Updated Data Confirm Clinical Benefit of Novel Immunotherapy Combos in HCC

Daniel Lin, MD, MS, highlights pivotal trials evaluating immunotherapy regimens in patients with hepatocellular carcinoma, remaining sequencing questions, and emerging regimens that are showing promise.

Findings from the phase 3 IMbrave150 trial (NCT03434379) and phase 1/2 CheckMate-040 (NCT01658878) have served to solidify the role of checkpoint inhibition in hepatocellular carcinoma (HCC), according to Daniel Lin, MD, MS. However, the question of optimal sequencing remains unanswered.

In May 2020, the FDA approved the combination of atezolizumab (Tecentriq) plus bevacizumab (Avastin) for use in patients with unresectable or metastatic HCC who have not previously received systemic treatment. Updated data from IMbrave150, the pivotal trial that supported the decision, showed that the regimen had a median overall survival (OS) of 19.2 months vs 13.4 months with sorafenib (Nexavar; HR, 0.66; 95% CI, 0.52-0.85). The median PFS with the combination versus the single agent was 6.9 months vs 4.3 months, respectively (HR, 0.65; 95% CI, 0.53-0.81).1

The dual immunotherapy combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) received a regulatory approval in March 2020 for use in patients with HCC who had previously received sorafenib based on earlier data from the phase 1/2 CheckMate-040 trial. At a minimum follow-up of 44 months, 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab elicited an objective response rate of approximately 30% and median OS of 22.2 months.2

“We now have this arsenal of tools that we can use to treat patients, but it is a little less clear in terms of whether [a patient who had] prior treatment with a PD-1 [inhibitor is] going to respond to PD-1 plus CTLA-4 inhibition,” Lin said. “We need more data to really answer that question.”

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on Gastrointestinal Malignancies, Lin, a medical oncologist and assistant professor at Sidney Kimmel Cancer Center, Jefferson Health, highlighted pivotal trials evaluating immunotherapy regimens in patients with HCC, remaining sequencing questions, and emerging regimens that are showing promise.

What do the updated results from phase 3 IMbrave150 trial and the phase 1/2 CheckMate-040 indicate about the use of immunotherapy in HCC?

Those 2 trials really solidified the role of checkpoint inhibition in HCC. They hit the mark more than the prior trials that we've seen with frontline nivolumab monotherapy, as well as second-line pembrolizumab [Keytruda]. With IMbrave150, it was pretty clear cut that frontline atezolizumab/bevacizumab was better than sorafenib [Nexavar] in terms of response rates and survival benefit.

Data with the nivolumab/ipilimumab from CheckMate-040 [showed that there is] definitely a role for this combination in the second-line and beyond setting, and certainly good [activity for patients with] Child-Pugh A [disease]. With 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab in particular, we saw a rather significant OS improvement of nearly 2 years, which is kind of unheard of [in this disease]. These 2 trials really solidified the role for the 2 combinations for [patients with] advanced HCC.

With more mature data from IMbrave150, what has been learned about the time to response with the combination?

Data from IMbrave150 [suggested] potentially earlier responses with the combination compared with sorafenib. More notably, the possibility of a response, meaning partial response or complete response, was higher with the combination at around 30%. What we know from most TKIs is that stable disease [is primarily] your best response with much less shrinkage of tumor.

Since the combination in CheckMate-040 was tested in a sorafenib-refractory population, is that combination suitable for patients who progress on atezolizumab/bevacizumab?

This is one of the key unanswered questions. Some smaller cohort studies that have reported out have suggested that in patients who are previously exposed to at least a single-agent PD-1 [inhibitor], that the addition of a CTLA-4 [inhibitor] may help to potentially overcome resistance and still produce a response. We've seen it, to some degree, in other cancer types like melanoma and renal cell cancer. This is an important question to be answered for HCC.

Would you say that the regimen examined in phase 2 Study 22 (NCT02519348) currently has a role in practice?

In practice, not yet. We have also yet to see the final results from the phase 3 HIMALAYA trial, which also looked at that particular combination of durvalumab [Imfinzi] with a single priming dose of tremelimumab in the frontline setting. It could be a relevant combination down the line, but not so much yet in terms of our standard-of-care practice.

Based on what has been reported with that combination so far, how do you think it will stack up with atezolizumab/bevacizumab?

The atezolizumab/bevacizumab outcomes are quite positive, and the tolerability is quite favorable. We also have the other frontline studies that we’re awaiting the data from: LEAP, COSMIC trial with pembrolizumab, lenvatinib, cabozantinib, and atezolizumab. At the end of the day, we really need to see how [these options] stack up against each other, what may be some differences in response, durability of response, and comparisons with toxicity. That will give is an idea of how to best select the optimal frontline option for patients with HCC.


  1. Finn RS, Qin S, Ikeda M, et al. IMbrave150: updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC).
  2. El-Khoueiry AB, Yau T, Kang Y-K, et al. Nivolumab (NIVO) plus ipilimumab (IPI) combination therapy in patients (Pts) with advanced hepatocellular carcinoma (aHCC): long-term results from CheckMate 040. J Clin Oncol. 2021;39(suppl 3):269. doi:10.1200/JCO.2021.39.3_suppl.269