To close, Dr. Saeed and Dr. Singal share their excitement for the future landscape, emerging agents and treatment strategies for patients with HCC.

Future Directions in the Management of Hepatocellular Carcinoma

 featuring Anwaar Saeed, MD, and Amit Singal, MD, MS.

In conclusion, Singal and Saeed express excitement over the rapid evolution of treatment options now providing survival benefit across multiple lines of therapy for patients with advanced hepatocellular carcinoma (HCC). This allows consideration of third-line therapy for some patients where none previously existed. Singal notes the phase 3 data demonstrating nearly 25% 4-year overall survival rates truly represents a paradigm shift.

Looking ahead, both physicians are eager to see immunotherapy and targeted therapies moved into earlier settings like the adjuvant and neoadjuvant space, as well as combination therapies for intermediate-stage disease. Equally important is ensuring HCC management utilizes multidisciplinary inputs, as this collaborative approach correlates with better outcomes.

Beyond the perioperative arena, Saeed highlights several other categories of emerging data worth following. These include chimeric antigen receptor T-cell therapy, intratumoral vaccines, bispecific antibodies engaging multiple immune checkpoints, and bridging strategies to transplant. She agrees the future looks bright.

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Drs Saeed and Singal discuss additional data presented at AASLD 2023 related to frontline systemic therapies and emerging combinations in unresectable HCC.

Additional Data Updates from AASLD 2023

Singal discusses an AASLD abstract examining clinical and imaging factors to predict risk of varices in hepatocellular carcinoma (HCC) patients, which can help determine need for pretreatment endoscopy before regimens like atezolizumab-bevacizumab. The model achieved a high negative predictive value, meaning it reliably identified low-risk patients unlikely to have varices. If validated, using it could avoid endoscopy in 50% of HCC cases.

Transitioning to emerging treatments, Saeed reviews phase 2 and phase 3 HCC study data presented at AASLD. A network meta-analysis found the regimens of sintilimab plus a bevacizumab biosimilar and camrelizumab-apatinib offered the best survival hazard ratios, followed by atezolizumab-bevacizumab and durvalumab-tremelimumab, which also showed efficacy vs sorafenib. However, she cautions that regional heterogeneity between trial populations limits head-to-head cross-study comparisons. A separate single-arm phase 2 study of tislelizumab- anlotinib reported encouraging response rate and disease control data, albeit in a trial where a number of patients had hepatitis B–associated HCC, a positive prognostic factor. Mature survival outcomes are still needed.

Expert oncologists review real-world data and discuss the impact on treatment selection in uHCC.

Real-World Data and Impact on Treatment Selection in uHCC

Singal and Saeed emphasize the importance of real-world data to address questions that prospective clinical trials cannot, including head-to-head regimen comparisons and outcomes in patient subgroups excluded from trials. Saeed discusses a small 28-patient study of atezolizumab-bevacizumab showing a median overall survival of 11 months, lower than the 19 months seen in IMbrave150. However, she cautions this early real-world analysis is too limited to draw conclusions against atezolizumab-bevacizumab efficacy and notes the heterogeneity underlying variation.

Singal agrees, highlighting how real-world cohorts often differ substantially from clinical trial populations, which select for high-performance status patients. He references the larger AB-Real study of 430 patients receiving first-line atezolizumab-bevacizumab, which showed a median survival of 15.7 months. While numerically lower, this effectiveness data is not meaningfully inferior to the trial efficacy findings. Reassuringly, safety seems consistent between the clinical trial and real-world utilization. Both physicians feel that atezolizumab-bevacizumab retains compelling efficacy and safety. Looking ahead, analyses of larger real-world cohorts can better define outcomes in excluded subgroups and help guide treatment decisions.

An expert analysis in data surrounding treatment outcomes in combination regimens.

Efficacy and Safety Outcomes in Combination Immunotherapy for uHCC

 featuring Anwaar Saeed, MD; and Amit Singal, MD, MS.

