- Currently, there is no clear treatment standard for patients with hepatocellular carcinoma (HCC) after immune checkpoint inhibitor (ICI) failure, making it challenging to determine the optimal second line therapy.
- There is sufficient data to suggest treatments with ipilimumab plus nivolumab as well as cabozantinib, regorafenib, and ramucirumab are appropriate second-line options after treatment with kinase inhibitor sorafenib, but it is difficult for clinicians to determine which is optimal.
- Glypican-3 (GPC3) targeting appears to be a promising area of emerging research for this population of patients, since GPC3 is overexpressed in the membrane of HCC cells.
- When cycling patients through secondary treatment options, clinicians must examine patient reported symptoms, as these are often better clinical guides for how a patient will do with a new therapy than results from quality-of-life (QOL) studies.
From January 19 to January 21, 2023, hematologists and oncologists gathered in San Francisco and virtually for the 20th American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium. This year’s meeting included a wide range of educational sessions, exhibits, and posters discussing the latest research, insights, and innovations in subsequent-line treatment options for HCC with progression.
Laura Goff, MD, hematologic oncologist, associate professor of medicine at Vanderbilt-Ingram Cancer Center (VICC), and executive medical director for the VICC Cancer Patient Care Center, shared her insights from this year’s ASCO Gastrointestinal Cancers Symposium.
What is the current standard course of treatment for patients with HCC with progression after ICI-based treatment? What are the unmet needs given the currently available treatment options?
There is no clear standard treatment after ICIs, as we do not currently have the data to guide us. We would like to know if dual ICI is helpful after atezolizumab plus bevacizumab. Are tyrosine kinase inhibitors (TKIs) active after bevacizumab? What about ramucirumab after bevacizumab? The greatest unmet need is active agents targeting novel pathways.
Can you review the treatment options for HCC previously treated with the kinase inhibitor sorafenib?
Currently, there is data suggesting ipilimumab plus nivolumab is a viable treatment option,1 as well as cabozantinib, regorafeniband, and ramucirumab (for alpha fetoprotein >400).2
Results presented from a phase 2 clinical trial in locally advanced or metastatic HCC (ClinicalTrials.gov identifier: NCT03519997) showed that, with the combination of 2 monoclonal antibodies, pembrolizumab and bavituximab, 32% of participants had a confirmed objective response rate by the Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, indicating promising antitumor activity, and the combination produced a 61% disease control rate.3 If approved, which patients would be considered ideal candidates for this therapy?
This study was performed in a first-line population. Additional data is needed to guide where this regimen would be appropriate. Upfront, double systemic therapy is the standard of care right now, and we may see this combination as a second choice to the STRIDE (Single Tremelimumab Regular Interval Durvalumab) regimen,4 but what I would need to understand is if this combination is the new front-line winner in terms of living longer or markedly improved side effects.
A study presented at ASCO 2023 indicated that treating patients with poor prognosis HCC with a combination of pembrolizumab and Y90 radioembolization reduced time to progression and increased overall survival, warranting investigation in larger randomized clinical trials.5 Based on the current evidence, how could this potential treatment be incorporated into HCC care?
Again, this is not yet ready to be incorporated into clinical care. I would need better evidence to see the survival advantages. Most of our similar combination studies have not been positive to date, so using both together without a controlled study that shows meaningful impacts on specific endpoints like survival is not something we could do in practice. This is a perfect combination to be explored in a clinical study with meaningful, tangible endpoints, such as helping people live longer and feel better, but it has been hard to demonstrate that so far.
A phase 1 study (ClinicalTrials.gov identifier: NCT05003895) is currently exploring the safety and feasibility of targeting the tumor-associated antigen GPC3 through chimeric antigen receptor (CAR) engineered T-cells via dose escalation.6 Can you review the rationale behind GPC3 targeting?
GPC3 is overexpressed in the membrane of HCC cells.7 This represents a way to identify liver cancer cells for targeting by the engineered T-cells.
Results from an investigation studying the use of cabozantinib in patients with HCC following immunotherapy treatment revealed that the therapy yielded a median of 2.1 months progression free survival and 7.7 months overall survival.8 How can clinicians determine the optimal second- or third-line treatments among the emerging options presented at this conference?
This remains an open question in the current environment after immunotherapy combinations. It feels a little bit like an educated guess situation, because I do not have a great guide. I try to get people as much exposure as possible to as many classes of agents as possible and try to see how they do clinically.
Based on evidence presented at ASCO 2023,9 can you review the current role that stereotactic body radiation therapy (SBRT) plays in unresectable HCC?
