Immunotherapy Combos Emerging in HCC Armamentarium

Ghassan K. Abou-Alfa, MD

The treatment arsenal for advanced hepatocellular carcinoma (HCC) is expected to become more robust with PD-1/PD-L1 inhibitor—based combination therapies, according to Ghassan K. Abou-Alfa, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center.

“[We’ve seen incredible progress] in liver cancer over the past few years, which is great for patients,” said Abou-Alfa. “We started with sorafenib (Nexavar) about 10 years ago, and now we have 7 approved drugs. On top of that, we have more [promising agents and combinations in the pipeline].”

For example, the combination of bevacizumab (Avastin) and atezolizumab (Tecentriq), which was evaluated in patients with newly diagnosed, unresectable HCC in the phase III IMbrave150 trial, reduced the risk of death versus sorafenib by 42% (HR, 0.58; 95% CI, 0.42-0.79; P = .0006) and led to a 41% reduction in the risk of disease progression or death (HR, 0.59; 95% CI, 0.47-0.76; P <.0001).¹ In January 2020, a supplemental biologics license application was submitted to the FDA for the combination as a treatment for patients with unresectable HCC who have not received prior systemic therapy.

Additionally, in January 2020, the combination of durvalumab (Imfinzi) and tremelimumab received an orphan drug designation from the FDA for the treatment of patients with HCC. The combination is under investigation in the phase III HIMALAYA trial (NCT03298451) in patients with unresectable, advanced HCC who have not received prior systemic therapy and who are ineligible for locoregional therapy.²

Furthermore, in June 2019, the FDA granted a breakthrough therapy designation to the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) for the frontline treatment of patients with unresectable HCC that is not amenable to locoregional therapy. The designation was granted based on data from the phase Ib KEYNOTE-524/Study 116 trial, in which the combination led to an objective response rate of 36.7%, based on both investigator assessment and independent review.³ The combination is currently being investigated in the phase III LEAP-002 trial (NCT03713593), in which lenvatinib will serve as the control arm.

“As we add more assets, we’ll have to fine-tune which patients will achieve the most benefit from a certain therapy,” said Abou-Alfa.

In an interview during the 2020 OncLive^® State of the Science Summit^™ on Gastrointestinal Malignancies, Abou-Alfa discussed the treatment options that have emerged in advanced HCC and the work being done to determine optimal sequencing strategies.

OncLive: Could you discuss the progress that has been made in liver cancer in recent years?

Abou-Alfa: [The treatment landscape] is getting very crowded. At the State of the Science Summit^™, we discussed the new drugs and the data supporting their use. The biggest question is how to sequence these drugs. Sorafenib and lenvatinib are first-line options. In the second-line setting, we have regorafenib (Stivarga), which is conditional on prior sorafenib exposure, cabozantinib (Cabometyx), and ramucirumab (Cyramza), which requires high alpha-fetoprotein (AFP). In addition, we have nivolumab (Opdivo) and pembrolizumab as immunotherapy options. Pembrolizumab and nivolumab have been evaluated as single agents in the first- and second-line settings. Nivolumab was compared with sorafenib in the first-line setting, and pembrolizumab was compared with placebo in the second-line setting. Both studies were negative.

Now, we’re evaluating combination therapies. For example, at the 2019 ESMO Asia Congress, we saw great results with bevacizumab and atezolizumab, a combination of antiangiogenic therapy and anti—PD-L1 therapy. We saw an incredible improvement in survival and great responses [with that combination]. We’re waiting for the manuscript [of the results]. On top of that, we have data for the combination of the TKI lenvatinib plus the anti–PD-1 therapy pembrolizumab. We’re just waiting for the phase III results. The third combination that we are very interested in is that of a PD-L1 inhibitor plus a CTLA-4 inhibitor, such as durvalumab plus tremelimumab, which is under investigation in the phase III HIMALAYA trial. We’re still waiting for the results of that study.

How do you decide which patient is best for which regimen?

We could sequence these therapies according to patient preference, tolerance, and adverse events, or we could rely on science to tell us whether a specific option is more beneficial for a patient with a certain demographic or biologic component. Admittedly, we're not there yet. The advent of those combination therapies is bringing everything into the first-line setting. The question is, “Do we squish everything down, or do we keep sorafenib and lenvatinib as first- or second-line options and then move everything to the third-line setting?” We would want to do that because these are beneficial drugs. Why should we take away certain assets that could be valuable for patients?

In the future, we’re going to focus more on [identifying] patients who are going to benefit the most. Although checkpoint inhibitors have a response rate ranging from 20% to 25%, we have to worry about the other 75% of patients who don’t have a response [to this approach]. We have to understand who those 25% of patients are, favor that approach for them, and then define the best approach for the other 75% of patients.

What could the field accomplish by the end of 2020?

I expect that a lot of the combination data will come out and as such, we will have a better understanding [with regard to] sequencing and [personalized] treatment. Of course, we’re looking for a cure, which could be based on some of the approaches we already have on hand. We will still have to look into [other] novel drugs and strategies. [We have evaluated] TKIs and checkpoint inhibitors. We’re working on combination therapies. We have to start looking at the next plan [of attack] because we can’t just keep rotating [drugs] or moving [them around] [haphazardly]. We’re also interested in exploring the use of CAR T-cell therapy in HCC.

Are there any ongoing trials evaluating CAR T-cell therapy?

CAR T-cell therapy is a great opportunity for patients with hematologic malignancies. We’re not there yet in solid tumors. Ongoing efforts [are evaluating CAR T-cell therapy in solid tumors], including in liver cancer. If anything, the challenge, aside from tolerability, is really the antigen. The antigen that makes the most sense to evaluate is AFP, but we would like to dig a little deeper to see where we could go with that.

Should some of these newer agents replace sorafenib as the comparator arm in clinical trials?

Sorafenib was the comparator because it was the only agent we had, and now prior sorafenib exposure is required. Interestingly, studies are using lenvatinib as the comparator arm. The study evaluating the combination of lenvatinib and pembrolizumab is being compared with lenvatinib because it’s a first-line therapy as well. I would say yes, we're going to see more applicable comparators that are more pertinent to the data that we have currently.

References

1. Cheng A-L, S Qin, M Ikeda, et al. IMbrave150: efficacy and safety results from a ph III study evaluating atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (sor) as first treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC). Ann Oncol. 2019;30(suppl 9; abstr LBA3). doi: 10.1093/annonc/mdz446.002.
2. Imfinzi and tremelimumab granted orphan drug designation in the US for liver cancer [news release]. AstraZeneca; January 21, 2020. bit.ly/37g8XwG. Accessed February 10, 2020.
3. Ikeda M, Sung MW, Kudo M, et al. A phase Ib trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC): updated results. Cancer Res. 2019;79(suppl 13; abstr CT061). doi: 10.1158/1538-7445.AM2019-CT061.