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Karen M. Winkfield, MD, PhD; Narjust Florez, MD, FASCO; Gilberto de Lima Lopes Junior, MD, MBA, FASCO; Coral Olazagasti, MD; Vonetta M. Williams, MD, PhD

 Fighting Disparities and Saving Lives: An Exploration of Challenges and Solutions in Cancer Care

Jeneth Aquino, DNP, FNP-BC; Beth Sandy, MSN, CRNP, FAPO; Allison M. Walker, ACNP, MSN, MSW, BS

Differentiating Adverse Events for Antibody-Drug Conjugates Across Solid Tumor Management

Benjamin P. Levy, MD; John O. Mascarenhas, MD; Tiffany A. Traina, MD, FASCO; Cathy Eng, MD, FACP, FASCO; John P. Leonard, MD

 42nd Annual CFS: Chemotherapy Foundation Symposium®: Innovative Cancer Therapy for Tomorrow

In season 4, episode 16 of Targeted Talks, Susanne G. Warner, MD, hepatobiliary and pancreas surgeon at the Mayo Clinic in Rochester, Minnesota, discusses the importance of tailoring treatments for patients with liver cancer, taking into account the staging of the cancer.

There are a variety of options available for the treatment of liver cancer, including liver-directed therapies like transplantation, resection, and ablation. Over the past few years imparticularly, the field has seen significant progress with the expanded criteria for surgery and the incorporation of minimally invasive techniques. These advancements have provided patients and clinicans with less invasive, yet effective options.

“I think that we're going to continue to see more [patients] being cured in a less invasive way. I do think we'll see more people treated with some combination of systemic therapy and liver-directed therapy, whether that be surgery or some other form… but I hope we see more people being cured in a less invasive manner,” said Warner.

One of the challenges highlighted by Warner is the need for accurate and consistent surveillance, specifically for patients who are at high-risk and who have underlying liver conditions. She also explains some of the disparities in healthcare access that can make it difficult for patients with liver cancer to recieve the treatments they need.

For community oncologists, Warner discusses the importance of collaboration between high-volume liver centers and specialists, and how the expertise of a variety of experts can better a patient's outcomes. Staying updated with the latest developments in the liver cancer space are crucial to provide patients with the best possible care.

“I think it's important for a surgeon to be involved in every [patient] with liver cancer’s journey at least once. I think there is no substitute for high quality liver-specific imaging, and when in doubt, engage your friendly neighborhood [clinician] who looks at livers a lot,” said Warner.

In season 4, episode 16 of Targeted Talks, Susanne G. Warner, MD,discusses the importance of tailoring treatments for patients with liver cancer, taking into account the staging of the cancer. 

Tailoring Treatments to Better Outcomes in Liver Cancer 

A global, randomized, phase 1b/2 trial is evaluating IO-108 in patients with metastatic and/or unresectable hepatocellular carcinoma.

First Patient Dosed With IO-108 in Phase 1b/2 HCC Trial 

Amezalpat received fast track designation from the FDA for the treatment of patients with hepatocellular carcinoma.

FDA Fast Tracks Amezalpat for HCC Treatment

The CheckMate 9DW study demonstrated the efficacy and manageable safety of first-line nivolumab plus ipilimumab in patients with unresectable hepatocellular carcinoma.

Nivolumab Plus Ipilimumab Improves OS and Response in Frontline uHCC

TACE with camrelizumab and rivoceranib significantly improves PFS in unresectable HCC, per phase 2 CARES-005 study results.

TACE Plus Camrelizumab and Rivoceranib Boosts PFS in Unresectable HCC

The FDA granted orphan drug designation to amezalpat in hepatocellular carcinoma based on phase 1b/2 data showing efficacy and safety with atezolizumab and bevacizumab in frontline treatment.

Amezalpat Gains FDA Orphan Drug Status in HCC

An expert discusses how first-line (1L) systemic therapy for unresectable hepatocellular carcinoma (uHCC) has evolved significantly from sorafenib monotherapy to include combination approaches such as atezolizumab plus bevacizumab, which demonstrated superior outcomes in the IMbrave150 trial. Key challenges include underlying liver dysfunction, heterogeneous tumor biology, and managing adverse events while preserving quality of life. Treatment goals focus on extending survival while maintaining liver function and performance status. The shift toward immunotherapy-based combinations has improved outcomes, though patient selection and sequencing strategies remain important considerations in optimizing first-line treatment decisions in clinical practice.

