Results of a phase 3 study appear to indicate better progression-free and overall survival outcomes with camrelizumab and rivoceranib vs sorafenib in unresectable hepatocellular carcinoma.
Findings from a phase 3 study (NCT03764293) that were presented at the 2022 European Society for Medical Oncology Congress (ESMO) showed that combining PD-1 and VEGFR2 inhibition with camrelizumab and rivoceranib significantly improved both progression-free and overall survival (OS) compared with sorafenib (Nexavar) for patients with unresectable hepatocellular carcinoma (HCC).1
The median OS with camrelizumab and rivoceranib was 22.1 months (95% CI, 19.1-27.2) compared with 15.2 months with sorafenib (95% CI, 13.0-18.5), which equated to a 38% reduction in the risk of death (HR, 0.62; 95% CI, 0.49-0.80; P <.0001). Median progression-free survival (PFS) with camrelizumab and rivoceranib was 5.6 months (95% CI, 5.5-6.3) compared with 3.7 months for sorafenib (95% CI, 2.8-3.7), which was a 48% reduction in the risk of progression or death (HR, 0.52; 95% CI, 0.41-0.65; P <.0001).
“This is the first positive international phase 3 study to report significant PFS and OS benefits with the combination of an immunotherapy and a small-molecule TKI over sorafenib for unresectable HCC,” lead investigator Shukui Qin, MD, Department of Medical Oncology, Cancer Center of Jinling Hospital, in Nanjing China, said during a presentation of the results. “Moreover, camrelizumab plus rivoceranib provides the longest OS, at 22.1 months, seen in a front-line pivotal phase 3 study in advanced HCC to date.”
In the phase 3 study, patients were evenly randomized between camrelizumab at 200 mg intravenously every 2 weeks plus oral daily rivoceranib at 250 mg (n = 272) or oral sorafenib at 400 mg twice daily (n = 271). The median age of patients in the combination arm was 58 years compared with 56 years in the sorafenib arm. Most patients across both groups were enrolled in Asia (82.7%), with 47 patients in each arm being non-Asian.
Baseline characteristics were similar across arms. In the camrelizumab plus rivoceranib arm, most patients had BCLC stage C disease (86.8%), a majority had an ECOG performance status of 1 (55.9%), and the AFP was 400 ng/ml or greater for 35.3%. Macroscopic vascular invasion and extrahepatic spread were seen in 73.5% of patients and the most common etiology was hepatitis B virus infection (76.5%). Slightly more than half of patients had received a local therapy (59.2%) before entering the study.
The confirmed objective response rate (ORR) by blinded independent review committee and RECIST v1.1 criteria was 25.4% with camrelizumab plus rivoceranib compared with 5.9% for sorafenib, representing superiority for the combination (P < .0001). These findings were similar for modified RECIST criteria-determined ORR, at 33.1% for the combination vs 10.0% for sorafenib (P < .0001). The median duration of response per RECIST v1.1 was 14.8 months with camrelizumab plus rivoceranib and 9.2 months for sorafenib.
By RECIST v1.1 criteria, there were 3 complete responses (CR) with camrelizumab plus rivoceranib compared with 1 CR for sorafenib. Using the modified RECIST criteria, there were 14 CRs with the combination compared with 3 for the single agent. When including stable disease, the disease control rate (DCR) by RECIST v1.1 with the combination was 78.3%, compared with 53.9% for the single agent. These rates were similar by the modified criteria.
The 6-month PFS rate with camrelizumab plus rivoceranib was 44.6% compared with 22.7% for sorafenib. For OS, there were 76.5% of patients alive at 12 months in the camrelizumab plus rivoceranib arm, compared with 60.8% with sorafenib. At month 18, the OS rate was 60.9% with the combination vs 45.2% with monotherapy.
These benefits were seen across subgroups, Qin said. By geographic region, the hazard ratio for OS was 0.55 favoring the combination in non-Asian patients. The small size of the population, however, limited statistical analyses, with a very broad confidence interval observed (95% CI, 0.29-1.02). “PFS and OS generally favored camrelizumab plus rivoceranib across subgroups,” Qin noted.
Grade 3/4 treatment-related adverse events (TRAE) were experienced by 80.5% of patients in the camrelizumab plus rivoceranib arm vs 52% in the sorafenib group. There was 1 grade 5 TRAE in each treatment group. Serious TRAEs were experienced by 24.3% of patients treated with the combination compared with 5.9% in the single agent arm. Dose modifications or interruptions for TRAEs were required for 80.5% in the combination group vs 50.2% in the monotherapy arm; however, treatment discontinuation of all treatment components was similar between groups at 3.7% for camrelizumab plus rivoceranib vs 4.5% for sorafenib.
The most frequently observed TRAEs of grade ≥3 in severity with the camrelizumab plus rivoceranib combination were hypertension (37.5%), AST increase (16.5%), ALT increase (12.9%), palmar-plantar erythrodysesthesia (PPE; 12.1%), and platelet count decrease (11.8%). For sorafenib, the most common grade ≥3 TRAEs were PPE (15.2%) and hypertension (14.9%).
“The combination of camrelizumab plus rivoceranib was generally well-tolerated, with a safety profile in line with each individual agent and the underlying disease,” Qin said. “These findings support that camrelizumab plus rivoceranib represents another new first-line treatment option for unresectable HCC.”
During a discussion of the findings, R. Katie Kelley, MD, from the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, described potential advantages with the use of an oral angiogenesis inhibitor, but also cautioned that careful patient selection was required, given the hepatotoxicity seen with the combination. Moreover, she noted challenges with extrapolating the data to a non-Asian population, particularly given the high rates of hepatitis B virus infection seen in the underlying etiology.
“The advent of multiple first- and later-line treatment options marks enormous progress in HCC and provides new opportunity to individualize treatment decisions,” said Kelley. “Region and etiology may impact outcomes in HCC trials involving immune checkpoint inhibitor therapies. Global trials require advanced planning with regulatory agencies to define minimum subpopulation thresholds.”
With the presentation, Elavar Therapeutics, the company developing the combination, announced plans to work with the FDA on a potential route to approval. Additionally, the company is planning to submit rivoceranib to the FDA for the treatment of recurrent or metastatic adenoid cystic carcinoma (ACC). Findings for this indication were presented at the 2022 American Society of Clinical Oncology Annual Meeting,2 showing an ORR by investigator-assessed RECIST 1.1 criteria of 15.1% (95% CI, 7.8%-25.4%) with rivoceranib and a DCR rate of 64.4% (95% CI, 52.3%-75.3%).
“Based on the positive results of the combination study, Elevar plans to work closely with the US Food & Drug Administration for submission of a new drug application [NDA] for rivoceranib in combination with camrelizumab as a treatment option for HCC,” Saeho Chong, chief executive officer of Elevar, said in a statement. “In addition, Elevar anticipates submission of a [new drug application] to the US Food & Drug Administration for rivoceranib as a treatment option for ACC by the end of 2022.”