Investigators hope to add to the advanced hepatocellular carcinoma (HCC) treatment paradigm, which has gained new treatment options in recent years with the emergence of immune checkpoint inhibitors targeting PD-1/PD-L1, with the initiation of the phase 3 CARES-310 trial (NCT03764293). CARES-310 aims to overcome the modest response many patients experience with immune checkpoint inhibitor monotherapy by combining the IgG4, PD-1–directed monoclonal antibody camrelizumab with the novel VEGFR2-directed tyrosine kinase inhibitor (TKI) rivoceranib.

"[Rivoceranib] blocks multiple pathways, but the main one is VEGF, which we know is very hyperactivated in HCC,” Amit Mahipal, MD, professor, hematology and oncology, University Hospitals Seidman Cancer Center, as well as a member of the Developmental Therapeutics Program, Case Comprehensive Cancer Center, both in Cleveland, Ohio, said in an interview with 

. "Based on prior drug experience, we know that the anti-VEGF agents do work in this cancer. In CARES-310, [the investigators] tried a combination of anti–PD-1 plus VEGF [inhibition] and compared it with sorafenib [Nexavar], which was the standard of care.”

Early-Phase Findings Provide Proof Of Concept For Camrelizumab/Rivoceranib In HCC

The combination of camrelizumab plus rivoceranib was first evaluated for the treatment of patients with advanced HCC in a phase 1/2 trial (NCT02942329), which also enrolled patients with gastric or esophagogastric junction cancer. In the phase 1a portion, patients received camrelizumab at 200 mg every 2 weeks and rivoceranib at dose levels ranging from 125 to 500 mg/d until unacceptable toxicity or disease progression; rivoceranib was given as a part of the combination at the recommended phase 2 dose (RP2D) of 250 mg in phase 1b. The primary end points were safety and determining the RP2D.

Findings from the study demonstrated that the objective response rate (ORR) in response-evaluable patients with HCC (n = 18) was 50% (95% CI, 24.7%-75.4%). In the safety population (n = 43), no dose-limiting toxicities (DLTs) were reported in the rivoceranib 125-mg cohort (n = 5), 1 grade 3 DLT of lipase elevation was reported in the 250-mg cohort (n = 33), and 3 patients in the 500-mg cohort (n = 5) experienced grade 3 immune-related pneumonitis. Common grade 1 or 2 treatment-related adverse effects (TRAEs) at the RP2D level included hypertension (42.4%), fatigue (39.4%), and proteinuria (36.4%).

Following the promising findings from the phase 1 trial, investigators initiated the phase 2 RESCUE study (NCT03463876), which evaluated camrelizumab plus rivoceranib in patients with advanced HCC. The study enrolled patients who were on their first line of therapy or were refractory or intolerant to their first line of targeted therapy. Patients received camrelizumab 200 mg every 2 weeks in combination with oral rivoceranib 250 mg/d. The primary end point was ORR; secondary end points included duration of response (DOR), overall survival (OS), progression-free survival (PFS), and safety.

Patients in the first-line cohort (n = 70) experienced an ORR of 34.3% (95% CI, 23.3%-46.6%) by independent review committee; the ORR was 22.5% (95% CI, 15.4%-31.0%) in the second-line cohort (n = 120). The median DOR was 14.8 months (95% CI, 5.5-not reached [NR]) and NR, respectively.

The study authors concluded that the combination of camrelizumab and rivoceranib displayed a high ORR with durable responses and a manageable safety profile in advanced HCC. They noted that the combination could offer a novel treatment option in the first- or second-line setting in advanced HCC.

Given the positive phase 1 and phase 2 data, investigators initiated CARES-310, an open-label, international study of camrelizumab plus rivoceranib vs sorafenib for the frontline treatment of adult patients with unresectable HCC. To be eligible for enrollment, patients must also have at least 1 measurable lesion per RECIST 1.1, an ECOG performance status of 1 or less, a life expectancy of at least 12 weeks, adequate organ function, Child-Pugh grade A disease, and Barcelona Clinic Liver Cancer stage B or C disease. Those with moderate-to-severe ascites, HIV infection, symptomatic interstitial lung disease, or other active malignancies besides HCC within 5 years or simultaneously were not eligible.