Recent Advances in Front-Line Systemic Therapy for Advanced uHCC

Video content above is prompted by the following: 

How has the frontline systemic therapy landscape for advanced uHCC evolved (Per NCCN Guidelines)?

Please briefly discuss challenges in advanced uHCC. What are the treatment goals?

How has your clinical practice adapted given 1L approvals in recent years?

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An expert discusses the patient case of a 57-year-old woman diagnosed with advanced unresectable hepatocellular carcinoma. The patient presented with abdominal pain, fatigue, and loss of appetite. She also has a history of Crohn disease, which is being controlled with infliximab. The patient also has a history of variceal bleeding and has been treated with antiviral therapy for chronic hepatitis B virus infection.

A 57-Year-Old Woman Diagnosed with Advanced Unresectable Hepatocellular Carcinoma

The panelist discusses first-line options including atezolizumab plus bevacizumab, lenvatinib, and sorafenib. Second-line treatments include regorafenib, cabozantinib, and ramucirumab. Clinical trials should be prioritized when available.

Initial Treatment Options for Liver-Confined Unresectable HCC

Please briefly review the treatment options for patients with hepatocellular carcinoma (HCC) confined to the liver but unresectable according to NCCN guidelines.

Please discuss standard treatment modalities and share your impressions on the initial treatment approach in this case.

The panelist discusses the case of a 60-year-old man diagnosed with unresectable hepatocellular carcinoma (HCC). The patient has a history of metabolic dysfunction-associated steatohepatitis managed with lifestyle changes and medication. Initially, there was no clinical or radiographic evidence of cirrhosis. The patient recently presented to his gastroenterologist complaining of abdominal pain in the upper right quadrant and fatigue. 

Unresectable HCC with Post-TACE Progression

Please present an overview of the provided case.

Pamela L. Kunz, MD, and the Oncology Brothers provide insights on the EMERALD-1 trial looking at durvalumab and bevacizumab plus TACE.

EMERALD-1: Durvalumab/Bevacizumab Plus TACE in Unresectable HCC

Pamela L. Kunz, MD, and the Oncology Brothers provide insights on the EMERALD-1 trial looking at durvalumab and bevacizumab plus TACE in patients with unresectable, embolization-eligible hepatocellular carcinoma.

Unpacking the EMERALD-1 Treatment Approach for HCC

Riccardo Lencioni, MD, professor in the department of radiology at the University of Pisa School of Medicine in Pisa, Italy, discusses how the new protocol from the phase 3 EMERALD-1 trial (NCT03778957) of durvalumab (Imfinzi), transarterial chemoembolization (TACE), and bevacizumab (Avastin) may be implemented in the community oncology setting for the treatment of hepatocellular carcinoma (HCC).

The randomized, double-blind, placebo-controlled, multicenter phase 3 

 is investigating a combined treatment approach for patients with unresectable hepatocellular carcinoma (HCC) who are eligible for TACE, a a minimally invasive, targeted procedure that aims to block the blood supply to the tumor and deliver chemotherapy directly to it.1 Patients in the study were randomly assigned to 1 of 3 groups. Enrollment in the phase 3 trial was open to patients who had confirmed HCC not amenable to curative therapy, a Child-Pugh score class A to B7, and an ECOG performance status of 0 or 1.

The primary end point of the study is progression-free survival (PFS) in arm A vs arm C by blinded independent radiology review using RECIST v1.1, and secondary end points include PFS for arm B vs arm C, overall survival, health-related quality-of-life measures, and safety. Lencioni presented updated findings from the study at the 

The treatment regimen included 2 different parts. The first part is represented by TACE, which is combined with durvalumab. Then at and upon completion of the TACE cycles, patients were started on the combination of durvalumab and atezolizumab.

Sangro B, Kudo M, Qin S, et al. A phase 3, randomized, double-blind, placebo-controlled study of transarterial chemoembolization combined with durvalumab or durvalumab plus bevacizumab therapy in patients with locoregional hepatocellular carcinoma: EMERALD-1. Ann Oncol.2020;31(suppl 3):S202-S203. doi:10.1016/j.annonc.2020.04.429

Riccardo Lencioni, MD, discusses how the new protocol from the phase 3 EMERALD-1 trial may be implemented in the community oncology setting for the treatment of hepatocellular carcinoma.


