Rivoceranib-Camrelizumab CRL: Manufacturing Delay Masks Best-in-Class OS Data but Cannot Hide Crowded-Market Differentiation Problem

FDA Issues Complete Response Letter for Elevar's HCC Combination

Elevar Therapeutics announced that the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) for its New Drug Application (NDA) for the combination of rivoceranib and camrelizumab as a first-line systemic treatment for unresectable or metastatic hepatocellular carcinoma (HCC). The FDA's decision was related to deficiencies identified during a cGMP inspection of a manufacturing site listed on the Rivoceranib NDA. Elevar Therapeutics is reviewing the letter and intends to work closely with the FDA to determine the appropriate path forward, reaffirming its commitment to patients with HCC and belief in the clinical data.

• The FDA's Complete Response Letter was specifically due to deficiencies identified during a cGMP inspection of a manufacturing site, rather than concerns about the clinical data. Elevar Therapeutics expressed disappointment but reiterated its commitment to patients and its intention to engage promptly with the FDA to understand the feedback and determine the most effective path forward.
• Elevar Therapeutics continues to believe in the strength of the clinical data supporting the combination, which was based on the global Phase 3 CARES-310 study. This study demonstrated a median overall survival of 23.8 months in patients with unresectable or metastatic HCC, representing the longest overall survival reported to date among first-line treatments for this condition, with consistent efficacy and a manageable safety profile.
• Prior to this regulatory decision, the combination regimen had already received significant clinical recognition. It was 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, formally acknowledging its clinical value. The final analysis of the CARES-310 study was also published in The Lancet Oncology in December 2025.

CARES-310 Data: Strong Efficacy for Rivoceranib/Camrelizumab in HCC

Recent clinical investigation in unresectable or metastatic hepatocellular carcinoma (HCC) has yielded meaningful efficacy data across several trial programs. The HIMALAYA trial evaluated durvalumab combined with tremelimumab (dual immune checkpoint blockade) and demonstrated significant survival improvements in advanced or unresectable HCC. A comparative safety analysis between real-world EudraVigilance pharmacovigilance data (236 reports encompassing 434 adverse drug reactions, of which 97.5% were classified as serious) and HIMALAYA trial data (1,722 ADRs) revealed broadly similar adverse event profiles, with gastrointestinal disorders predominating in both datasets (25.1% vs. 25.6%, respectively). Notable discrepancies included higher reporting of immune-related and hepatic toxicities in routine clinical practice relative to trial data, underscoring the importance of real-world safety surveillance. The COSMIC-312 trial, a phase III study of cabozantinib plus atezolizumab, demonstrated prolonged progression-free survival but failed to improve overall survival, with preclinical mechanistic work implicating concurrent COX-2/PGE₂-mediated immunosuppression as a key resistance pathway limiting antitumor efficacy.

The tislelizumab meta-analysis — a systematic review encompassing seven studies and 1,178 patients — characterised the efficacy and safety profile of this anti-PD-1 monoclonal antibody across the HCC population. Pooled objective response rate (ORR) was 22.3%, adjusted to 17.2% following correction for publication bias (Egger's p = 0.027). Pooled overall survival (OS) was 13.66 months (95% CI: 11.97–15.35) with no heterogeneity (I² = 0%), while progression-free survival (PFS) ranged from 4.58 months under a fixed-effect model to 5.86 months under a random-effects model, reflecting substantial inter-study heterogeneity (I² = 93.15%). Grade ≥3 treatment-related adverse events occurred in 28.9% of patients, supporting a broadly manageable safety profile. A separate pooled analysis of TKIs combined with sintilimab and TACE (TKIs-Sin-TACE) across six studies (n = 336 patients with BCLC stage B/C HCC) reported a pooled ORR of 39% (95% CI: 26–55%), disease control rate of 74% (95% CI: 60–84%), 10-month OS of 73% (95% CI: 54–86%), and 20-month OS of 30% (95% CI: 16–49%), with grade ≥3 treatment-related adverse events aggregated at 23% (95% CI: 12–42%).

The HAIC plus lenvatinib plus PD-1 inhibitor triple combination study in unresectable HCC delivered notably high response rates, with an ORR of 69.7% (95% CI: 51.3–84.4%), disease control rate of 90.9% (95% CI: 75.7–98.1%), median PFS of 9.7 months (95% CI: 9.3–11.6), and median OS of 17.4 months (95% CI: 15.4–24.3). The safety profile was favorable, with low incidence of moderate-to-severe adverse events and no treatment-associated mortalities, a finding attributed in part to the mechanistic synergy between HAIC-induced immunogenic cell death and lenvatinib's attenuation of VEGF-mediated immunosuppression. Complementing these findings, a first-in-human phase I study of BAY 3547926 (Ac-GPC3) — an actinium-labeled antibody-chelator conjugate targeting glypican-3, a surface antigen overexpressed in more than 70% of HCCs — commenced recruitment in March 2025, with approximately 148 participants to be enrolled across dose escalation, monotherapy expansion, and standard-of-care combination cohorts. Primary endpoints encompass treatment-emergent adverse event characterisation, recommended dose determination, ORR, disease control rate, duration of response, and PFS, positioning this agent as a potential first-in-class targeted alpha-therapy in the HCC landscape.