“It is worth mentioning that this study was primarily recruiting in Asia, although there were some European and US sites,” Mahipal said. “It certainly lends itself to drivers of HCC that impact liver disease in that part of the world, primarily hepatitis B. But that does not mean that the results may not be generalizable to a broader population.”

Patients were randomly assigned 1:1 to the camrelizumab plus rivoceranib arm (n = 272) or the sorafenib arm (n = 271). Intravenous camrelizumab 200 mg was administered every 2 weeks and oral rivoceranib 250 mg was given once daily. Patients in the control arm received oral sorafenib 400 mg twice daily. Treatment in both arms continued in 28-day cycles until progressive disease, unacceptable toxicity, or withdrawal by the patient or investigator.

The coprimary end points were OS and PFS. Secondary end points included ORR, DOR, disease control rate, time to progression, and safety.

CARES-310 Produces Robust Data At Primary PFS Analysis

In September 2023, investigators published data from the primary PFS analysis and the interim OS analysis of CARES-310 in 

. The data cutoff for PFS was May 10, 2021, and the cutoff for OS was February 8, 2022.

At baseline, the median age in the combination arm was 58 years (range, 48-66) compared with 56 years (range, 47-64) in the monotherapy arm. Most patients in both arms were males (83% vs 85%), Asian (83% vs 83%), had an ECOG performance status of 1 (56% vs 57%), Barcelona Clinic Liver Cancer stage C (86% vs 85%), and a PD-L1 tumor proportion score of less than 1% (81% vs 78%).

At a median follow-up of 7.8 months (IQR, 4.1-10.6), the median PFS was 5.6 months (95% CI, 5.5-6.3) in the camrelizumab plus rivoceranib arm compared with 3.7 months (95% CI, 2.8-3.7) in the sorafenib arm (stratified HR, 0.52; 95% CI, 0.41-0.65; 1-sided log-rank 

 < .0001). The 6-month PFS rates were 48.2% (95% CI, 41.9%-54.3%) vs 25.3% (95% CI, 19.8%-31.1%), respectively, and the 12-month rates were 29.8% (95% CI, 24.1%-35.8%) vs 12.4% (95% CI, 8.3%-17.3%), respectively.

At a median follow-up of 14.5 months (IQR, 9.1-18.7), the median OS in the combination arm was 22.1 months (95% CI, 19.1-27.2) vs 15.2 months (95% CI, 13.0-18.5) in the monotherapy arm, conferring a reduction in the risk of death of 38% with the combination vs sorafenib (stratified HR, 0.62; 95% CI, 0.49-0.80; 1-sided log-rank 

 < .0001). The 12-month OS rates were 76.5% (95% CI, 71.0%-81.1%) vs 60.8% (95% CI, 54.6%-66.4%), respectively, and the 18-month OS rates were 60.9% (95% CI, 54.2%-66.9) vs 45.2% (95% CI, 38.8%-51.4%), respectively.

“This reminds me of data from the [phase 3] LEAP-002 study [NCT03713593] where lenvatinib [Lenvima] was used as the control arm,” Aiwu Ruth He, MD, PhD, scientific lead, liver and biliary cancers, MedStar Georgetown University Hospital, Washington, DC, said in an interview with 

. “The median OS of [that] TKI plus immunotherapy [regimen] was in the same ballpark as the CARES-310 regimen and the only difference is [that] the control arm was lenvatinib, which is the reason why that study was not positive.”