It may be beneficial in selected patients that we might be able to treat safely using SBRT, because the best data we have currently show a potential benefit for survival, but I want to see additional studies combining SBRT with sorafenib in patients who are not eligible for immunotherapy.
Several abstracts presented at ASCO 2023 assess health-related quality of life (HRQOL) in advanced HCC.10,11 Can you expand on HRQOL as part of outcome-based decision making?
As doctors who care for patients with cancer, we certainly care a lot about QOL and symptom control, but it is difficult to measure. We look at QOL scores being preserved or potentially improving during treatment, and those types of outcomes are helpful in our decision-making when getting a sense of how patients are going to do on a regimen, especially with new therapies. Still, they are tricky studies to execute, and it’s difficult to make a clear, direct correlation based off an individual’s experience, mostly because capturing that experience on a scale is difficult to translate. Currently, we use an individual’s experience to give some sense of whether a new treatment is going to be incredibly difficult; it is useful and important to assess QOL but challenging to do methodically, so we focus a lot on patient-reported symptoms. We find that data on QOL from studies is useful, especially if you do not have a lot of clinical experience with a new regimen. However, over time, our own patients’ experience and their reported symptoms really give us a better sense on how this treatment will truly impact people.
This Q&A was edited for clarity and length.
Laura Goff, MD, reported affiliations with QED Therapeutics, Inc; Genentech, Inc; Merck & Co, Inc; AstraZeneca Pharmaceuticals, LP; Exelixis, Inc; Boehringer Ingelheim Pharmaceuticals Inc; Cardinal Health; Atheneum Partners; Bristol-Myers Squibb Company; Agios Pharmaceuticals, Inc; ASLAN Pharmaceuticals; BeiGene, Ltd; and Basilea Pharmaceutica, Ltd.
1. Yau T, Kang YK, Kim TY, 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
2. Asaoka Y, Tateishi R, Yamada Y, et al. Real world data of systemic therapy for hepatocellular carcinoma in Japan: HERITAGE study. Poster presented at: American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium; January 19-21, 2023; San Francisco, CA. Abstract 510.
3. Hsieh D, Kainthla R, Zhu H, Beg M. Phase 2 trial of pembrolizumab (pembro) and bavituximab (bavi) in advanced hepatocellular carcinoma (HCC). Poster presented at: American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium; January 19-21, 2023; San Francisco, CA. Abstract 584.
4. Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1(8). doi:10.1056/EVIDoa2100070
5. Somasundaram A, Helft P, Harris WP, et al. A study of pembrolizumab (pembro) in combination with Y90 radioembolization in patients (pts) with poor prognosis hepatocellular carcinoma (HCC). Poster presented at: American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium; January 19-21, 2023; San Francisco, CA. Abstract 534.
6. Xie C, Monge CB, Mabry-Hrones D, et al. A phase I study of GPC3 targeted CAR-T cell therapy in advanced GPC3-expressing hepatocellular carcinoma (HCC). Poster presented at: American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium; January 19-21, 2023; San Francisco, CA. Abstract TPS624.
7. Guo M, Zhang H, Zheng J, Liu Y. Glypican-3: a new target for diagnosis and treatment of hepatocellular carcinoma. J Cancer. 2020;11(8):2008-2021. doi:10.7150/jca.39972
8. Palmer ME, Storandt MH, Gile J, et al. Multisite institutional study of efficacy and safety of cabozantinib following immunotherapy in patients with advanced hepatocellular carcinoma. Poster presented at: American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium; January 19-21, 2023; San Francisco, CA. Abstract 559.
9. Dawson LA, Winter KA, Knox JJ, et al. Randomized phase III study of sorafenib vs. stereotactic body radiation therapy (SBRT) followed by sorafenib in hepatocellular carcinoma (HCC). Oral presentation at: American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium; January 19-21, 2023; San Francisco, CA. Abstract 489.
10. Finn RS, Qin S, Kudo M, et al. Tislelizumab versus sorafenib in first-line treatment of unresectable hepatocellular carcinoma: Impact on health-related quality of life in RATIONALE301 population. Abstract presented at: American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium; January 19-21, 2023; San Francisco, CA. Abstract 495.
11. Llovet JM, Kudo M, Merle P, et al. Health-related quality of life (HRQoL) impact of lenvatinib (len) plus pembrolizumab (pembro) versus len plus placebo (pbo) as first-line (1L) therapy for advanced hepatocellular carcinoma (aHCC): phase 3 LEAP-002 study. Poster presented at: American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium; January 19-21, 2023; San Francisco, CA. Abstract 506.
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Reviewed February 2023