First-line Toripalimab Plus Sorafenib Elicits Responses in Unresectable Hepatocellular Carcinoma

The addition of toripalimab to standard-of-care sorafenib (Nexavar) in the frontline setting demonstrated preliminary efficacy and tolerability in patients with unresectable hepatocellular carcinoma (HCC), allowing some to achieve tumor downstaging and proceed to surgical resection, according to data from a phase 2 study(NCT04926532).¹

Findings presented at the 2023 International Liver Cancer Association Conference demonstrated that the combination elicited an objective response rate (ORR) of 42.9% in evaluable patients (n = 28), including a complete response rate of 14.3% and a partial response rate of 28.6%. The disease control rate (DCR) was 71.4%. Moreover, the median duration of response (DOR) was 3.4 months (95% CI, 1.2-29.4) with the doublet. The median progression-free survival (PFS) was 11.6 months (95% CI, 1.5-21.8), and the median overall survival (OS) was not yet reached.

“Toripalimab combined with sorafenib has encouraging efficacy and tolerable toxicity in the first-line treatment of patients with unresectable HCC,” lead study author Xin-Rong Yang, of Zhongshan Hospital, Fudan University in Shanghai, China, and colleagues, wrote in a poster presentation of the data. “[Based on these data], toripalimab plus sorafenib might be a [viable] first-line treatment option for [patients with] unresectable HCC.”

Despite the known efficacy of sorafenib for patients with advanced HCC in the front line, most patients treated with this agent experience disease progression within a year. Accordingly, there is a need for safe, effective therapeutics that can increase long-term survival rates in this population. Investigators hypothesized that the immune checkpoint inhibitor toripalimab may enhance patient responses when combined with sorafenib due to its favorable safety profile and activity observed in other solid tumors.

The single-arm, open-label, prospective trial aimed to assess the initial safety and activity when combining immunotherapy with standard targeted therapy for the treatment of patients with advanced HCC. The median follow-up time was 14.7 months (range, 2.3-31.3).

The study enrolled patients between the ages of 18 and 75 years with a confirmed diagnosis of unresectable HCC.² To be included in the analysis, patients were required to have stage IIB or III disease and be either ineligible to undergo resection or have been unwilling to undergo resection and be treated with chemoembolization. Other key inclusion criteria include a Child-Pugh liver function score of grade A or B in the week before the first dose of the study drug and an ECOG performance status of 0 or 1 a week before treatment initiation, at least 1 measurable lesion based on RECIST v1.1 criteria, and a life expectancy of longer than 3 months.

All patients were treated with 240 mg of intravenous toripalimab on day 1 of the 21-day treatment cycle and 400 mg of oral sorafenib twice daily for days 1 to 21. The regimen was administered every 3 weeks until disease progression or unacceptable toxicity.

The study’s primary end points were ORR by RECIST v1.1 criteria and safety. Secondary end points included PFS, OS, DCR, and DOR. A key exploratory end point included monitoring indicators for the efficacy and sensitivity of immunotherapy drugs.

A total of 30 patients diagnosed with HCC were enrolled on the study by the data cutoff date of January 17, 2023. The median age of patients in the overall population was 60.5 years (range, 42-75) and 86.7% were male. All patients had Child-Pugh A classification. Regarding the distribution of patients by China Liver Cancer Stage, 23.3%, 20.0%, 23.3%, 30.0%, and 3.3% had stage IB, IIA, IIB, IIIA, and IIIB disease, respectively. Distant metastasis was observed in 20.0% of all patients, 26.7% had portal vein tumor thrombus (PVTT), and 10.0% had hepatic vein invasion.

Safety analysis revealed that any-grade treatment-related adverse effects (TRAEs) occurred in 86.7% of patients. Of these, 33.3% were grade 1/2 and 36.7% were grade 3. No TRAEs higher than grade 3 were reported. Twenty percent of the 30 safety-evaluable patients discontinued treatment and withdrew from the study due to AEs during the treatment period.

Additional data on post-treatment outcomes showed that 23.3% of patients proceeded to surgical resection after receiving the study treatment. Among patients who underwent surgical resection, 42.9% experienced post-operative recurrence. The median PFS in those who received surgery was 22.2 months (95% CI, 9.2-35.2). The study is currently ongoing.

References

1. Yang XR, Cheng WJ, Wu SY, et al. The efficacy and safety of toripalimab combined with sorafenib for unresectable hepatocellular carcinoma: An open-label, prospective, single-arm phase II study. Presented at: 2023 International Liver Cancer Association Conference; September 7-9, 2023; Amsterdam, Netherlands. Poster 92.
2. Toripalimab plus sorafenib in patients with advanced-stage hepatocellular carcinoma (toripalimab). ClinicalTrials.gov. Updated June 15, 2021. Accessed September 18, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04926532