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Pierre Gholam, MD, professor at Case Western Reserve University School of Medicine in Cleveland, Ohio, discusses the phase 3 RATIONALE-301 (NCT03412773) study of frontline tislelizumab (BGB-A317) vs sorafenib (Nexavar) for patients with hepatocellular carcinoma (HCC).

The global, phase 3 RATIONALE-301 trial randomized 674 patients to receive tislelizumab, an IgG4 anti-PD-1 monoclonal antibody, or sorafenib, a tyrosine kinase inhibitor. Enrollment was open to patients with treatment-naive HCC who had a Child-Pugh class A, an ECOG performance status of 0 or 1, and no tumor thrombus involving main the trunk of portal vein, inferior vena cava, or clinical evidence of portal hypertension with bleeding varices at screening.

showed noninferiority of tislelizumab compared with sorafenib for overall survival and objective response rate. There were also improvements in tolerability demonstrated.

This study was the comparison of frontline tislelizumab, which is another IgG4 anti-PD-1 monoclonal antibody, to sorafenib. The first-line study aimed to see whether this new agent was non-inferior to sorafenib with the possibility of testing for superiority of the data.

 This study ultimately showed that tislelizumab achieved the 15.9-month median overall survival in the first-line compared with 14.1 months in the sorafenib arm. There were some subset analyses which suggested that tislelizumab may have some differential efficacy in patients older than 65 years, potentially patients with more advanced disease in terms of tumor spread, perhaps patients with hepatitis C infection, and female patients. There was otherwise not a lot of difference in terms of adverse event profile between the 2 arms.

Notably, the progression-free survival was oddly longer for sorafenib at 3.6 months than for a tislelizumab at 2.2 months, a somewhat peculiar finding that I think has yet to be explained. Overall, there were fewer discontinuations and those modifications with tislelizumab as compared [with] sorafenib. If one looked at adverse events leading to death, they were comparable between the 2 arms.

Pierre Gholam, MD, discusses the phase 3 RATIONALE-301 study of frontline tislelizumab vs sorafenib for patients with hepatocellular carcinoma.

Gholam Explores the Phase 3 RATIONALE-301 Study of Sorafenib in HCC

Joan Culpepper-Morgan, MD, chief of gastroenterology at Harlem Hospital in New York City, provides an overview on different treatment approaches for patients with hepatocellular carcinoma (HCC).


In the first-line, treatment options for advanced HCC include lenvatinib (Lenvima) and sorafenib (Nexavar). The combination of atezolizumab (Tecentriq) and bevacizumab (Avastin), as well as durvalumab (Imfinzi) plus tremelimumab (Imjudo), are also some immune checkpoint inhibitors available in this space. In addition, curative intent therapies are also often used for the treatment of patients with HCC.

Further, patients have access to a variety of treatments, including liver-directed therapy, resection, ablation, and surgical intervention. According to Morgan, diagnosing the tumor as early as possible is of the utmost importance when treating this patient population. Because of this need, experts are continuously working to provide new options for patients and are always pushing to grow the treatment landscape of HCC.

 Usually, HCC has been treated, I would call it, anatomically. If we could diagnose the tumor early enough, the patient could get either chemoembolization of the tumor in a particular segment of their liver, meaning that an interventional radiologist could put in a catheter into the artery that feeds the tumor, and actually try to kill the tumor that way with chemotherapy directed at the tumor at that site.


Other ways of, of anatomically attacking the tumor include radiofrequency ablation, [which is] basically a targeted microwave. Just placing that very targeted microwave probe that's frequently done by a surgeon into the tumor is accessible, and also killing the tumor in that spot. Other options have included surgery, just removing that segment of the liver, if it's really evident that it has not spread. When the tumor has spread though, we are looking at more chemotherapy-directed medications that could actually kill the tumor.

Joan Culpepper-Morgan, MD, provides an overview on different treatment approaches for patients with hepatocellular carcinoma.

