

Data presented during the 2022 International Liver Cancer Association Conference showed that less than one-third of patients who received the sequence experienced treatment-related adverse events (TRAEs) that were grade 3 or 4 in severity. Notably, no treatment-related deaths occurred.

“The futility analysis in cohort A based on objective response rate [is] allowed to continue recruitment,” Marco Sanduzzi-Zamparelli, MD, lead study author of the BCLC group, Liver Unit, Hospital Clinic of Barcelona, and colleagues wrote in a poster shared at the meeting.

Study Rationale and Design

In the past few years, systemic treatment for patients with HCC has dramatically shifted. For example, in May 2020, the FDA approved the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) for those with unresectable or metastatic HCC who have not previously received systemic treatment.² Then in April 2022, the FDA accepted a biologics license application for priority review seeking the approval of a single priming dose of tremelimumab added to regular interval durvalumab (Imfinzi; the STRIDE regimen) for the frontline treatment of patients with unresectable HCC.³

Previous data from the phase 3 RESORCE trial (NCT01774344) showed that regorafenib (n = 379) improved median overall survival vs placebo (n = 194) in patients with HCC who had progressed on sorafenib (HR, 0.63; 95% CI, 0.50-0.79; P < .0001).⁴ The median overall survival with regorafenib was 10.6 months (95% CI, 9.1-12.1) vs 7.8 months (95% CI, 6.3-8.8) with placebo. Moreover, second-line nivolumab was also found to be safe and active in patients with advanced HCC, according to findings from the phase 1/2 CheckMate 040 trial (NCT01658878).⁵

The investigator-initiated GOING trial enrolled patients with a diagnosis of HCC who had acceptable liver function, an ECOG performance status of 0 or 1, an acceptable hematologic profi le, and adequate renal function. In addition, they needed to have developed radiological tumor progression on sorafenib treatment within 2 months of study inclusion and be eligible for regorafenib treatment per the definition utilized in the RESORCE trial or have tolerated between 200 mg and 400 mg of sorafenib for at least 30 days. They also were required to have at least 1 measurable lesion per RECIST 1.1 criteria.

Patients could not have myocardial infarction in the last year or active ischemic heart disease, nor could they have a history of clinically meaningful variceal bleeding within the past 3 months. Those with severe peripheral arterial disease, cardiac arrhythmia under treatment with drugs different than ơ-blockers or digoxin, or those with clinically meaningful ascites were excluded.

The trial included 2 cohorts: those with HCC who progressed on and tolerated sorafenib (cohort A) and those who discontinued treatment with atezolizumab/bevacizumab (cohort B). Participants received regorafenib at a daily dose of 160 mg for 8 weeks, and then they received regorafenib at the dose tolerated at week 8 in combination with nivolumab at 240 mg every 2 weeks. Treatment continued until unacceptable toxicity, symptomatic progression, patient decision, or death.

The primary aim of the trial was to measure safety in the form of AE rate, TRAE rate, and rates of AEs that resulted in treatment discontinuation or death. A futility analysis based on radiologic response utilizing the nonbinding Lan and DeMets beta-spending functions (with a boundary of P = .814) will be conducted when 32.8% of patients in cohort A have data of tumor assessment by at least week 16.

Among 30 evaluable patients in cohort A, the median age was 65 years (range, 58-72), and most patients were male (n = 26). Moreover, 53.3% of patients had cirrhosis, 15 patients had Child-Pugh A disease, and 86.7% had an ECOG performance status of 0; 76.7% of patients had BCLC stage C disease, and 23.3% had BCLC stage B disease. Additionally, 36.7% of patients had extrahepatic disease, 56% had vascular invasion, and 23.3% had BCLC post progression.

Efficacy and Safety Findings

The median follow-up in the GOING study was 3.4 months (range, 2.4-6.2).¹ The median duration of treatment with regorafenib was 6.1 months (range, 2.6-8.9), and the median duration of treatment with nivolumab was 6.7 months (range, 4.0-9.3).

Treatment-emergent AEs were experienced by all patients and were treatment related in 96.7% of patients. Severe treatment-emergent and -related AEs occurred in 46.7% and 33.3% of patients, respectively. Treatment-related serious AEs (TR-SAEs) associated with either agent occurred in 13.3% of patients; 10% experienced TR-SAEs associated with regorafenib alone, and 10% reported TR-SAEs linked with nivolumab alone. TRAEs resulted in treatment interruption in 26.7% of patients.

The most common TRAEs reported in more than 10% of patients who received the treatment regimen were hand-foot-skin reaction, asthenia, diarrhea, decreased appetite, arterial hypertension, hypertransaminasaemia, hyperbilirubinaemia, increased aspartate aminotransferase, abdominal pain, dysphonia, and increased alanine aminotransferase (TABLE¹ ).

The most common reason for study discontinuation was physician decision (n = 4), followed by disease progression (n = 2) and AEs (n = 1; 1 of them being a TRAE). Five patients died; 4 died from disease progression, and 1 died from an AE not associated with treatment.

On July 20, 2022, a total of 48 patients were included in cohort A, and 6 patients were included in cohort B. Four evaluations by an external data safety monitoring board have been realized for cohort A, and 1 is anticipated for cohort B.

REFERENCES

1. Sanduzzi-Zamparelli M, Matilla A, Lledo JL, et al. Early nivolumab addition to regorafenib in patients with hepatocellular carcinoma progressing under fi rst line therapy (GOING trial). interim analysis and safety profile. Presented at: 2022 International Liver Cancer Association Conference; September 1-4, 2022; Madrid, Spain.

2. FDA approves Genentech’s Tecentriq in combination with Avastin for people with the most common form of liver cancer. News release. Genentech. May 29, 2020. Accessed September 6, 2022. https:// bit.ly/2Aneztc

3. Tremelimumab accepted under priority review in the US for patients with unresectable liver cancer in combination with Imfi nzi. News release. AstraZeneca. April 25, 2022. Accessed September 6, 2022. https://bit.ly/3vfl 0c6

4. Bruix J, Qin S, Merle P, et al; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2017;389(10064):56-66. doi:10.1016/S0140- 6736(16)32453-9

5. El-Khouiery AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492-2502. doi:10.1016/S0140- 6736(17):31046-2