Nivolumab/Ipilimumab Establishes Unprecedented Efficacy and Safety Standards in Advanced HCC

Aiwu Ruth He, MD, PhD

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) has found a solid foothold in the frontline management of advanced hepatocellular carcinoma (HCC) and has set a new record for median overall survival (OS) with robust response rates compared with the TKIs sorafenib (Nexavar) and lenvatinib (Lenvima), according to Aiwu Ruth He, MD, PhD.

On April 11, 2025, the FDA granted full approval to nivolumab plus ipilimumab for the treatment of patients with previously untreated, unresectable or metastatic HCC.1 This regulatory decision was backed by data from the phase 3 CheckMate 9DW trial (NCT04039607), in which, at a median follow-up of 35.2 months (range, 26.8-48.9), nivolumab plus ipilimumab (n = 335) elicited a median OS of 23.7 months (95% CI, 18.8-29.4).1,2 In comparison, the median OS was 20.6 months (95% CI, 17.5-22.5) for patients who received control therapy with sorafenib or lenvatinib (n = 333; HR, 0.79 [95% CI, 0.65-0.96; P = .018]).

“[The CheckMate 9DW trial is] a global study with the best median OS [we have seen] so far, as well as the highest overall response rate [ORR] in a global phase 3 study [in this population],” He said in an interview with OncLive®. “What is also amazing is that [with nivolumab plus ipilimumab], now we are reaching 2 years of [median] OS [duration], the ORR is 36%, and the [median] duration of response [DOR] is also amazing, at 30.4 months. This is an effective regimen, and it adds to the treatment options for patients with this disease.”

In the interview, He, a gastrointestinal medical oncologist at the MedStar Health Lombardi Cancer Center in Washington, DC, discussed the significance of this approval; key efficacy, safety, and quality of life [QOL] findings from the pivotal trial; and what the superior efficacy of an immunotherapy combination means for the future of HCC management and research.

OncLive: What unmet needs currently exist for patients with advanced HCC?

He: We’ve made a lot of progress [in the treatment of patients with advanced HCC], but the key unmet need is still survival; we would like to have better survival in those patients, and we also want to have higher response rates with treatment in this disease. With [historically] approved therapies, the best ORR is [approximately] 30%, and the median OS is [approximately] 19 months. We are still looking for a systemic therapy that would induce better responses, tumor shrinkage, and improved survival.

In previous studies, we’ve shown—especially with immunotherapy in HCC—that a good response translates into better cancer control, and, in many cases, leads to improved survival. That’s why response rate is important, especially [with the use of] immunotherapy in HCC.

What was the design of CheckMate 9DW?

The CheckMate 9Dw study was designed based on promising data from one of the arms in the phase 1/2 CheckMate 040 study [NCT01658878]. That study showed that nivolumab plus ipilimumab generated a promising survival benefit and a high ORR. CheckMate 9DW was a confirmatory study that tested this combination in the first-line treatment of patients with advanced HCC. It [enrolled] patients with advanced HCC, good liver function, and Child-Pugh A disease.

[Patients were randomly assigned to receive] nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for 4 cycles, followed by fixed-dose nivolumab at 480 mg every month. The control arm was investigator’s choice of either lenvatinib or sorafenib. The primary end point was OS, and there were important secondary end points, such as ORR, DOR, and time to symptom deterioration. There were also some exploratory end points, such as progression-free survival [PFS] and safety. The study enrolled 668 patients.

Why was lenvatinib used as one of the treatment choices in the control arm? What is significant about nivolumab/ipilimumab’s ability to outperform this agent in CheckMate 9DW?

When we opened CheckMate 9DW, lenvatinib was FDA approved [for the first-line treatment of patients with unresectable HCC]. The CheckMate 9DW protocol was amended to allow lenvatinib to be [one option for] investigator’s choice of control, because CheckMate 9DW is a global study, so not all the sites all over the world have access to lenvatinib for a control arm. However, in this study, 85% of patients enrolled in the control arm received lenvatinib.

