Akce Gives Insights on How Immunotherapy is Changing the HCC Treatment Landscape

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As June is Cancer Immunotherapy Month, Mehmet Akce, MD, discusses the future of immunotherapy in HCC in an interview with Targeted Oncology.

Immunotherapy has begun to shift the hepatocellular carcinoma (HCC) treatment landscape in both the first and later lines setting.

Numerous studies are currently investigating immunotherapy combinations for the treatment of patients with HCC. For example, the IMbrave 150 study (NCT03434379) compared the efficacy of atezolizumab (Tecentriq) and bevacizumab (Avastin) against sorafenib (Nexavar) in the first-line setting. It revealed that combination had superior overall survival, objective response rate (ORR), and progression-free survival (PFS).1

Single agent PD-1 inhibitors have also achieved between and 15% and 20% ORR. However, more research is needed to better identify which patients can derive benefit from immunotherapy-based treatment approaches. Currently, there is no biomarker to identify these patients.

As June is Cancer Immunotherapy Month, Mehmet Akce, MD, an assistant professor in the Department of Hematology and Medical Oncology at the Winship Cancer Institute of Emory University and a member of the Association of Community Cancer Centers, discusses the future of immunotherapy in HCC in an interview with Targeted Oncology.

TARGETED ONCOLOGY: Can you discuss the evolution of immunotherapy in the treatment of HCC?

AKCE: Immune checkpoints are expressed on the lymphocytes to prevent their over activation and the cancer cells usually take advantage of this physiological mechanism to create a favorable environment for themselves, prevent the activation of the T lymphocytes, which results in immune evasion. Immune checkpoint inhibitors are monoclonal antibodies that are developed to block the interaction of the immune checkpoints with their ligands on the tumor cells. This approach has revolutionized the cancer treatment in several different malignancies and that includes HCC. As single agent or combined with other agents, immune checkpoint inhibitor-based therapy has emerged as a new systemic therapy approach in advanced HCC.

When is immunotherapy used for this setting? What are the data for the different lines of therapy?

In advanced HCC, we have evidence for the first line treatment as well as second line treatment. For example, the immunotherapy-based treatment atezolizumab and bevacizumab combination was studied in the IMbrave150 study in a 2:1 randomization against sorafenib in previously untreated advanced HCC. This study has achieved superior overall survival (OS) and PFS with atezolizumab and bevacizumab compared with single-agent sorafenib.1 Therefore, it became one of the first line treatment options for advanced HCC.2 This is one of the best available first line immunotherapy-based systemic therapies in advanced HCC.

Other checkpoint inhibitors as a single agent anti-PD antibody or in combination other agents such as anti–CTLA-4 antibody are also used in HCC, but mostly in the second line. Initially single-agent nivolumab (Opdivo) was studied in a phase 1b study in advanced HCC where it achieved about a 15% to 20% ORR and based on that, it was approved as a second line treatment in advanced HCC afterprior sorafenib treatment.3 This particular trial had patients with prior sorafenib versus no sorafenib, sorafenib progressors or intolerant patients, and the response rates were not dependent on either the etiology or the prior sorafenib exposure.

Anti-PD-1 inhibitor pembrolizumab (Keytruda) was also studied in HCC after prior sorafenib in a different trial. KEYNOTE 224 (NCT02702414) was a phase 2 trial with single-agent pembrolizumab in 104 patients with advanced HCC post sorafenib, and 80% of the patients were sorafenib progressors and 20% of them were sorafenib intolerant. The design of the trial was slightly different because it excluded patients with main portal invasion, as opposed to CheckMate 040 (NCT01658878) [of nivolumab]. But this study also achieved 17% ORR and it was also approved in patients with prior sorafenib experience in advanced HCC.4

I should note that later, 2 separate single agent immunotherapy trials with these 2 agents in different settings revealed negative results. For example, nivolumab was studied in a first line setting compared with sorafenib and it did not meet the primary end point of OS.5 There were patients who derived benefit in certain subgroup of patients certainly with prolonged survival, but ultimately it did not really meet the primary end point of the trial. Several patients likely received multiple different therapies beyond progression on those clinical trials and other treatments became available, this may have impacted the results.

In KEYNOTE-240 trial pembrolizumab was studied compared with placebo in the second line setting. This trial also did not meet the primary end points of OS and PFS.6 But the response rates were still in the range of 15% to 20%. There were patients who derived benefit, certainly, and there were patients who received pembrolizumab and lived much longer. These trial results may also be impacted with the subsequent treatments that the patients had received. But ultimately, it was a negative study as well. This really suggests that there are populations of patients with HCC who would be inclined to benefit from immunotherapy more compared with others.

Unfortunately, so far, we do not have any biomarkers to predict who will benefit from these therapies. That is an intense area of research. As we know more about patients who would benefit from immunotherapy-based treatments, I think we would be able to choose those patients in a better way so that we can channel the patients to immunotherapy-based treatment approaches more efficiently.

In multicohort Checkmate-040 trial, nivolumab and ipilimumab (Yervoy), a PD-1 and CTLA-4 antibody combination was studied in advanced HCC patients with prior sorafenib exposure.7 This trial included 148 patients with 3 different arms in different dosages of both ipilimumab and nivolumab. For all treated patients, the ORR ranged between27% to 32% by investigator assessment. The responses were independent of etiology, tumor cell PD-L1 expression, or alpha fetoprotein levels. The first arm of the study looked into nivolumab 1 mg/kg, plus ipilimumab 3 mg/kg every 3 weeks for a total of 4 doses and then continued with single-agent nivolumab every 4 weeks was approved based on this study's results.8 This approval is for patients who had prior sorafenib. I should note that none of those treatment approaches were studied in patients who had prior atezolizumab and bevacizumab, which is a first line approved immunotherapy-based treatment. Therefore, the sequencing of immunotherapy-based approaches is challenging, and we definitely need more clinical trial data to answer this crucial question.

