Frontline Camrelizumab/Rivoceranib Prolongs OS vs Sorafenib in Unresectable HCC

The combination of camrelizumab and rivoceranib represents a promising and unique treatment option for patients with unresectable hepatocellular carcinoma (HCC), according to Arndt Vogel, MD. 

“We don’t have biomarkers to guide our treatment, but having more options is always useful to, in the end, improve the overall survival [OS] of our patients,” Vogel said during an interview with OncLive® at the 2024 ASCO Annual Meeting(ASCO 2024).

In the final OS analysis of the phase 3 CARES-310 trial (NCT03764293), the combination elicited a median OS of 23.8 months vs 15.2 months with sorafenib (Nexavar; HR, 0.64; 95% CI, 0.52-0.79; 1-sided P < .0001).¹

In July 2023, prior data from CARES-310 supported the submission of a new drug application (NDA) seeking the FDA approval of the combination for the frontline treatment of patients with unresectable HCC.² In May 2024, the FDA issued a complete response letter (CRL) to the NDA, citing deficiencies related to the FDA’s inspection of the developer’s manufacturing site.³

In the interview, Vogel discussed key findings from the updated OS analysis of CARES-310, safety considerations to note with rivoceranib plus camrelizumab in patients with unresectable HCC, and potential future directions for this combination in this patient population.

Vogel is a clinician scientist at Toronto General Hospital/Princess Margaret Cancer Center and the Longo Family Chair in Liver Cancer Research in the Division of Gastroenterology and Hepatology at the University of Toronto in Ontario, Canada.

OncLive: What was the rationale for combining camrelizumab with rivoceranib in CARES-310?

Vogel: In CARES-310, 2 drugs were evaluated: a checkpoint inhibitor and a TKI with specific activity against VEGF. This combination makes a lot of sense because we have seen before that not only do checkpoint inhibitors alone have efficacy, but also the combination of VEGF-directed therapy and a checkpoint inhibitor seems to have synergistic activity. Additionally, in the [phase 3] IMbrave150 study [NCT03434379] and the [phase 2/3] ORIENT-32 study [NCT03794440], we have seen interesting data with combinations [that include] bevacizumab [Avastin].

[In CARES-310], bevacizumab was replaced with a TKI [and combined with] VEGF-directed therapy. We have preclinical and clinical evidence that this is meaningful. When we look at the efficacy data [from CARES-310, these prior findings were] confirmed in the study.

What key findings were previously reported from CARES-310?

We have seen the first efficacy data and the safety profile of the combination. The data have been published in The Lancet. We have seen significantly improved progression-free survival [PFS] and OS [with camrelizumab plus rivoceranib vs sorafenib]. In the initial publication, we observed a median OS of 22.1 months [with the combination], which was statistically better compared with sorafenib but also clinically meaningful. In the control arm, we observed a median OS of 15.2 months, which was already good. However, in the experimental arm, [the median OS] was clearly improved. Additionally, all secondary end points, such as overall response rate and PFS, were improved [with the combination]. At ASCO 2024, we presented updated data on these efficacy end points.

What final OS findings were presented at ASCO 2024?

These data were impressive. We have now seen in the experimental arm a median OS of 23.8 months, which is the longest median OS we have observed in the first-line setting in HCC. In the control arm with sorafenib, the median OS did not change much. It remained 15.2 months, which we have observed before and which we have also seen in more recent phase 3 studies when sorafenib was used as a control arm. Overall, there were no new safety signals [with the combination]. In terms of efficacy, we saw an improvement in median OS.

What might the future like look like for camrelizumab plus rivoceranib in unresectable HCC, especially in light of the CRL issued for this combination in this patient population?

In terms of efficacy, [camrelizumab plus sorafenib] is an interesting combination. However, when we consider efficacy, we always need to take toxicity into account. We now have combinations that are well tolerated.

Cross-trial comparisons are always challenging, specifically when we consider that CARES-310 mainly recruited in Asia, and other studies have a higher percentage of Caucasian patients. Although we have seen in CARES-310 that there is a high rate of treatment-related adverse effects [with the combination], the safety profile nevertheless looks tolerable and manageable. It is definitely a combination that should be approved. [This combination would be] helpful for the first-line setting in HCC.

What other gastrointestinal cancer presentations from ASCO 2024 were you excited to see?

In the plenary session, we saw [findings from the phase 3] ESOPEC study [NCT02509286]. With my German background, it was nice to see a German immuno-oncology study in the plenary session. [In ESOPEC], the FLOT regimen [fluorouracil, leucovorin, oxaliplatin, and docetaxel], which was also developed in Germany, was compared with the CROSS trial regimen [in patients with esophageal cancer]. We have seen a clear improvement in pathologic complete response rate and OS [with FLOT vs CROSS], strongly indicating that systemic chemotherapy in the perioperative setting is probably more meaningful for patients with gastric tumors. CROSS still has value, but in the head-to-head comparison, we have now seen that the chemotherapy [regimen used in ESOPEC] was better.

[We also saw findings from the phase 3] CheckMate 9DW trial [(NCT04039607) of nivolumab [Opdivo] plus ipilimumab (Yervoy)] from a liver cancer perspective. We have been waiting for [findings from] this study for a long time. We have seen a lot of promising data [with this combination in patients with sorafenib-exposed advanced HCC] in the [phase 1/2] CheckMate 040 study [NCT01658878]. It was good to see the final data with the combination of nivolumab plus ipilimumab compared with sorafenib or lenvatinib [Lenvima] in the first-line setting. There may be even more options for HCC management in the future.

References

1. Vogel A, Chan SL, Ren Z, et al. Camrelizumab plus rivoceranib vs sorafenib as first-line therapy for unresectable hepatocellular carcinoma (uHCC): final overall survival analysis of the phase 3 CARES-310 study. J Clin Oncol. 2024;42(suppl 16):4110. doi:10.1200/JCO.2024.42.16_suppl.4110
2. Elevar Therapeutics announces FDA acceptance for filing of new drug application for rivoceranib in combination with camrelizumab as a first-line treatment for unresectable hepatocellular carcinoma. News release. Elevar Therapeutics. July 17, 2023. Accessed June 6, 2024. https://elevartherapeutics.com/2023/07/17/elevar-therapeutics-announces-fda-acceptance-for-filing-of-new-drug-application-for-rivoceranib-in-combination-with-camrelizumab-as-a-first-line-treatment-for-unresectable-hepatocellular-carcinoma/
3. Announcement on receipt of complete response letter regarding camrelizumab for injection. News release. Jiangsu Hengrui Pharmaceuticals Co., Ltd. May 17, 2024. Accessed June 6, 2024. https://static.sse.com.cn/disclosure/listedinfo/announcement/c/new/2024-05-18/600276_20240518_01L3.pdf