Neoadjuvant Nivolumab/Ipilimumab Combo Elicits Responses, Safety in Resectable HCC

Neoadjuvant treatment with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) led to responses and was well tolerated in patients with resectable hepatocellular carcinoma (HCC), according to a preliminary analysis of the phase 1b PRIME-HCC trial (NCT03682276) presented at the 2023 International Liver Cancer Association Conference.

Findings showed that evaluable patients treated with the combination (n = 23) experienced a radiological overall response rate (ORR) of 26% with a complete response (CR) rate of 4% and a partial response rate of 22%. Notably, the disease control rate was 96%, and 1 patient (4%) experienced primary progression.

Regarding safety (n = 26), any-grade adverse effects (AEs) occurred in 88% of patients, and 23% of patients experienced grade 3 AEs. No grade 4 or 5 AEs were reported. The rates of any-grade treatment-related AEs (TRAEs) and grade 3 TRAEs were 72% and 8%, respectively. Two patients received steroids for grade 3 TRAEs. The median time to surgery was 2.4 months (interquartile range [IQR], 2.2-2.6), and 1 patient experienced a delay in surgery because of treatment-related grade 2 hypothyroidism.

“We know that for early-stage HCC, liver resection can be a potentially curative treatment. However, relapse rates are as high as 70% in the first 5 years,” Antonio D’Alessio, MD, said in a presentation of the data. “We learned earlier this year from [the phase 3] IMbrave050 trial [NCT04102098] that [an] adjuvant immune checkpoint inhibitor combination can be an option [for patients with resectable HCC]. However, there's a strong biological rationale supporting the use of immune checkpoint inhibitors in the neoadjuvant setting.”

D’Alessio is a clinical research fellow in the Division of Cancer of the Department of Surgery and Cancer at the Imperial College of London at Hammersmith Hospital in the United Kingdom.

The single-arm, open-label PRIME-HCC study conducted across 3 sites in the United Kingdom enrolled patients at least 18 years of age with a histological or radiological diagnosis of resectable HCC who were ineligible for liver transplant. Other key inclusion criteria consisted of measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, Child-Pugh class A disease, and adequate hematological and organ function.

Patients were excluded if they had a history of autoimmune disease, had extrahepatic disease, received prior treatment with an immune checkpoint inhibitor, or received prior transplant.

All patients received 3 mg/kg of intravenous (IV) nivolumab once every 3 weeks plus 1 mg/kg of IV ipilimumab once every 6 weeks before undergoing surgery between days 44 and 85.

The safety and feasibility of the combination served as the trial’s primary end point. Secondary end points included ORR per RECIST v1.1 criteria and pathologic response rate. Long-term survival outcomes and a translational analysis for biomarker discovery were exploratory end points.

As of the April 5, 2023, data cutoff, 36 patients were screened, and 26 were enrolled onto the study. Of those 26, 3 patients were not evaluable for radiological response because they were still on treatment (n = 2) or had cholangiocarcinoma (n = 1). In the 23 patients evaluable for radiological response, 4 patients were not evaluable for pathological response because surgery was withheld for hepatic decompensation that was not treatment related (n = 1), resection was converted to radiofrequency ablation (n = 1), resection was not performed due to a CR (n = 1), and surgery was awaited (n = 1).

Among the safety-evaluable population, the median age was 66 years (range, 44-81), and 73% of patients were male. Half of patients had liver cirrhosis. Etiology consisted of hepatitis B (15%), hepatitis C (27%), alcohol (27%), and non-alcoholic fatty liver disease/non-alcoholic steatohepatitis/cryptogenic (31%). Eighty-one percent of patients had an ECOG performance status of 0, and 73% of patients had Barcelona Clinic Liver Cancer stage A disease. The median tumor diameter was 3.5 cm (IQR, 2.5-5.2), and patients had a median of 1 liver nodule (range, 1-3). Nineteen percent of patients had a baseline alpha-fetoprotein level of at least 400 µg/L.

Additional data showed that among patients evaluable for pathological response (n = 19), 42% experienced a major pathological response (MPR) of at least 70%, and 32% had a complete pathological response. At a median follow-up of 14.5 months (95% CI, 7.4-21.6), no patients who achieved a MPR experienced disease relapse. In patients without an MPR, the median relapse-free survival was 32.8 months (95% CI, not reached [NR]–NR).

Further safety data showed that the most common any-grade TRAEs included hepatotoxicity (38%), fatigue (19%), skin toxicity (19%), thyroid toxicity (19%), colitis (15%), hypoadrenalism (4%), and myocarditis (4%). Grade 3 hepatotoxicity occurred in 8% of patients.

Findings from the translational analysis showed that a baseline enrichment of peritumoral CD4+ and CD8+ T cells was associated with MPR. Additionally, cell-free DNA (cfDNA) in plasma correlated with tumor burden, and decreased levels of cfDNA were observed in responders.

Disclosures: Dr D’Alessio reported receiving educational support for congress attendance and consultancy fees from Roche and AstraZeneca; study funding from Bristol Myers Squibb; and grant funding from the EILF-European Association for the Study of the Liver, the National Institute for Heath Research Imperial BRC, and Cancer Research UK.

Reference

D’Alessio A, Pai M, Spalding D, et al. Predictors of response to neoadjuvant immunotherapy in resectable hepatocellular carcinoma: preliminary clinical and translational analyses from the PRIME-HCC study. Presented at: 2023 International Liver Cancer Association Conference; September 7-9, 2023; Amsterdam, Netherlands.