Hengrui/Elevar's HCC Drug: Best-in-Class Efficacy Data Undone by Persistent Manufacturing Failures

FDA Rejects Hengrui-Elevar Combo for Third Time Over Manufacturing

The FDA has issued a third Complete Response Letter (CRL) for Hengrui Pharma and Elevar Therapeutics' oncology drug combination of rivoceranib and camrelizumab, intended for first-line unresectable or metastatic hepatocellular carcinoma. The latest rejection stems from manufacturing deficiencies identified at a rivoceranib production facility, following previous CRLs in 2024 and 2025 primarily related to camrelizumab's manufacturing. Elevar Therapeutics is reviewing the FDA's feedback and plans to work closely with the agency to address the identified issues.

• Hengrui Pharma and Elevar Therapeutics' combination of the oral tyrosine kinase inhibitor (TKI) rivoceranib and anti-PD-1 antibody camrelizumab demonstrated longer overall survival compared to sorafenib in a Phase 3 trial for first-line unresectable or metastatic hepatocellular carcinoma. This clinical efficacy highlights the potential therapeutic benefit of the combination, despite the ongoing regulatory challenges.
• The FDA has issued three Complete Response Letters (CRLs) for the combination, consistently citing manufacturing deficiencies. In 2024 and 2025, camrelizumab faced rejections due to issues at its production plant, which subsequently led to CRLs for rivoceranib. The latest 2026 rejection reversed this pattern, with deficiencies at a rivoceranib facility leading to a CRL for camrelizumab, indicating persistent and shifting manufacturing concerns.
• The most recent setback involved the FDA issuing a Form 483 listing deficiencies after inspecting a rivoceranib production plant. Elevar Therapeutics is now required to provide satisfactory responses to these deficiencies. The agency may then conduct reinspections to confirm compliance with current good manufacturing practices (cGMP) and potentially a preapproval inspection (PAI) before considering approval for either drug.

Rivoceranib/Camrelizumab: Safety Profile Amid Regulatory Delays

Across multiple studies, the combination of camrelizumab and rivoceranib (apatinib) demonstrates a consistent trade-off between enhanced efficacy and increased toxicity when compared to monotherapy or other standard-of-care regimens. In a first-line setting for primary liver cancer (PLC), the combination resulted in a 70.4% incidence of grade 3/4 treatment-related adverse events (TRAEs), substantially higher than the 26.4% observed with sorafenib, and included two treatment-related deaths. Similarly, for advanced hepatocellular carcinoma (HCC), immunotherapy-based combinations including camrelizumab plus rivoceranib were associated with a significantly higher risk of adverse events than sorafenib. A 2024 network meta-analysis reinforces this observation, concluding that while immune checkpoint inhibitor (ICI) monotherapies have the lowest toxicity risk, the addition of a kinase inhibitor like rivoceranib provides greater progression-free survival benefits at the cost of higher toxicity rates and an increased risk of treatment discontinuation.

The specific safety profile of the combination varies by indication and treatment setting. In patients with metastatic clear cell renal cell carcinoma who failed first-line TKI therapy, the most common grade 3-4 TRAEs for camrelizumab plus apatinib were increased alanine aminotransferase (26.8%), increased aspartate aminotransferase (22.0%), and proteinuria (22.0%), with no treatment-related deaths reported. For advanced esophageal cancer, camrelizumab-based regimens showed a total adverse event incidence of 71.4%, with the majority (64.0%) being grade 1-2; common events included fatigue (20.8%), anorexia (19.3%), and leukopenia (15.6%). Conversely, in a study of third-line or later therapy for metastatic colorectal cancer (mCRC), the incidence of total, grade 1-2, and grade 3-4 adverse events did not differ significantly between the camrelizumab plus apatinib group and the apatinib monotherapy group (P > 0.05).

Addressing Unmet Needs in Unresectable or Metastatic HCC

Despite significant therapeutic advances, unresectable or metastatic hepatocellular carcinoma (HCC) continues to present major clinical challenges, with high rates of recurrence and mortality. Key unmet needs revolve around overcoming the limited efficacy of and resistance to current treatments, as well as improving patient identification and management for populations with advanced disease.

• Widespread Therapeutic Resistance: A primary challenge is that most patients eventually develop primary or acquired resistance to standard-of-care therapies, including tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), and chemotherapy. This resistance is often driven by non-genetic, adaptive mechanisms that allow tumor cells to survive therapeutic stress, weakening drug effectiveness and contributing to the aggressive nature of the disease.

• Limited Efficacy and Toxicity of Current Regimens: Even with the establishment of new first-line standards like ICI-based combination therapies, clinical benefits remain limited for some subsets of patients with advanced and metastatic disease. Furthermore, existing treatments can be associated with significant systemic toxicity and adverse events that reduce quality of life, highlighting the need for more effective and better-tolerated therapeutic options.

• Need for Predictive Biomarkers and Improved Patient Selection: The lack of reliable and validated biomarkers remains a critical gap, making it difficult to predict treatment response and stratify patients for optimal therapy. Early and accurate detection also continues to be a major clinical challenge, as many patients are asymptomatic until their disease is very advanced, which delays diagnosis and limits curative treatment options.

• Difficult-to-Treat Patient Populations: Specific subpopulations present a profound unmet need, including patients with high-risk features like macrovascular invasion or those with p53-mutant HCC (~30% of cases), which drives tumorigenesis and chemoresistance. Additionally, while novel modalities like CAR-T cell therapies are under investigation, their clinical application in solid tumors like HCC still faces significant hurdles.

The Clinical Promise of Rivoceranib/Camrelizumab in HCC

The clinical trial landscape for unresectable or metastatic hepatocellular carcinoma (HCC) is shaped by pivotal studies that have established therapeutic benchmarks and common endpoints. These trials typically utilize overall survival (OS) as the primary endpoint, with progression-free survival (PFS) and objective response rate (ORR) serving as key secondary measures. The following table summarizes the design parameters and endpoints from significant trials and analyses that define the current treatment paradigm.