Camrelizumab With Rivoceranib Elicits PFS and OS Benefit Over Sorafenib 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), published in The Lancet, 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 P < .0001), respectively.

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 P < .0001).

“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.

In an interview with OncLive^®, 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.

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

Mahipal: 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.

Since 2020, when 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.

There was [the combination of] 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.

Reference

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