Lenvatinib was FDA approved based on [findings from] the phase 3 REFLECT study [NCT01761266], which is a noninferiority study. Lenvatinib was noninferior to sorafenib in terms of OS benefit. However, In the REFLECT study, from the data collected for secondary study end points, lenvatinib generated better PFS and ORR in comparison with sorafenib. Therefore, we know lenvatinib may be a more potent TKI compared with sorafenib in terms of tumor shrinkage and PFS. We suspect it is a higher bar for a global phase 3 study to meet the primary study end point when lenvatinib is used as a control arm instead of sorafenib.

CheckMate 9DW was the first global study to read positive using lenvatinib as a control arm. There was another global study that generated good results and used lenvatinib as the control arm; however, that trial did not meet its primary end point because the lenvatinib arm performed so well. In CheckMate 9DW, in the control arm, the median OS was 20.6 months. That is the longest OS for any control arm in this disease, and the nivolumab/ipilimumab combination still beat the well-performing control arm. That is significant. Therefore, this study also showed us that despite the good performance of lenvatinib as a control arm, the combination of nivolumab and ipilimumab still yielded a significant and clinically meaningful improvement in survival.

What were the key efficacy findings from CheckMate 9DW?

The median OS [with nivolumab plus ipilimumab] was 23.7 months, the longest so far for advanced HCC. That’s exciting and created a new landmark for this disease. The ORR was 36%. This brings back the memory of CheckMate 040. In most phase 3 studies, the data [with the investigational agents] are usually not as good compared with the initial phase 1/2 data [of those agents in their respective populations]. However, the CheckMate 9DW study held onto the good numbers [with nivolumab plus ipilimumab] that were shown in the phase 1 study. Even [though it] is a large, global study with a diverse patient population, it still achieved a high ORR and a good median OS.

[The regimen] also works quickly. The median time to response was 2.2 months, and the median DOR was amazing, at 30.4 months. Patients [who received the combination] had durable responses and [favorable outcomes]. The median OS in responders was not reached. Those patients do extremely well.

What is the safety profile of this combination? Are there any patients in whom you would hesitate to use this regimen?

[The rates of serious] grade 3/4 serious treatment-related adverse effects [AEs] were 25% in the nivolumab-plus-ipilimumab arm and 13% in the lenvatinib/sorafenib arm. There were 12 treatment-related deaths in the nivolumab-plus-ipilimumab arm and 3 treatment-related deaths in the lenvatinib/sorafenib arm. Those cases were studied carefully. Among the 12 cases in the nivolumab-plus-ipilimumab arm, most of these patients who had immune-mediated AEs [experienced partial or complete resolution of those AEs with steroid treatment]. However, prolonged hospitalization [was required for some] frail or elderly patients with severe liver dysfunction, who then developed other complications and eventually succumbed to those complications. I would be cautious [using this regimen] for patients who have severe liver dysfunction, as well as for elderly and frail patients; if they develop immune-mediated AEs, they may develop other complications as well.

What QOL findings have been reported from this trial?

[QOL was measured using] 2 questionnaires. [We saw a] delay in deterioration of patients’ functional status [with the use of nivolumab plus ipilimumab]. We worry about the AEs [associated with this regimen]. However, if you look at the large group of patients [in this trial], their QOL has been maintained for a longer time with nivolumab plus ipilimumab [vs lenvatinib or sorafenib].

Based on this approval, where does nivolumab plus ipilimumab fit into the HCC treatment paradigm?

It has its place in the frontline setting as a potent regimen for advanced HCC because of its prolonged disease control, survival benefit, high response rate, and rapid time to response. It may also have a role in patients who need a good response, and [may be used to bridge patients to] resection or curative treatment options. The combination has set a higher bar for future phase 3 studies that test novel therapeutics in this disease.

References

1. FDA approves nivolumab with ipilimumab for unresectable or metastatic hepatocellular carcinoma. FDA. April 11, 2025. Accessed April 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-ipilimumab-unresectable-or-metastatic-hepatocellular-carcinoma
2. Galle PR, Decaens T, Kudo M, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line treatment for unresectable hepatocellular carcinoma (uHCC): first results from CheckMate 9DW. J Clin Oncol. 2024;42(suppl 17):LBA4008. doi:10.1200/JCO.2024.42.17_suppl.LBA4008