Frontline Toripalimab Plus Bevacizumab Improves PFS, OS in Advanced HCC

The addition of toripalimab to bevacizumab (Avastin) led to a statistically significant improvement in progression-free survival (PFS) and overall survival (OS) vs sorafenib (Nexavar) as frontline treatment in patients with advanced hepatocellular carcinoma (HCC), meeting the primary end points of the phase 3 HEPATORCH trial (NCT04723004).¹

Moreover, the safety profile of toripalimab was consistent with its known adverse effect (AE) profile, and no new safety signals were reported. Based on these data, the developer of toripalimab, Junshi Biosciences, intends to submit a supplemental new drug application seeking the approval of the combination in this population in the near future. More information will be released at an upcoming international conference.

“Currently, the combination of immune checkpoint inhibitors and anti-angiogenesis targeted therapies has become a vital first-line treatment for advanced liver cancer. The HEPATORCH phase 3 clinical study evaluating toripalimab combined with bevacizumab achieved its primary end point, potentially offering a new treatment option with better survival benefits for advanced liver cancer patients,” professor Jia Fan, principal investigator and academician of the Chinese Academy of Sciences and president of Zhongshan Hospital, stated in a news release.

“Toripalimab has already been approved for marketing in the United States. As the first innovative biological drug independently developed and produced in China to receive FDA approval, toripalimab has received international recognition for its quality. We look forward to a day when more [patients with] advanced liver cancer can benefit from domestically developed innovative drugs,” Jia added.

HEPATORCH is an ongoing, multicenter, open-label, randomized, active-controlled phase 3 trial comparing the combination of toripalimab and bevacizumab with sorafenib in patients with locally advanced or metastatic HCC who could not be radically cured.²

The combination was previously evaluated as frontline treatment in patients with unresectable locally advanced or metastatic HCC in a single-arm phase 2 trial (NCT04605796). To be eligible for enrollment patients were required to have Barcelona Clinic Liver Cancer (BCLC) stage C or B, Child-Pugh stage A, ECOG performance status of 0 or 1, at least 1 measurable lesion, and no prior systemic therapy.³

Patients in the study received 240 mg of intravenous (IV) toripalimab plus 15 mg/kg of IV bevacizumab on day 1 every 3 weeks until disease progression, unacceptable toxicity, or consent withdrawal.

The primary end points were tolerability and investigator-assessed objective response rate (ORR) per RECIST v1.1 criteria. The secondary end points included independent review committee–assessed ORR per modified RECIST criteria, disease control rate (DCR), PFS, duration of response (DOR), time to progression (TTP), time to response, and OS.

By the data cut-off of June 23, 2021, 54 patients had been enrolled. Baseline demographics indicated that the median age was 54 years (range, 26-68). Additionally, most patients were male (n = 48); and had HBV infection (87.0%), BCLC stage C (74.1%), and prior local therapy (74.1%). At the time of the analysis all patients had received at least one cycle of toripalimab plus bevacizumab (median, n = 10 [range, 1-18]).

Among 52 evaluable patients, the ORR per RECIST v1.1 criteria was 32.7% (n = 17/52) with 1 complete response and 16 partial responses. The DCR was 78.8% (n = 41/52). When analyzed according to modified RECIST criteria the ORR was 46.2% (95% CI, 32.2%-60.5%) and the DCR was 94.2% (95% CI, 84.1%-98.8%). The median PFS was 9.9 months (95% CI, 5.5-11.0) and the median OS was not reached.

Regarding safety most treatment-related AEs (TRAEs) were grade 1 or 2. Grade 3 or greater TRAEs occurred in 25.9% of patients, and serious AEs occurred in 27.8% of patients. Grade 3 or greater immune-related AEs occurred in 11.1% of patients. Death due to treatment-emergent AEs did not occur in the study.

To be eligible for enrollment in the phase 3 HEPATORCH trial patients between the ages of 18 and 75 must have received a histological or cytological diagnosis of HCC or a clinical diagnosis of HCC in cirrhotic patients according to the American Association for the Study of Liver Diseases guideline. In addition, patients must have unresectable BCLC B or C disease; no prior exposure to systemic therapy for HCC; at least 1 measurable lesion per RECIST v1.1 criteria; Child-Pugh class A with no history or hepatic encephalopathy; an ECOG performance status of 0 or 1; life expectancy of at least 12 weeks; and adequate main organ function.²

Eligible patients will be randomly assigned 1:1 to receive 240 mg of toripalimab as an intravenous infusion every 3 weeks plus 15 mg/kg of bevacizumab every 3 weeks as a continuous infusion; or 400 mg of oral sorafenib twice daily.

In addition to the primary end points of PFS and OS, investigators will evaluate the following as secondary end points: ORR, DOR, DCR, TTP, the incidence of AEs and serious AEs as assessed by the Common Terminology Criteria for Adverse Events, version 5.0, correlation between tumor mutation burden and efficacy of the combination, and serum levels and incidence of anti-drug antibodies with the combination.

“The incidence and mortality rates of HCC in China have remained consistently high, posing a serious threat to public health. Junshi Biosciences is committed to putting patients first, with the mission of ‘providing patients with world-class, trustworthy, and affordable and innovative drugs.’ In this study, toripalimab demonstrated its powerful synergy as a cornerstone of immuno-oncology, significantly improving survival rates for patients with advanced HCC. Moving forward, we will actively communicate with regulatory authorities to expedite the approval of relevant indications, and we hope our efforts will benefit more patients with advanced liver cancer,” Jianjun Zou, MD, PhD, general manager and chief executive officer of Junshi Biosciences, said.¹

References

1. Junshi Biosciences announces phase 3 study of toripalimab combined with bevacizumab for the first-line treatment of advanced hepatocellular carcinoma meets primary end point. News release. Junshi Biosciences. June 11, 2024. Accessed June 12, 2024. https://www.globenewswire.com/news-release/2024/06/12/2897253/0/en/Junshi-Biosciences-Announces-Phase-3-Study-of-Toripalimab-Combined-with-Bevacizumab-for-the-First-line-Treatment-of-Advanced-Hepatocellular-Carcinoma-Meets-Primary-Endpoint.html
2. Evaluate the safety and efficacy of toripalimab combined with bevacizumab versus sorafenib therapy for HCC. ClinicalTrials.gov. Updated August 14, 2023. Accessed June 12, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT04723004
3. Toripalimab plus bevacizumab as first-line treatment for advanced hepatocellular carcinoma: a single-arm phase II study. J Clin Oncol. 2022;40(suppl 4):435. doi:10.1200/JCO.2022.40.4_suppl.435