Singal and Saeed discuss the favorable safety profile seen with durvalumab plus tremelimumab in the HIMALAYA trial. The rate of treatment-related adverse events (AEs) is not higher compared to expectations for PD-1/PD-L1 and CTLA-4 combinations. Specifically, about 30% of patients had any-grade immune-related AEs, with 20% requiring high-dose steroids. Importantly, most immune-related AEs occurred within the first 3 months, so the chances of new events decrease during continued therapy for those deriving benefit.

They note durvalumab-tremelimumab avoids the need for VEGF inhibitors and, thus, pretreatment endoscopy to rule out varices, which can be challenging logistically. Singal adds that having even a single episode of an immune-related AE seems to correlate with improved survival outcomes, likely reflecting appropriate immune activation. So these events can be positioned to patients as an indicator that therapy is working, should they opt to continue treatment.

In terms of efficacy comparisons to IMbrave150, the trial populations differed, with more patients with hepatitis B enrolled in IMbrave150. Since this subgroup has better outcomes, it may partially explain the additional 1 month of median survival seen with atezolizumab-bevacizumab. But the impressive 4-year survival rates now reported with durvalumab-tremelimumab reinforce that it represents an equally viable first-line regimen.

An expert analysis in data surrounding treatment outcomes in combination regimens, noting immune-mediate adverse events and overall impact on treatment response.

Dr. Saeed outlines the use of combination tremelimumab plus durvalumab in uHCC, discussing updates from the HIMALAYA trial presented at AASLD 2023.

AASLD 2023 Updates: HIMALAYA Trial for uHCC

Saeed discusses the phase 3 HIMALAYA trial results leading to recent FDA approval of durvalumab plus tremelimumab for unresectable hepatocellular carcinoma (uHCC). This combination regimen was informed by earlier phase 2 data showing improved survival with durvalumab plus tremelimumab over durvalumab alone.

In HIMALAYA, the durvalumab-tremelimumab arm demonstrated statistically significant improvement in median overall survival of 16 months compared with sorafenib, leading to its approval for HCC regardless of line of therapy. Recently presented 4-year overall survival data from HIMALAYA shows unprecedented long-term benefit, with 25% of patients on durvalumab-tremelimumab still alive at 4 years. This is a major improvement over the historical 5-year survival rate of less than 10% seen previously with other therapies.

Saeed notes these impressive long-term survival results set a new benchmark for outcomes with immunotherapy combinations in HCC. It provides confidence in a real survival advantage with this approach that can be conveyed to patients. Overall, he says this durvalumab-tremelimumab regimen represents an important step forward and a foundation to build upon for further progress.

A comprehensive review of clinical data of atezolizumab plus bevacizumab for the treatment of unresectable HCC.

Atezolizumab plus Bevacizumab in the Treatment of Unresectable HCC

Singal and Saeed discuss the IMbrave150 study published in 2020, which led to FDA approval of the combination of atezolizumab plus bevacizumab as a first-line treatment for unresectable hepatocellular carcinoma (HCC). This regimen showed superior progression-free and overall survival compared to sorafenib, along with higher response rates. It was also well tolerated, albeit with a requirement for pretreatment upper endoscopy due to the bleeding risk with bevacizumab. Unfortunately, there are no clear predictive biomarkers to select patients most likely to benefit from atezolizumab-bevacizumab.

 examined changes in alpha fetoprotein (AFP) levels over time as a potential prognostic marker for patients on atezolizumab-bevacizumab. Those with rising AFP trajectories had worse outcomes compared to those with decreasing AFP levels. In practice, Singal finds AFP trends informative but still relies primarily on imaging to determine response and guide treatment decisions. Saeed agrees more validation is needed to define how best to incorporate AFP kinetics into clinical decision-making, both for first-line atezolizumab-bevacizumab as well as for other regimens when determining sequencing strategies. She suggests analyzing AFP data from other trials like HIMALAYA to further explore its potential prognostic utility. Ultimately, having molecular markers and biomarkers beyond just AFP will be crucial to guide therapy selection and sequencing in HCC.