Since the findings for both primary end points of CARES-310 were significant, ORR by blinded independent review committee per RECIST 1.1 was evaluated sequentially. The confirmed ORR was 25% (95% CI, 20%-31%) in the combination arm compared with 6% (95% CI, 3%-9%) in the monotherapy arm (1-sided 

 < .0001). The median DOR was 14.8 months (95% CI, 8.4-NR) compared with 9.2 months (95% CI, 5.3-NR), respectively, although study authors noted that these data were not yet mature.

In terms of safety, TRAEs of any severity occurred in 97% of patients in the combination arm compared with 93% in the monotherapy arm. Grade 3 or higher TRAEs occurred in 81% vs 52% of patients, respectively. In the combination arm, the most common grade 3 or 4 TRAEs included hypertension (38%), increased aspartate aminotransferase (16%), and increased alanine aminotransferase (13%).

Study authors concluded that camrelizumab plus rivoceranib displayed a significant and clinically meaningful PFS and OS benefit compared with sorafenib for the treatment of patients with unresectable HCC. They highlighted that the median OS achieved by patients in the investigational arm of CARES-310 was the longest observed in any phase 3 trial evaluating a systemic therapy in unresectable HCC and noted that the combination could represent a new and effective frontline treatment option for these patients.

In July 2023, Elevar Therapeutics, the manufacturer of rivoceranib, announced that the FDA had accepted the new drug application (NDA) for the combination of rivoceranib and camrelizumab as a frontline treatment for patients with unresectable HCC. The NDA is supported by findings from CARES-310; the FDA set a Prescription Drug User Fee Act target action date of May 16, 2024, for the NDA. The combination also received approval from the National Medical Products Administration in China as a first-line therapy for patients with liver cancer.

 “CARES-310 is a positive trial and if the FDA approves [the regimen], it would be practice changing in the first line,” Mahipal said.

Qin S, Chan SL, Gu S, et al. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. 

. 2023;402(10408):1133-1146. doi:10.1016/S0140-6736(23)00961-3

Xu J, Zhang Y, Jia R, et al. Anti-PD-1 antibody SHR-1210 combined with apatinib for advanced hepatocellular carcinoma, gastric, or esophagogastric junction cancer: an open-label, dose escalation and expansion study. 

. 2019;25(2):515-523. doi:10.1158/1078-0432.CCR-18-2484

Xu J, Shen J, Gu S, et al. Camrelizumab in combination with apatinib in patients with advanced hepatocellular carcinoma (RESCUE): a nonrandomized, open-label, phase II trial. 

. 2021;27(4):1003-1011. doi:10.1158/1078-0432.CCR-20-2571

A study to evaluate SHR-1210 in combination with apatinib as first-line therapy in patients with advanced HCC. ClinicalTrials.gov. Updated June 22, 2023. Accessed January 10, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT03764293

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 January 10, 2024. https://www.globenewswire.com/news-release/2023/07/17/2705640/0/en/Elevar-Therapeutics-Announces-FDA-Acceptance-for-Filing-of-New-Drug-Application-for-Rivoceranib-in-Combination-with-Camrelizumab-as-a-First-line-Treatment-for-Unresectable-Hepatoce.html

Articles

Amit Mahipal, MD, discusses data on camrelizumab plus rivoceranib in advanced HCC and the phase 3 CARES-310 trial, which is currently enrolling patients.

Frontline Camrelizumab/Rivoceranib Combination Shows Promise in Unresectable HCC

Combination therapy consisting of the anti–PD-1 antibody camrelizumab with the VEGFR2-targeted TKI rivoceranib elicited a statistically significant and clinically meaningful benefit in progression-free survival (PFS) and overall survival (OS) compared with sorafenib (Nexavar) in patients with unresectable hepatocellular carcinoma (HCC), suggesting that this combination may provide a new first-line standard of care for this patient population, according to Amit Mahipal, MD.

