Sequential Combo of Regorafenib and Nivolumab Shows Manageable Safety in Sorafenib-Pretreated HCC

Marco Sanduzzi-Zamparelli, MD

The sequential treatment of regorafenib (Stivarga) followed by nivolumab (Opdivo) was found to have an acceptable toxicity profile in patients with hepatocellular carcinoma (HCC) who progressed on and tolerated first-line sorafenib (Nexavar), according to early data from the 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 regimen experienced treatment-related adverse effects (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.

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 Moreover, in April 2022, the FDA accepted for priority review a biologics license application 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 (OS) over 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 OS 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 profile, and adequate renal function.⁶ 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 RESORCE 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 v1.1 criteria.

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

The trial was comprised of 2 cohorts: those with HCC who progressed on and tolerated sorafenib comprised cohort A, and those who discontinued treatment with atezolizumab/bevacizumab comprised cohort B.

Participants received regorafenib at a daily dose of 160 mg for 8 weeks. Thereafter, patients 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 non-binding Lan & DeMets beta-spending functions with a boundary of P = .814 will be conducted when 32.8% of patients in cohort A had 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 BCLCpC2.

The median follow-up was 3.4 months (range, 2.4-6.2). 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; they 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 over 10% of patients who received the combination were hand-foot-skin reaction (any grade, 56.6%; grade 3, 10%), asthenia (any grade, 43.3%), diarrhea (any grade, 36.7%; grade 3, 3.3%), decreased appetite (any grade, 30%), arterial hypertension (any grade, 30%; grade 3, 6.7%), hypertransaminasaemia (any grade, 30%; grade 3, 3.3%), hyperbilirubinaemia (any grade, 20%; grade 3, 3.3%), increased aspartate aminotransferase (any grade, 20%; grade 3, 3.3%), abdominal pain (any grade, 20%), dysphonia (any grade, 16.7%), and increased alanine aminotransferase (any grade, 13.3%).

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 did 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 first line therapy (GOING trial). Interim analysis and safety profile. Presented at: 2022 International Liver Cancer Association Conference; September 1-4, 2022; Madrid, Spain. Poster 102
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 Imfinzi. News release. AstraZeneca. April 25, 2022. Accessed September 6, 2022. https://bit.ly/3vfl0c6
4. Bruix J, Qin S, Merle P, et al. 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
6. Regorafenib followed by nivolumab in patients with hepatocellular carcinoma (GOING) (GOING). ClinicalTrials.gov. Updated May 11, 2022. Accessed September 6, 2022. https://clinicaltrials.gov/ct2/show/NCT04170556