Anwaar Saeed, MD, and Amit Singal, MD, discuss the evolving treatment landscape for hepatocellular carcinoma, highlighting FDA approvals and biomarkers.

The Evolving Landscape of Hepatocellular Carcinoma

The video opens with Saeed and Singal welcoming viewers to the program on advances in treatment for patients with unresectable hepatocellular carcinoma (HCC). They note this is an exciting time for drug development in this disease, with recent approvals of targeted therapies and immunotherapies leading to major improvements in outcomes over the past 3 to 5 years.

Singal then outlines the evolution of the HCC treatment landscape, recalling how a decade ago, sorafenib was the only available first-line systemic therapy option, with a median survival of around 11 months. It took 10 years for the next first-line drug, lenvatinib, to be approved, offering similar survival but higher response rates and longer progression-free survival compared to sorafenib. Just a couple years ago, immunotherapy entered the first-line setting with approval of the combination of atezolizumab plus bevacizumab. This regimen demonstrated the first survival benefit over sorafenib in phase 3 testing. Most recently, the combination of durvalumab plus tremelimumab was also approved upfront after showing superior survival and response rates vs sorafenib.

Beyond the first-line setting, Singal notes there is excitement about testing these newer regimens even earlier, including in the adjuvant setting after resection/ablation and in combination with transarterial chemoembolization for patients with localized disease.

Anwaar Saeed, MD, and Amit Singal, MD, discuss the evolving treatment landscape for hepatocellular carcinoma, highlighting FDA approvals and the utility of clinical biomarkers.

Anwaar Saeed, MD, associate professor, medicine, chief, Gastrointestinal Medical Oncology, University of Pittsburgh Medical Center, discusses biomarkers that signal the potential efficacy of frontline immunotherapy regimens in patients with advanced esophageal squamous cell carcinoma (ESCC).

The tissue-agnostic biomarkers microsatellite instability (MSI)–high disease and mismatch repair deficiency (dMMR) should be tested for in every solid tumor type and can also drive first-line treatment approaches in ESCC, Saeed says. If patients have these biomarkers, they can receive standard-of-care chemotherapy with either nivolumab (Opdivo), per the phase 3 CheckMate 648 trial (NCT03143153), or pembrolizumab (Keytruda), per the phase 3 KEYNOTE-590 trial (NCT03189719), Saeed explains. In CheckMate 648, patients with advanced ESCC were randomized 1:1:1 to receive nivolumab plus chemotherapy, nivolumab plus ipilimumab (Yervoy), or chemotherapy alone. The patients in the nivolumab/chemotherapy arm achieved a median overall survival (OS) of 13.2 months vs 10.7 months in the chemotherapy alone arm. In KEYNOTE-590, patients with advanced ESCC were randomized 1:1 to either pembrolizumab plus chemotherapy or placebo plus chemotherapy. In this trial, patients who received pembrolizumab achieved a median OS of 12.6 months vs 9.8 months with placebo.

Additionally, with the May 2022 FDA approval of ipilimumab plus nivolumab for patients with ESCC, this chemotherapy-free regimen is another potential frontline treatment option. This approval was based on additional findings from CheckMate 648, in which the patients who received nivolumab plus ipilimumab achieved a median OS of 12.7 months vs 10.7 months in those who received chemotherapy alone.

PD-L1 expression is another relevant biomarker in ESCC and other upper gastrointestinal cancers and should be tested for in all patients regardless of their histology, Saeed notes. If patients have high PD-L1 expression, they should receive chemotherapy with either pembrolizumab or nivolumab, Saeed says.

Patients with ESCC can also be tested for tumor mutational burden (TMB), although most patients with MSI-high disease will also have high TMB, Saeed explains. The definition of high TMB for every disease type, including ESCC, is still unclear, Saeed notes. However, patients with higher TMB along with high PD-L1 expression may benefit most from the use of immunotherapy regimens, Saeed concludes.

Anwaar Saeed, MD, discusses biomarkers that signal the potential efficacy of frontline immunotherapy regimens in patients with advanced esophageal squamous cell carcinoma.

Anwaar Saeed, MD

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