Camrelizumab/Rivoceranib improves PFS and OS compared to sorafenib for unresectable HCC

Results presented at ESMO 2022 show survival benefits of camrelizumab plus rivoceranib in patients with unresectable HCC.

Combined use of the PD-1 inhibitor camrelizumab and the VEGFR2 TKI rivoceranib significantly improved both progression-free survival (PFS) and overall survival (OS) compared to sorafenib (Nexavar) for patients with an unresectable hepatocellular carcinoma (HCC), according to the results of a phase 3 study (NCT03764293) presented at the ESMO Congress 2022.1

Median OS with camrelizumab and rivoceranib was 22.1 months (95% CI, 19.1-27.2) versus 15.2 months with sorafenib (95% CI, 13.0-18.5 ), which was equivalent to a 38% reduction in the risk of death (RR, 0.62; 95% CI, 0.49-0.80; P P

“This is the first positive international Phase 3 study to report significant benefits in PFS and OS with the combination of immunotherapy and small molecule TKI compared to sorafenib for unresectable HCC said lead researcher Shukui Qin, MD, Department of Medical Oncology, Cancer Center. from Jinling Hospital in Nanjing, China, said during a presentation of the results. “Furthermore, camrelizumab plus rivoceranib provides the longest OS, at 22.1 months, observed in a pivotal first-line Phase 3 study in advanced HCC to date.”

In the Phase 3 study, patients were equally randomized to camrelizumab 200 mg intravenously every 2 weeks plus oral rivoceranib 250 mg daily (n=272) or oral sorafenib 400 mg twice times a day (n = 271). The median age of patients in the combination arm was 58 years versus 56 years in the sorafenib arm. Most patients in both groups were recruited from Asia (82.7%), with 47 patients in each group being non-Asian.

Baseline characteristics were similar in all arms. In the camrelizumab plus rivoceranib arm, most patients had stage C BCLC disease (86.8%), a majority had an ECOG performance status of 1 (55.9%), and AFP was 400 ng /ml or more for 35.3%. Gross vascular invasion and extrahepatic spread were observed in 73.5% of patients and the most common etiology was hepatitis B virus infection (76.5%). Just over half of the patients had received local therapy (59.2%) before entering the study.

The objective response rate (ORR) confirmed by a blinded independent review board and RECIST v1.1 criteria was 25.4% with camrelizumab plus rivoceranib versus 5.9% for sorafenib, representing superiority for association (P P

According to RECIST v1.1 criteria, there were 3 complete responses (CR) with camrelizumab plus rivoceranib versus 1 CR for sorafenib. Using the modified RECIST criteria, there were 14 CRs with the association versus 3 for the single agent. Including stable disease, the disease control rate (DCR) by RECIST v1.1 with the combination was 78.3%, compared to 53.9% for the single agent. These rates were similar under the modified criteria.

The 6-month PFS rate with camrelizumab plus rivoceranib was 44.6% versus 22.7% for sorafenib. For OS, 76.5% of patients were alive at 12 months in the camrelizumab plus rivoceranib arm, compared to 60.8% in the sorafenib arm. At month 18, the OS rate was 60.9% with the combination versus 45.2% with monotherapy.

These benefits were seen across all subgroups, Qin said. By geographic region, the relative risk for OS was 0.55 favoring the association in non-Asian patients. The small size of the population however limited the statistical analyses, with a very wide confidence interval observed (95% CI, 0.29-1.02). “PFS and OS generally favored camrelizumab over rivoceranib in all subgroups,” Qin noted.

Grade 3/4 treatment-related adverse events (TRAE) were experienced by 80.5% of patients in the camrelizumab plus rivoceranib arm versus 52% in the sorafenib group. There was 1 grade 5 ETRA in each treatment group. Serious AETRs were experienced by 24.3% of patients treated with the combination versus 5.9% in the single-agent arm. Dose modifications or interruptions for EITRs were required for 80.5% in the combination arm versus 50.2% in the monotherapy arm; however, discontinuation of all treatment components was similar between groups at 3.7% for camrelizumab plus rivoceranib versus 4.5% for sorafenib.

The most common Grade ≥ 3 TEAEs with camrelizumab plus rivoceranib were hypertension (37.5%), AST increased (16.5%), ALT increased ( 12.9%), palmar-plantar erythrodysaesthesia (EPI; 12.1%) and decreased number of platelets (11.8%). For sorafenib, the most common grade ≥3 TEAEs 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 results confirm that camrelizumab plus rivoceranib represents another new first-line treatment option for unresectable HCC.”

During a discussion of the results, R. Katie Kelley, MD, of the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, described the potential benefits of using an inhibitor of oral angiogenesis, but also cautioned that careful patient selection was needed given the hepatotoxicity seen with the combination. Additionally, she noted challenges with extrapolating the data to a non-Asian population, especially given the high rates of hepatitis B virus infection seen in the underlying etiology.

“The advent of multiple front-line and post-treatment options marks tremendous progress in HCC and provides a new opportunity to individualize treatment decisions,” Kelley said. “Region and etiology can impact the results of HCC trials involving immune checkpoint inhibitor therapies. population.

Along with the presentation, Elavar Therapeutics, the company developing the combination, announced its intention to work with the FDA on a potential path to approval. Additionally, the company plans to submit rivoceranib to the FDA for the treatment of recurrent or metastatic adenoid cystic carcinoma (ACC). Results for this indication were presented at the 2022 ASCO Annual Meeting, showing an investigator-assessed RECIST 1.1 ORR of 15.1% (95% CI, 7.8% at 25.00, 4%) with rivoceranib and a DCR rate of 64.4% (95% CI, 52.3%-75.3%).2

“Based on the positive results of the combined study, Elevar plans to work closely with the U.S. Food & Drug Administration for the submission of a new drug application. [NDA] for rivoceranib in combination with camrelizumab as a treatment option for HCC,” Saeho Chong, CEO of Elevar, said in a statement. “In addition, Elevar plans to submit a [new drug application] to the United States Food & Drug Administration for rivoceranib as a treatment option for ACC by the end of 2022.”

References

1) Qin S, Chan SL, Gu S, et al. Camrelizumab (C) plus rivoceranib (R) vs sorafenib (S) as first-line treatment for unresectable hepatocellular carcinoma (uHCC): a phase III randomized trial. Anne Oncol. 2022;33(Supplement 7). doi:10.1016/j.annomnc.2022.08.032.

2) Kang H, Ahn MJ, Muzaffar J, et al. A Phase 2 study of the oral vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor, rivoceranib, for recurrent or metastatic (R/M) adenoid cystic carcinoma (ACC). J Clin Oncol. 2022;40 (suppl 16):abstr 6020. doi:10.1200/JCO.2022.40.16_suppl.6020.

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