News|Articles|July 13, 2026

FDA Issues Third CRL for Rivoceranib Plus Camrelizumab in First-Line HCC Over Additional Manufacturing Concerns

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Key Takeaways

The complete response letter cited manufacturing-site cGMP deficiencies for rivoceranib, and no new issues were raised regarding CARES-310 efficacy or safety.
CARES-310 randomized 543 systemic-therapy–naïve unresectable/metastatic HCC patients to camrelizumab/rivoceranib versus sorafenib with OS and PFS as co-primary endpoints by blinded independent review.
Final results showed OS 23.8 vs 15.2 months (HR, 0.64) and PFS 5.6 vs 3.7 months (HR, 0.54), with broad prespecified subgroup consistency.
Grade ≥3 TRAEs were dominated by hypertension and transaminase elevations; discontinuation occurred in 17.6% for camrelizumab, 16.9% for rivoceranib, and 4.4% for both.
Rivoceranib/camrelizumab is approved in China for first-line unresectable HCC and is incorporated into 2025 BCLC strategy and ESMO guidance as a treatment option.

The decision does not reflect new concerns about the clinical efficacy or safety data from the phase 3 CARES-310 trial.

The FDA has issued a complete response letter (CRL) for the new drug application (NDA) seeking approval for rivoceranib plus camrelizumab (SHR-1210) as a first-line systemic treatment for patients with unresectable or metastatic hepatocellular carcinoma (HCC), marking the third time the agency has declined to approve the combination for this indication.¹

The CRL was related to deficiencies identified during a current Good Manufacturing Practice (cGMP) inspection of a manufacturing site listed on the rivoceranib NDA, according to an announcement from Elevar Therapeutics, Inc.¹ Notably, the agency did not identify new concerns with the clinical efficacy or safety data from the pivotal phase 3 CARES-310 trial (NCT03764293), which demonstrated a median OS of 23.8 months with rivoceranib plus camrelizumab vs 15.2 months with sorafenib (Nexavar)—the longest OS reported to date among first-line treatment regimens for HCC.^1,2

Elevar stated it is reviewing the contents of the CRL and intends to engage with the FDA promptly to fully understand the agency's feedback and determine the most effective path forward, including the appropriate steps to resolve the manufacturing deficiencies.¹

"While we are disappointed by this outcome, we remain committed to patients with hepatocellular carcinoma and to advancing the development of rivoceranib and camrelizumab," Dong-Gun Kim, chief executive officer of Elevar Therapeutics, stated in a news release. "We continue to believe in the strength of the clinical data supporting this combination and remain committed to pursuing opportunities that may bring this treatment option to patients in need."

Prior Regulatory Submissions for Rivoceranib

In addition to the current regulatory decision, 2 prior CRLs have been previously issued to the NDA for rivoceranib by the FDA.

The initial CRL, issued on May 16, 2024, cited good manufacturing practice deficiencies at the Hengrui Pharma manufacturing facility responsible for producing camrelizumab as well as incomplete bioresearch monitoring clinical inspections that were constrained by FDA travel restrictions.

Despite a subsequent resubmission, the agency issued a second CRL for the combination in the frontline unresectable HCC setting for reasons that were not publicly disclosed.

How was the CARES-310 trial designed?

CARES-310 is a randomized, open-label, international, multicenter phase 3 trial that enrolled patients at least 18 years of age with histologically or cytologically confirmed unresectable or metastatic HCC who had not previously received systemic therapy.³ Additional eligibility criteria included an ECOG performance status of 0 or 1, Child-Pugh class A liver function, Barcelona Clinic Liver Cancer (BCLC) stage B or C disease not amenable to surgery or locoregional therapy, adequate organ function, and a life expectancy of at least 12 weeks. Patients with known hepatocholangiocarcinoma, sarcomatoid HCC, mixed cell carcinoma, lamellar cell carcinoma, or other active malignancies were excluded.

A total of 543 patients were randomly assigned 1:1 to receive either camrelizumab at 200 mg intravenously every 2 weeks in combination with oral rivoceranib at 250 mg once daily or oral sorafenib at 400 mg twice daily. The study's co-primary end points were OS and progression-free survival (PFS), each assessed by a blinded independent review committee using RECIST 1.1. Secondary end points included overall response rate, disease control rate, duration of response, and overall safety and tolerability.

What efficacy data From CARES-310 supported the NDA?

Final OS results published in The Lancet Oncology in December 2025 demonstrated a statistically significant and clinically meaningful benefit with rivoceranib plus camrelizumab vs sorafenib.² At a median follow-up of 22.1 months, the median OS was 23.8 months (95% CI, 20.6–27.2) in the combination arm vs 15.2 months (95% CI, 13.2–18.5) with sorafenib (HR, 0.64; 95% CI, 0.52-0.79; P < .0001). The median PFS was also significantly prolonged with the combination at 5.6 months (95% CI, 5.5-7.4) vs 3.7 months (95% CI, 3.1-3.7) with sorafenib (HR, 0.54; 95% CI, 0.44-0.67; P < .0001). Consistent efficacy was observed across multiple prespecified patient subgroups.

What was the safety profile in CARES-310?

The safety profile of rivoceranib plus camrelizumab was manageable and consistent with the known profiles of each individual agent. The most common grade 3 or higher treatment-related adverse effects (TRAEs) in the combination arm included hypertension (38.2%), increased aspartate aminotransferase (17.3%), palmar-plantar erythrodysesthesia syndrome (12.1%), and increased alanine aminotransferase (14.0%). TRAEs led to discontinuation of camrelizumab in 17.6% of patients and rivoceranib in 16.9%; the rate of discontinuation of both agents simultaneously was 4.4%.

What prior indications does rivoceranib hold?

Rivoceranib plus camrelizumab is already approved in China as a first-line treatment for unresectable HCC, where it has been marketed since January 2023 by Chinese license holder Jiangsu Hengrui Pharmaceuticals Co., Ltd. under the brand name Aitan.¹

The combination was also included as a first-line treatment option for HCC in the 2025 Barcelona Clinic Liver Cancer treatment strategy and European Society for Medical Oncology guidelines.

References

Elevar Therapeutics receives FDA complete response letter for combination of rivoceranib and camrelizumab as a first-line treatment for unresectable or metastatic hepatocellular carcinoma. News release. Elevar Therapeutics, Inc. July 10, 2026. https://www.biospace.com/press-releases/elevar-therapeutics-receives-fda-complete-response-letter-for-combination-of-rivoceranib-and-camrelizumab-as-a-first-line-treatment-for-unresectable-or-metastatic-hepatocellular-carcinoma
Qin S, Gu S, Chan SL, et al; CARES-310 Study Group. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): final analysis of a randomised, open-label, international, phase 3 study. Lancet Oncol. 2025;26(12):1598-1611. doi:10.1016/S1470-2045(25)00543-1
Flaherty C. Third NDA for rivoceranib/camrelizumab is resubmitted to FDA for unresectable HCC. OncLive. January 29, 2026. Accessed July 13, 2026. https://www.onclive.com/view/third-nda-for-rivoceranib-camrelizumab-is-resubmitted-to-fda-for-unresectable-hcc