Addressing the Urgent Unmet Needs in Unresectable HCC

Despite notable therapeutic advances over the past decade, unresectable and metastatic hepatocellular carcinoma (HCC) continues to carry a poor prognosis, driven by a combination of late-stage diagnosis, intrinsic tumor biology, and the limited durability of available systemic agents. Current standard-of-care options—including tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs)—have meaningfully expanded the treatment landscape, yet their clinical benefits remain constrained by resistance, tolerability, and patient selection challenges.

• Late diagnosis limits intervention: HCC is typically not identified until the disease has reached an advanced stage, significantly narrowing the window for curative or effective intervention and contributing to an unfavorable prognosis.

• Modest and time-limited survival benefit with TKIs: Sorafenib, long considered the foundational systemic therapy for advanced HCC, offers only approximately 2.8 months of incremental survival benefit and is frequently associated with resistance—partly attributable to cancer stem cell populations—as well as a significant adverse effect burden.

• Persistent resistance across drug classes: Despite the availability of TKIs, cytotoxic chemotherapy, and ICIs, most patients eventually develop resistance. Critically, this resistance often occurs in the absence of identifiable genetic alterations, implicating non-genetic, adaptive mechanisms—such as USP22-centered positive feedback loops—that convert transient stress signals into stable, drug-tolerant states across targeted therapy, chemotherapy, and immunotherapy settings.

• Limited and heterogeneous ICI efficacy: While ICI-based regimens have improved overall and progression-free survival versus TKIs, their clinical success remains uneven. Survival benefit appears concentrated in patients with HBV-related HCC and preserved liver function (Child-Turcotte-Pugh Class A), with no statistically significant advantage observed in HCV-related or non-viral HCC subgroups.

• Failure of novel therapeutic targets in clinical translation: Despite preclinical rationale, clinical evaluation of several promising targets—including c-Met, TGF-β, and FGFR—has failed to demonstrate meaningful clinical benefit, underscoring the challenge of translating mechanistic insights into effective therapies.

• Unresolved sequencing and transitional care questions: Significant gaps remain in clinical guidance regarding the optimal timing for transition from locoregional to systemic therapies, as well as the sequencing of available agents—areas where prospective data remain sparse.

• Emerging but immature modalities: CAR-T cell therapy, while scientifically promising, continues to face substantial challenges in the context of solid tumors, and its clinical application in HCC remains investigational with no established role in current practice.

Evolving Treatment Landscape for Unresectable or Metastatic HCC

The treatment landscape for unresectable or metastatic hepatocellular carcinoma (HCC) has undergone a profound transformation over the past five years, shifting away from sorafenib monotherapy — the sole approved systemic option for nearly a decade following its 2007 introduction — toward a more diversified, biomarker-informed therapeutic armamentarium. A critical inflection point was the IMbrave150 trial, which established atezolizumab plus bevacizumab (atezo/bev) as the first immunotherapy regimen to demonstrate superior survival over sorafenib in unresectable HCC, cementing its position as a preferred first-line standard of care. Durvalumab plus tremelimumab subsequently joined the first-line landscape, with network meta-analyses of up to 17 phase III trials (2010–2023) confirming that tremelimumab/durvalumab delivers overall survival benefit comparable to atezo/bev (HR 1.35, 95% CI: 0.93–1.92). Lenvatinib, having demonstrated non-inferiority to sorafenib in the phase III REFLECT trial, also remains an established first-line option, alongside emerging combination regimens including sintilimab plus bevacizumab biosimilar, camrelizumab plus rivoceranib, and lenvatinib plus pembrolizumab, all of which show similar OS effects to the frontrunner combinations. Real-world SEER-Medicare data (2014–2019, n = 11,766) corroborate this paradigm shift, with sorafenib's first-line utilization declining sharply from 84.5% (2014–2017) to 41.3% (2018–2019), and median OS among patients receiving systemic therapy reaching 12.0 months versus 2.2 months for those receiving no treatment.