Which ongoing clinical trials of immunotherapy for HCC look promising?

We know that single agent immune checkpoint inhibitors achieve about a 15% to 20% ORR in HCC. The HCC tumor microenvironment is an immuno-suppressed tumor microenvironment. This is mostly driven by VEGF pathway and other components of the tumor microenvironment like tumor-associated macrophages, regulatory T cells, myeloid derived suppressor cells, and dendritic cells may contribute to immunosuppressed tumor microenvironment. There are strategies to overcome this immune suppressed tumor microenvironment and we know that several of the already approved multi-kinase inhibitors in advanced HCC have immunomodulatory effects. These agents in combination with checkpoint inhibitors have promising results so far in smaller studies.

For example, one these combination approaches is lenvatinib (Lenvima) plus pembrolizumab, a multi-kinase inhibitor and PD-1 inhibitor, which was studied in the first line setting in a phase 2 study of 104 patients and that achieved a 36% ORR with an 88% disease control rate.9

Lenvatinib and pembrolizumab versus lenvatinib plus placebo was recently studied in a phase 3 trial, LEAP-002 (NCT03713593), and the results of this study, study, are awaited.

There are also other PD-1 and CTLA-4 inhibitor combinations such as durvalumab (Imfinzi) and tremelimumab, which was studied in the second line and achieved 25% ORR and 57.5% disease control rate (NCT02519348). The same combination is being studied in the phase 3 HIMALAYA trial (NCT03298451), which compares durvalumab with and without tremelimumab versus sorafenib in the first line setting.

The COSMIC-312 (NCT03755791) trial compares cabozantinib (Cabometyx) plus atezolizumab versus sorafenib versus cabozantinib) in the first line setting.

Another phase 3 trial with CheckMate 9DW (NCT04039607) is comparing nivolumab and ipilimumab versus sorafenib or lenvatinib in the first line setting of advanced HCC. These are, I think, crucial phase 3 trials which will redesign the landscape of the treatment in the first line setting and beyond in advanced HCC. Much of those trials have already finished accrual and we are waiting for results.

How is immunotherapy filling unmet needs for HCC and what still need to be explored?

Fifteen percent to 20% of the patients derive benefit from single agent immunotherapy approaches with checkpoint inhibitors and about 30% would benefit from combination approaches either with another checkpoint inhibitor such as CTLA-4 antibody or a VEGF pathway inhibitor like bevacizumab. This already provides good response and disease control rate in a disease where we did not have a lot of systemic therapy options. But certainly, these can be improved significantly by identifying biomarkers, designing clinical trials in patients with immunotherapy resistant HCC, and special HCC subgroups such as patients with Child Pugh Class B or recurrent HCC post-transplant. Almost all of the trials I mentioned excluded patients with prior liver transplant and were studied in patients with good liver function and Child Pugh Class A except a separate arm of CheckMate 040 trial which enrolled patients with Child Pugh B 7 and 8 and reported a modest response rate.10 But in clinical practice, we see a significant number of patients with more advanced liver dysfunction. So, we need more clinical trial data to support the use of these potentially highly active agents for advanced liver dysfunction and Child Pugh Class B. Lastly, there's also recurrent HCC after transplant, and we need to investigate how to incorporate novel therapies in this small patient population where we need established therapies. These are some of the special subgroups of patients where we should seek for answers in advanced HCC management.


1. Finn RS, Qin S, Ikeda M, et al; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745

2. FDA approves atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma. FDA. Updated June 1, 2020. Accessed June 23, 2021. https://bit.ly/2SjMv3m

3. FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib. FDA. Updated September 25, 2017. Accessed June 23, 2021. https://bit.ly/3wQnD2j

4. FDA grants accelerated approval to pembrolizumab for hepatocellular carcinoma. FDA. Updated December 14, 2018. Accessed June 23, 2021. https://bit.ly/3gPNNfT

5. Yau T, Park JW, Finn RS, et al. CheckMate-459: a randomized, multi-center phase 3 study of nivolumab (nivo) vs sorafenib (sor) as first-line (1l) treatment in patients (pts) with advanced hepatocellular carcinoma (ahcc). Ann Oncol. 2019;30(suppl 5):v851-v934. doi:10.1093/annonc/mdz394

6. Finn RS, Ryoo BY, Merle P, et al; KEYNOTE-240 investigators. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J Clin Oncol. 2020;38(3):193-202. doi:10.1200/JCO.19.01307

7. Yau T, Kang Y, Kim T, et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial. JAMA Oncol. 2020;6(11):e204564. doi:10.1001/jamaoncol.2020.4564

8. FDA grants accelerated approval to nivolumab and ipilimumab combination for hepatocellular carcinoma. FDA. Updated March 11, 2020. Accessed June 23, 2021. https://bit.ly/3zQv1N1

9. Finn RS. Ikeda M, Zhu AX, et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J Clin Oncol. 2020;38(26):2960-2970. doi:10.1200/JCO.20.00808

10. Kudo M, Matilla A, Santoro A, et al. CheckMate 040 cohort 5: a phase I/II study of nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B cirrhosis. J hepatol. 2021. Published online May 30, 2021. doi:10.1016/j.jhep.2021.04.047