Results from the phase 3 CARES-310 trial (NCT03764293)

, showed that at a median follow-up of 14.5 months (IQR, 9.1-18.7), the median OS was extended with the combination (n = 272) vs sorafenib (n = 271) at 22.1 months (95% CI, 19.1-27.2) vs 15.2 months (95% CI, 13.0-18.5), respectively (HR, 0.62; 95% CI, 0.49-0.80; 1-sided 

Furthermore, at the primary PFS analysis with median follow-up of 7.8 months (IQR, 4.1-10.6), rivoceranib plus camrelizumab elicited a median PFS of 5.6 months (95% CI, 5.5-6.3) vs 3.7 months (95% CI, 2.8-3.7) with sorafenib (HR, 0.52; 95% CI, 0.41-0.65; 1-sided 

“The phase 3 CARES-310 trial tested the combination of a PD-1 [inhibitor] plus TKI [therapy, with] camrelizumab plus rivoceranib. It’s a positive trial, and if FDA approved, would be practice-changing in the first-line treatment of [patients with] HCC,” Mahipal said.

, Mahipal discussed clinical outcomes with camrelizumab plus rivoceranib as first-line treatment in unresectable HCC, based on data from the randomized, open-label, international phase 3 CARES-310 trial. Mahipal is a professor at Case Western Reserve University and GI Oncology Program leader at University Hospitals in Rochester, Minnesota.

: What has been the focus of recent research in unresectable HCC? What has caught your eye?

: HCC has been a dynamic field for the past few years. For a long time [the field of] HCC was almost stuck, where we had 1 TKI, like sorafenib, but there was no real improvement in treatment for almost 15 to 20 years.

atezolizumab (Tecentriq) and bevacizumab (Avastin) was first FDA approved

, there has been a lot of excitement about immunotherapy in this [patient] group. That has led to the approval of 

tremelimumab [Imjudo] plus durvalumab [Imfinzi], which was approved as a first-line [regimen] in [October] 2022.

In the past few months, we have been talking about newer trials looking at combinations of a TKI plus immunotherapy. There are some trials, which were unfortunately negative, with a TKI plus an immuno-oncology [IO] agent, like 

lenvatinib [Lenvima] plus pembrolizumab [Keytruda]. Overall, these trials were negative.

cabozantinib [Cabometyx] plus atezolizumab, which [resulted in] a negative trial

, as well. Recently one of the first positive trials with a TKI plus IO therapy [looked at the] combination of camrelizumab plus rivoceranib. This is an anti–PD-1 and TKI combination, and that was recently presented as a positive phase 3 trial.

There are other trials in this space as well, but this is the only phase 3 trial that we know has positive data and is therefore more likely to have a regulatory approval. There are other therapies like ipilimumab [Yervoy] plus nivolumab [Opdivo], which are being looked at in the second- and third-line space, including the first-line space as well. We are waiting for that data to come out, which could also change how we treat patients.

Could you expand on the CARES-310 trial, highlighting the novelty of rivoceranib when compared with other available agents?

In this randomized phase 3 trial, investigators looked at a combination of camrelizumab, [which results in] anti–PD-1 blockade, and rivoceranib, which is a TKI. [Rivoceranib] has multiple pathway blockers, but the main thing that it does is block VEGF or anti-VEGFR2, a vascular endothelial growth factor.

We know that [VEGF is] hyperactivated in HCC, and based on prior drug experience, we know that the anti VEGF agents do work in this cancer. In this trial, investigators compared this combination with sorafenib, which was the standard of care.

Looking to the study design, investigators enrolled patients with advanced HCC that who are not suitable for any locoregional therapy with good performance status and a Child-Pugh A score, randomly assigning approximately 550 patients into the 2 arms. This trial was primarily done in Asia, but there were non-Asian patients, as well. That was one of the stratification factors, along with high-risk features, like macrovascular invasion, as well as alpha fetoprotein [level]. The primary end point for the trial was OS as well as PFS.

The trial has completed accrual. Accrual was not really an issue, and it did not require endoscopy prior to enrollment, which some of the other drugs, like bevacizumab, do require. That’s not required so we [would be able to] start treatment sooner if this combination therapy were to be approved.