Discussing Treatment Options for Patients With HCC

Richard S. Finn, MD, professor of Medicine at the Geffen School of Medicine at UCLA in the Department of Medicine, Division of Hematology/Oncology, discusses the next potential regimen to emerge for the frontline treatment of hepatocellular carcinoma (HCC).

In early 2023, Finn presented findings from the SKYSCRAPER-14/IMbrave152 study of the combination of atezolizumb (Tecenriq) plus bevacizumab (Avastin; atezo/bev) vs atezo/bev with tiragolumab (RG6058, MTIG7192A), in which demonstrated the addition of tiragolumab demonstrated improvement in responses.

 The landscape has changed very rapidly for frontline HCC. What the next frontline HCC regimen will be is not known yet. Interesting data is what I presented at ASCO this year atezo/bev in combination with tiragolumab, and anti-TIGIT antibody.

 The data showed an objective response rate in this phase 1 study of over 40% This regimen is now going into phase 3, the SKYSCRAPER-14/IMbrave152 study. This study will look at atezo/bev vs atezo/bev and tiragolumab. If positive, which will take some time to accrue and read out, this might become a new standard of care. Right now, there are no other frontline phase 3 studies going up against atezo/bev.

 Another study we're waiting to see data on in earlier-stage liver cancer is Imbrave050 [NCT04102098]. This study demonstrated that the use of atezo/bev after curative resection for liver cancer, decreased recurrence-free survival. We're waiting for regulatory approval for that regimen for these patients at high-risk disease after surgery.

 But still, there are several other adjuvant studies that we're waiting to see results from, including studies looking at durvalumab and bevacizumab in this population, as well as studies with nivolumab and pembrolizumab. Also, there are important studies in intermediate-stage disease where we have several phase 3 studies waiting to read out about the combination of immunotherapy regimens with chemoembolization. I should also mention the frontline study that we're waiting to read out that has completed enrollment and is the study of ipi/nivo vs sorafenib and /or lenvatinib, and we're waiting for those results.

UCLA professor, Richard S. Finn, MD, discusses the next possible regimen for hepatocellular carcinoma.

What Will Be the Next Frontline Therapy for HCC?

Ghassan K. Abou-Alfa, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, discusses the phase 3 RATIONALE-301 trial (NCT03412773) which evaluated frontline tislelizumab vs sorafenib (Nexavar) in patients with hepatocellular carcinoma (HCC).

In the RATIONALE-301 trial, tislelizumab demonstrated improved health-related quality of life, physical functioning, fatigue, and HCC symptom index when compared with sorafenib. However, the agent did not reduce pain significantly vs sorafenib.

According to Alfa, the findings from this study, as well as those from a phase 3 study (NCT03764293) and the phase 3 LEAP-002 study (NCT03713593), highlight the question as to what the role is of single-agent, anti-PD-1 in regard to HCC.

The third study was another intriguing point for all of us. This is another anti-PD-1, tislelizumab, vs sorafenib in an inferiority study looking for equivalency between the 2, which is fair and an appropriate question as we have seen from other alternative studies like nivolumab [Opdivo] vs sorafenib, pembrolizumab [Keytruda] vs placebo, and recently, the HIMALAYA study [NCT03298451] of durvalumab [Imfinzi] single-agent vs sorafenib, which was looked at also for inferiority. Intriguingly, that study was positive, because it did not show any non-inferiority and it showed a clear non-separation between the 2 arms of the study, bringing up an important point in regard to what is the role of single-agent, anti-PD-1 in regard to HCC.

These are great results, but we have to build the story together. Interestingly, it appears to be that they're not all equal in regard to either single-agent or combination therapies. Number 2, we're getting a sense that some of them are probably better than others. Of course, number 3 is that the dynamics in the field are evolving so fast that even comparisons among studies is not correct, not necessarily fair. On top of this, we now have the combination of camrelizumab [SHR-1210] and rivoceranib [Apatinib] with again, 22 months vs sorafenib. Also, we have the lenvatinib [Lenvima] plus pembrolizumab, which again is a negative study, but close to 22 months as well.

Ghassan K. Abou-Alfa, MD, discusses the phase 3 RATIONALE-301 trial of frontline tislelizumab vs sorafenib in patients with hepatocellular carcinoma.


HCC

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