The second-line setting has grown considerably more complex following the approval of regorafenib, cabozantinib, and ramucirumab, each having demonstrated superior overall survival versus placebo in phase III trials. Cabozantinib, studied in the CELESTIAL trial — notably the only phase III study to enroll patients in the third-line setting — confirmed efficacy irrespective of alpha-fetoprotein levels, albumin-bilirubin score, age, and duration of prior sorafenib exposure. Meta-analyses of second-line therapies post-sorafenib have demonstrated meaningful improvements in disease control rate (RR 1.36, 95% CI: 1.16–1.60, p = 0.0002), time to progression (HR 0.64, 95% CI: 0.51–0.81, p = 0.0002), and progression-free survival (HR 0.60, 95% CI: 0.46–0.77, p < 0.0001), with regorafenib appearing comparatively more effective among available second-line agents. ICI-based combinations have also shown heightened efficacy in Asia-Pacific populations and in patients with HBV infection, though they did not demonstrate superiority over molecular-targeted drugs in patients without macrovascular invasion or extrahepatic spread. Real-world data from 58 patients across 20 centers treated with second-line systemic therapy following atezo/bev progression (2020–2024) reported a median PFS of 4.1 months and median OS of 7.8 months, with extrahepatic spread, prognostic nutritional index, and AFP level identified as independent OS predictors — underscoring the ongoing challenge of sequencing therapies in the post-immunotherapy context.

Looking ahead, resistance mechanisms and combination strategies are shaping the next phase of clinical development. Genome-wide CRISPR/Cas9 screening has identified NFKB1 and MET as critical drivers of lenvatinib resistance, with preclinical data suggesting synergistic activity when QNZ and cabozantinib are combined with lenvatinib. Elevated SOX4/STAT6/MTHFD2 axis activity has been associated with resistance to both immunotherapy and TKIs, while IL-33 has been implicated in sorafenib resistance through PD-L1 upregulation via NF-κB pathway activation — a mechanism potentially addressable with anti-IL-33 or anti-ST2L neutralizing antibodies. Cabozantinib is being evaluated in combination with atezolizumab in the first-line phase III COSMIC-312 trial, and novel modalities including targeted alpha-therapy with BAY 3547926 (Ac-GPC3), directed at glypican-3 expressed in over 70% of HCCs, have entered early-phase recruitment as of March 2025. The identification of reliable predictive biomarkers and the elucidation of immunotherapy resistance mechanisms remain central priorities as the field works to expand the proportion of patients — currently estimated at approximately one-third — who derive meaningful and durable benefit from ICI-based regimens.

Beyond HCC: Rivoceranib and Camrelizumab's Broader Pipeline

The rivoceranib/apatinib and camrelizumab combination is being investigated across several oncology indications beyond unresectable or metastatic HCC, with all identified trials employing a single-arm intervention model. The studies span both common and rare malignancies, reflecting the broad mechanistic rationale for combining VEGFR-targeted therapy with PD-1 blockade.

Note: Across all identified trials, the VEGFR-2 inhibitor used in combination with camrelizumab is recorded as apatinib, the earlier branded formulation, rather than rivoceranib (the internationally approved designation). Prior exposure to PD-1/PD-L1 or VEGF-targeted agents was an exclusion criterion in the urachal carcinoma trial. No grade 5 toxicities were reported in the UrC cohort; grade 3–4 adverse events occurred in 45% of patients.

Manufacturing Hurdles Stall First-Line HCC Combination

The recent Complete Response Letter (CRL) from the FDA for Elevar Therapeutics' combination of rivoceranib and camrelizumab in first-line unresectable or metastatic hepatocellular carcinoma (HCC) marks a critical juncture for the company and the broader oncology community. While the news is undoubtedly a setback, it is important to note that the FDA's decision was tied to manufacturing site deficiencies, not the clinical data itself. This distinction is crucial, as the combination has demonstrated compelling efficacy in clinical studies.

Research indicates that camrelizumab plus apatinib (rivoceranib) offers comparable overall survival benefits to current first-line standards like atezolizumab plus bevacizumab in unresectable HCC. Studies have highlighted its ability to achieve high objective response rates and disease control rates, with some even reporting complete remission in advanced BCLC stage C HCC patients. Beyond HCC, this combination has shown promise across a spectrum of solid tumors, including gastric cancer, esophageal squamous cell carcinoma, and small cell lung cancer, underscoring the potential breadth of its therapeutic application.

However, the path forward is not without its challenges. The delay in approval means Elevar must navigate a rapidly evolving and competitive first-line HCC landscape, where established immune checkpoint inhibitor-based regimens are already entrenched. Furthermore, while effective, the camrelizumab and rivoceranib combination has been associated with a higher incidence of treatment-related adverse events compared to atezolizumab plus bevacizumab, a factor that will require careful consideration in clinical practice. The manufacturing issues themselves present a fundamental hurdle, demanding swift and comprehensive resolution to ensure regulatory compliance and build confidence in the drug's supply chain. Ultimately, Elevar's ability to address these manufacturing concerns efficiently and strategically position its therapy will be paramount to realizing the full potential of this promising combination for patients with HCC and other advanced malignancies.