Please expand on the results of the phase 3 study.

The primary end point looked at OS in the intention-to-treat population and the median OS was 22.1 months [with the combination] compared with 15.2 months with sorafenib alone. This is something we have not seen in HCC yet. We were [previously] seeing a maximum survival of approximately 18 to 19 months, but now we’re looking at an almost 2-year median survival, at almost 22 months, with this combination.

The data [in the control arm were also better] than [what] we typically see with sorafenib, as we see about a year [survival] usually, rather than 15 months. As I mentioned, this was primarily an Asian study, but there were certain proportions of patients that were from outside Asia and Europe, such as the United States.

This trial also achieved its second primary end point of PFS, which was increased from 3.7 months [with sorafenib] to 5.6 months in the combination arm.

Were there any safety concerns of note in the trial?

We did see AEs based on both the TKI and PD-1 blockade when combining the 2 therapies. One other toxicity that came out with the combination is hypertension, which was very commonly seen in approximately 70% of the patients; about 37% of the patients had grade 3 or 4 hypertension. The rest of the AEs were nothing surprising, such as some hepatitis, some diarrhea, and hand-foot syndrome that we expect from TKIs, but again, the hypertension was something that really jumped out, which was not otherwise commonly seen.

We learned from our experience with using bevacizumab and some other drugs, which causes hypertension, how to manage it. [The data from CARES-310] show that we really need to be vigilant about it if this combination were to get an approval, and make sure that we can manage the hypertension early on, so that it doesn’t go to grade 3 or grade 4.

What can be concluded about the research landscape in unresectable HCC?

It’s an exciting field. We are used to poor outcomes in HCC, but now we’re improving the outcomes. A big thing in HCC treatment is patients also have comorbid conditions that can cause death such as cirrhosis, or liver failure.

The treatment paradigm changing has been challenging because you can get treatment to control HCC, but it’s sometimes hard to control the cirrhosis; however, we now have therapies for hepatitis B and hepatitis C. We have seen a great improvement in the quantity and the quality of life for our patient population. Hopefully, we’ll continue to build on these regimens that we have, to make them better.

Qin S, Chan SL, Gu S, et al. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. 

Amit Mahipal, MD, discusses clinical outcomes with camrelizumab plus rivoceranib in unresectable HCC, based on data from the phase 3 CARES-310 trial.

Camrelizumab With Rivoceranib Elicits PFS and OS Benefit Over Sorafenib in Unresectable HCC

Dr He on the Evaluation of Camrelizumab Plus Rivoceranib in Unresectable HCC

Aiwu Ruth He, MD, PhD, scientific lead, Liver & Biliary Cancers, MedStar Georgetown University Hospital, discusses the evaluation of camrelizumab plus rivoceranib in unresectable hepatocellular carcinoma (HCC).

The phase 3 CARES-310 trial (NCT03764293) evaluated treatment with the PD-1 inhibitor camrelizumab in combination with the VEGFR-2 inhibitor rivoceranib in patients with unresectable HCC. Evaluable patients were randomly assigned to receive the experimental combination vs the historical standard of care, sorafenib (Nexavar), in the frontline setting.

Notably, results from the randomized, open-label, international clinical trial were published in 

on July 24, 2023. Treatment with the investigational combination produced a statistically significant improvement in median progression-free survival and overall survival (OS) vs sorafenib, He reports. At the interim analysis of OS, the median follow-up was 14.5 months (interquartile range, 9.1-18.7), and the median OS was 22.1 months (95% CI, 19.1-27.2) in the combination arm vs 15.2 months (95% CI, 13.0-18.5) with sorafenib (HR, 0.62; 95% CI, 0.49-0.80; 1-sided P less than .0001), He details.

