Lack of Biomarkers Complicates Selection of Immunotherapy in HCC

Advanced hepatocellular carcinoma (HCC) has poor survival outcomes for most patients, but newer combination therapies incorporating immunotherapy have shown promise, particularly for a subset of patients with durable responses. The challenges of interpreting data from the combination trials were discussed in a virtual Case-Based Roundtable event moderated by Mark Yarchoan, MD, associate professor and medical oncologist at Johns Hopkins Hospital in Baltimore, Maryland. Participants discussed their impressions of the most recent dual immunotherapy trial and the difficulty of employing biomarkers such as PD-L1 expression in HCC in particular.

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DISCUSSION QUESTIONS

• What are your impressions of the efficacy outcomes from the CheckMate 9DW trial (NCT04039607)?​
• When comparing nivolumab (Opdivo) plus ipilimumab (Yervoy) to lenvatinib (Lenvima) or sorafenib (Nexavar), what stands out to you?​

Mark Yarchoan, MD: The progression-free survival on next-line therapy, PFS2, was clearly better with nivolumab/ipilimumab than tyrosine kinase inhibitor therapy.¹ It does make you wonder if some of these patients responded later or had continued disease benefit after stopping therapy. What do you think about this?

Husam S. Tarawneh, MD: This means that we probably have to continue the treatment. Many times, we do scans at 9 weeks or 12 weeks, or depending on the patient's symptoms, so we have to stick with the treatment. Give it 1 year or so, as long as the patient is not [experiencing progression] and tolerating the treatment.

Krishnan Rao, MD: It also has implications for sequencing. If your PFS2 is better with the immunotherapy, it would hint at the fact that that's probably a better way to sequence things. There's some action going on in this person with the immunotherapy, in spite of the disease progression, that's benefiting PFS2.

Yarchoan: What are your perceptions of these data? Is this impressive to you based on the patients you've seen?

Bety Ciobanu, MD: It's important we have an overall survival benefit.² It's a little bit unsettling [to have] crossover of the curves in the initial part. I was wondering if there is a way we can select the patients who truly benefit from this regimen, because first of all, they have to survive the initial 12 months or so that these curves are still intertwining. For a young patient who is very motivated, I think it's reasonable to consider this regimen, but how do you how do you approach this in the beginning when the patients may have progression on the immunotherapy, or the immunotherapy may not hold the disease? You're going to be tempted to switch the treatments if the patients do not respond very fast. [Also], a lot of these patients are older, and nivolumab/ipilimumab, especially 3 mg of ipilimumab, may not be tolerated that well.

Yarchoan: The question is comparing nivolumab/ipilimumab with lenvatinib or sorafenib, but…clearly nivolumab/ipilimumab wins. The more interesting question is how this compares with the other contemporary doublets. We're all told not to do cross-trial comparisons, but at some point, we have to pick a regimen for our patient.

Zhineng Jayson Yang, MD: How important is it to complete the 4 doses of ipilimumab? Did the trial look at patients who received 2 doses vs 4 doses? Are the outcomes significantly different?

Yarchoan: We were a part of this trial, and I know there are a whole bunch of secondary analyzes that are planned, but I don't know the answer to that one. I don't think it's been published. I know in melanoma, there are data that [suggest] you generally know if the patient's benefiting or not after 2 doses, but I don't know in this cancer.

Ciobanu: Is there any hint about the PD-L1 expression that can select the patients for this tail of the [survival] curve?

Yarchoan: There has been a lot of work to try to develop biomarkers for immunotherapy in HCC, and the results are pretty underwhelming. PD-L1 has been looked at in virtually every single frontline trial that I can think of. It has never predicted benefit in this tumor type. There were some analyses from the CheckMate 459 study [NCT02576509] of nivolumab vs TKI therapy, and a similar analysis from atezolizumab [Tecentriq] plus bevacizumab [Avastin]. It showed patients who have more CD8 cells in their tumor seem to benefit more from immunotherapy.^3-5

But I would never select one of these frontline therapies based on PD-L1 status and the way that they measure immune infiltration is not something we can do as standard practice. So it's a challenge. There was this [theory] that the patients with Wnt/β-catenin [activation] benefit less from immunotherapy, but that didn't hold up in CheckMate 459, so it's been very challenging. I think we have no real biomarkers, unfortunately.

Ciobanu: We are using combined positive score status in other gastrointestinal cancers. That considers not only the tumors but the immune cells. Is that something that was looked into in HCC to see if that will select better the patients, or was TMB [tumor mutational burden], or anything else?

Yarchoan: TMB has been looked at in other PD-1 trials in HCC. Obviously, it's an important biomarker across cancers, but in HCC, it provides no predictive value at all, and it's unclear why. In fact, in CheckMate 459, there were a couple of patients with mismatch repair deficiency, and they appeared to not respond to nivolumab, which is strange. I don't know what's going on. I do know there's a large correlative analysis that's planned from these samples. It has not been done yet, so I don't think we know for the nivolumab/ipilimumab data.

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DISCLOSURES: Yarchoan reported institutional grant/research support from Bristol-Myers Squibb, Exelixis, Incyte and Genentech; honoraria from Exelixis, AstraZeneca, Replimune, Hepion, Lantheus, Genentech and Incyte; is the co-inventor of a patent related to neoantigen vaccines; and is a co-founder with equity of Adventris Pharmaceuticals. There were no other known relevant disclosures.

REFERENCES:

1. Decaens T, Yau T, Kudo M, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line (1L) treatment for unresectable hepatocellular carcinoma (uHCC): Expanded analyses from CheckMate 9DW. Ann Oncol. 2024;35(suppl 2):S657. doi:10.1016/j.annonc.2024.08.1025

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

3. Yau T, Park JW, Finn RS, et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022;23(1):77-90. doi:10.1016/S1470-2045(21)00604-5

4. Kuwano A, Yada M, Miyazaki Y, et al. Tumor‑infiltrating CD8⁺ T cells as a biomarker for chemotherapy efficacy in unresectable hepatocellular carcinoma. Oncol Lett. 2023;25(6):259. Published 2023 Apr 28. doi:10.3892/ol.2023.13845

5. Yim SY, Lee SH, Baek SW, et al. Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial. Clin Mol Hepatol. 2024;30(4):807-823. doi:10.3350/cmh.2024.0333