Tislelizumab Pushes HCC Field Forward With 2024 NCCN Guideline Category 1 Recommendation

Alan P. Venook, MD

Identifying a biomarker to predict which patients with hepatocellular carcinoma (HCC) are most likely to respond to checkpoint inhibitor therapy is a necessary next step in the field especially as the addition of tislelizumab-jsgr (Tevimbra) to the NCCN Clinical Practice Guidelines in Oncology for HCC as a category 1 other recommended regimen provided another checkpoint inhibitor option, according to Alan P. Venook, MD.

“[Within gastrointestinal cancers], the changes have mostly been in HCC, and the evolution of different combinations of biologics and immunotherapies have made their way to the top of the heap,” Venook, a member of the HCC NCCN guideline panel, said of the 2024 guideline changes in an interview with OncLive®. “I can’t emphasize enough how these are living documents and how rapidly they can change. Our goal is to stay on top of it and stay ahead.”

The Most Notable 2024 NCCN Guideline Revisions in HCC:¹

• For first-line systemic therapy:
  • Tislelizumab was added under other recommended regimens (category 1)
  • Repotrectinib (Augtyro) was added under useful in certain circumstances (category 2B) for NTRK gene-fusion positive tumors
  • Nivolumab (Opdivo), atezolizumab (Tecentriq) plus bevacizumab (Avastin), and nivolumab plus ipilimumab (Yervoy; for tumor mutational burden high tumors) were removed from useful in certain circumstances regimens
• For subsequent-line systemic therapy if disease progression occurred:
  • Nivolumab plus ipilimumab (for tumor mutational burden-high tumors) was removed from useful in certain circumstances regimens
• Treatment top pathways were revised to:
  • Resection (preferred)
  • Transplant (preferred if transplant criteria are met)
    • Refer to liver transplant center and bridge therapy as indicated
  • Locoregional therapy
    • Ablation (preferred)
• The following new sections were added: Principles of Mixed HCC-CCA, Principles of Pathology, and Principles of Liver Functional Assessment

In the interview, Venook highlighted notable NCCN guideline updates in HCC from 2024 as well as next steps in the field, and considerations when implementing the changes into practice. He is the Madden Family Distinguished Professorship in Medical Oncology and Translational Research at UCSF, the Shorenstein Associate Director for Program Development at the Helen Diller Family Comprehensive Cancer Center, and a professor in the Department of Medicine at UCSF in San Francisco, California.

Venook also provided insights on NCCN guideline updates in colon, rectal, and biliary tract cancers in a concurrent article. He is chair of the Colon Cancer and Rectal Cancer NCCN Guidelines and a member of the Biliary Tract Cancer NCCN Guideline panel.

OncLive: What 2024 HCC NCCN guideline updates have had an immediate influence on how you practice?

Venook: There are a series of studies that have been [conducted] in HCC, [and] we just met [to discuss] them. HCC is evolving so rapidly. Our meeting [on the guidelines] will be [released via additional updates] in 2025, but in terms of the newest publicly released version, the main [update] is that we’ve added tislelizumab as a category 1 recommendation for [other recommended regimens as] first-line systemic therapy. That [is from] a study that examined tislelizumab compared with sorafenib [Nexavar] in patients [with unresectable HCC], and it showed an advantage in [objective response rate] with tislelizumab.

What we don’t know is [if] one of these different checkpoint inhibitors, these immunotherapies, is any different from the other. We have a bunch of [similar] studies, and I’m not sure that these are huge advances. What it amounts to in HCC is we have a number of agents that are approved or in the NCCN guidelines for first-line management. Distinguishing one from the other is impossible and it is likely that these [agents] will never be compared head-to-head because they are [manufactured by] different companies that have the indication from different study designs and it’s not clear that they want to put their drugs up against each other.

The interesting finding in HCC is we’ve gone from years where there were no changes in the guidelines to now a very robust set of recommendations that include numbers of drugs that are recommended. The missing piece for the HCC field globally is still that all these studies are highly selective for patients with reasonably good liver function, so I’m not clear that these changes are dramatic in terms of offering options for many patients, and it is a [situation where there are similar available] drugs for some patients.

Are there any other notable guideline advancements in HCC?

If you go back over the past couple of years, it’s worth discussing how much has changed in HCC. We’ve added checkpoint inhibitors and immunotherapies, but we also have a range of combinations that are moving the bar a bit further along. The key for HCC is [determining] a biomarker to predict who’s going to respond to checkpoint inhibitors because it turns out that these patients do not have MSI-H [disease]. Typically, they don’t have high tumor mutational burden, and yet some respond, but others don’t.

The flaw in the studies with HCC has been that they typically [examined] median survival outcomes [and] it’s not clear that these treatments make a difference because many patients get no benefit at all. You have to look for the subset of patients who benefit, and make sure your end points assess that landmark percentage of patients without progression at a certain period of time.

What is key to note for community oncologists who are adapting to the recent guideline changes?

The key is you have to always download the new versions. The amazing thing about the guidelines is that they’re living documents, and we update them regularly. If you have a version on your desktop that’s even a few months old, there may very well be changes. For example, we met last week about hepatobiliary cancer and a few weeks ago we had a call about colorectal cancer trying to incorporate changes from the 2024 ESMO Congress [into the guidelines].

The most important thing is [staying current]; it’s very challenging, but the NCCN works hard to keep these guidelines timely and up to date. Practitioners need to know that they should check on the latest version because there may be news.

The other thing to know is that we try to steer away from very rare [situations]. For example, there are some drugs targeting the NTRK mutation, and [repotrectinib] is approved for any cancer with this particular fusion. To our knowledge, there has never been a case of HCC that’s had one, even though [repotrectinib] is technically approved in that setting. There are some treatments that are approved agnostic to the disease and based on the molecular features, but in the guidelines, we try to steer clear of [high-level recommendations] if there’s no evidence that these [mutations] exist, let alone experience that these [targeted therapies] work [for a specific tumor type].

Reference

1. NCCN. Clinical Practice Guidelines in Oncology. Hepatocellular carcinoma, version 3.2024. Accessed November 18, 2024. https://www.nccn.org/professionals/physician_gls/pdf/hcc.pdf