Regarding safety, common grade 3/4 treatment-related adverse effects (TRAEs) seen with the combination included hypertension (camrelizumab plus rivoceranib, 38%; sorafenib, 15%), palmar-plantar erythrodysaesthesia syndrome (12%; 15%), increased aspartate aminotransferase (17%; 5%), and increased alanine aminotransferase (13%; 3%). Serious TRAEs occurred in 24% of patients with camrelizumab/rivoceranib vs 6% with sorafenib.

Upon further examination of the safety outcomes, data revealed that the combination of camrelizumab plus rivoceranib produced several toxicities commonly associated with anti-VEGFR therapies, with patients often experiencing hypertension and proteinuria, He states. Similarly, patients also experienced hand-foot syndrome and fatigue with the experimental regimen, He says, adding that these toxicities are associated with TKIs.

Videos

Aiwu Ruth He, MD, PhD, discusses the evaluation of camrelizumab plus rivoceranib in unresectable hepatocellular carcinoma. 

Dr Gholam on Camrelizumab Plus Rivoceranib in Unresectable HCC

Pierre Gholam, MD, associate professor, Department of Medicine, School of Medicine, Digestive Health Research Institute, Case Western Reserve University, discusses findings from the phase 3 CARES-310 trial (NCT03764293) of camrelizumab plus rivoceranib in patients with unresectable hepatocellular carcinoma (HCC).

CARES-310 evaluated the PD-1 inhibitor camrelizumab in combination with the VEGFR-2 inhibitor rivoceranib vs the historical standard of care, sorafenib (Nexavar), in the frontline setting for patients with unresectable HCC, Gholam begins. The findings from this study, which were published in 

, demonstrated that at a median follow-up of 7.8 months (interquartile range, 4.1-10.6), the camrelizumab/rivoceranib combination elicited a median progression-free survival of 5.6 months (95% CI, 5.5-6.3) vs 3.7 months (95% CI, 2.8-3.7) with sorafenib (HR, 0.52; 95% CI, 0.41-0.65; 1-sided 

 < .0001). Furthermore, at a median follow-up of 14.5 months (interquartile range, 9.1-18.7), the median overall survival favored the combination arm, at 22.1 months (95% CI, 19.1-27.2) vs 15.2 months (95% CI, 13.0-18.5) with sorafenib (HR, 0.62; 95% CI, 0.49-0.80; 1-sided 

The most common grade 3/4 treatment-related adverse effects (AEs) observed in this trial were hypertension (camrelizumab/rivoceranib arm, 38%; sorafenib arm, 15%), palmar-plantar erythrodysaesthesia syndrome (12%; 15%), increased aspartate aminotransferase (17%; 5%), and increased alanine aminotransferase (13% vs 3%). Twenty-four percent of patients in the camrelizumab/rivoceranib arm experienced serious treatment-related AEs vs 6% of those in the sorafenib arm.

CARES-310 primarily enrolled patients at sites in Asia, and small numbers of patients were also enrolled at sites in Europe and the United States, Gholam says. Therefore, the findings from this trial may be influenced by drivers of HCC that are common in Asia, such as hepatitis B, Gholam notes. However, these findings may still be generalizable to a more global population, Gholam emphasizes. Future regulatory decisions may define the optimal use of camrelizumab plus rivoceranib in patients with unresectable HCC, Gholam concludes. 

Pierre Gholam, MD, discusses findings from the phase 3 CARES-310 trial of camrelizumab plus rivoceranib in patients with unresectable hepatocellular carcinoma. 

Research Efforts Are Underway in the HCC Treatment Paradigm | Supplements and Featured Publications

Frontline Camrelizumab/Rivoceranib Combination Shows Promise in Unresectable HCC

Camrelizumab With Rivoceranib Elicits PFS and OS Benefit Over Sorafenib in Unresectable HCC

Dr He on the Evaluation of Camrelizumab Plus Rivoceranib in Unresectable HCC

Dr Gholam on Camrelizumab Plus Rivoceranib in Unresectable HCC