Editor’s Note: Primary liver cancer is one of the leading causes of cancer death worldwide, and its treatment strategies have seen significant advancements in recent years. At the recent 2024 Chinese Society of Clinical Oncology (CSCO) Guideline Conference, Professor Xinlei Gong from Jinling Hospital, Nanjing University School of Medicine, delivered an outstanding lecture on the topic of “Updates in Systemic Therapy for Hepatocellular Carcinoma.” “Oncology Frontier” has compiled the main points of his lecture to provide readers with a deeper understanding of the latest advancements in systemic therapy for liver cancer.
Global Epidemiology of Liver Cancer
The latest global cancer statistics reveal that in 2022, over 750,000 people worldwide died from liver cancer, making it the third leading cause of cancer death after lung and colorectal cancer, and the sixth most common cancer diagnosis, with an estimated 865,000 new cases and 758,000 deaths in 2022[1].
Liver cancer is the fourth most common malignant tumor in China and the second leading cause of cancer death, presenting a severe challenge for prevention and control. In 2022, China reported 368,000 new liver cancer cases, accounting for 42.4% of the global new cases, and 317,000 deaths, accounting for 41.7% of global liver cancer deaths. Although the five-year relative survival rate for cancer patients in China increased from 30.9% in 2003-2005 to 40.5% in 2012-2015, the survival rate for liver cancer improved only marginally from 10.1% to 12.1%. To achieve the goal of increasing the five-year survival rate for malignant tumors by 15% as outlined in the “Healthy China 2030” plan, multiple measures must be implemented to improve liver cancer treatment, including enhancing early diagnosis, optimizing treatment protocols, promoting the development of innovative drugs, strengthening multidisciplinary collaboration, and raising public awareness of liver cancer prevention and early screening.
Evolution of CSCO Guidelines
Since 2018, the CSCO guidelines for primary liver cancer have undergone two significant updates, with the 2024 version actively in progress. In 2018, CSCO released its first guidelines for primary liver cancer, supplementing the standards for diagnosis and treatment. The 2020 update introduced several new treatment options in systemic therapy, including various targeted drugs and immunotherapy combinations. The 2022 update emphasized combination therapy with immunotherapy as the main strategy, incorporating more treatments and drugs aligned with Chinese clinical practice and patient needs, reflecting the ongoing evolution towards precision and personalized medicine.
Advances in Systemic Therapy Drugs
In 2007, Sorafenib was approved in the U.S. as the first targeted therapy drug for hepatocellular carcinoma (HCC), marking a milestone in first-line treatment. Over the next decade, China approved the FOLFOX4 chemotherapy regimen as a first-line treatment option. Since 2017, the field of systemic therapy for liver cancer has seen the emergence of new drugs and treatment regimens, including Lenvatinib, Donafenib, Atezolizumab combined with Bevacizumab, Sintilimab combined with a Bevacizumab biosimilar, Camrelizumab combined with Apatinib, Tislelizumab, and more. Additionally, second-line treatments such as Regorafenib, Pembrolizumab, Cabozantinib, Apatinib, Nivolumab combined with Ipilimumab, Ramucirumab, and Tislelizumab have been approved. These advancements have significantly expanded treatment options for patients and highlighted the crucial role of precision and individualized treatment strategies in enhancing HCC treatment outcomes.
Key Clinical Studies
CARES-310 Study
The CARES-310 study, led by Professor Shukui Qin, is a global, multicenter, phase III randomized clinical trial[2]. Published in “The Lancet” in August 2023, this study marked the first time a phase III oncology clinical trial led by Chinese researchers was published in the main issue of “The Lancet” since its inception 200 years ago.
The study evaluated the efficacy and safety of Camrelizumab combined with Rivoceranib as a first-line treatment for unresectable HCC compared to Sorafenib monotherapy. Conducted across 95 research centers in 13 countries/regions, 543 HCC patients were randomly assigned (1:1) to the Camrelizumab + Rivoceranib (C+R) group or the Sorafenib group. The primary endpoints were progression-free survival (PFS) and overall survival (OS) assessed by a blinded independent review committee (BIRC) based on RECIST v1.1 criteria. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), time to progression (TTP), and safety.
Results showed that the C+R group had significantly better median PFS (5.6 vs. 3.7 months; HR 0.52, P<0.0001) and median OS (22.1 vs. 15.2 months; HR 0.62, P<0.0001) compared to the Sorafenib group. Subgroup and post hoc analyses also favored the C+R group in terms of PFS and OS. The C+R group had a higher response rate (mRECIST ORR: 33.1% vs. 10.0%), faster time to response (TTR: 1.9 vs. 3.7 months), and longer duration of response (DoR: 14.8 vs. 9.2 months). Common grade 3 or 4 treatment-related adverse events (TRAEs) in the C+R group included hypertension (38% vs. 15%), hand-foot syndrome (12% vs. 15%), increased AST (17% vs. 5%), and increased ALT (13% vs. 3%).
RATIONALE-301 Study
The RATIONALE-301 study is a global, multicenter, open-label, phase III randomized clinical trial that compared Tislelizumab to Sorafenib as a first-line treatment for unresectable HCC[3]. A total of 674 patients were randomized (1:1) to the Tislelizumab group or the Sorafenib group. The primary endpoint was OS, with secondary endpoints including ORR, PFS, DoR, DCR, clinical benefit rate (CBR), health-related quality of life (HRQoL), and safety.
The study showed that Tislelizumab was non-inferior to Sorafenib in median OS (15.9 vs. 14.1 months; HR 0.85, P=0.0398), with 24-month OS rates of 39.0% vs. 31.8% and 36-month OS rates of 29.2% vs. 20.3%, suggesting a trend towards longer OS with Tislelizumab. Subgroup analysis confirmed consistent OS results with the overall population. Tislelizumab had a higher ORR (14.3% vs. 5.4%) and longer DoR (36.1 vs. 11.0 months). Although Tislelizumab had shorter median PFS (2.1 vs. 3.4 months; HR 1.11), 6-month PFS rate (28.8% vs. 35.8%), and similar 12-month PFS rate (19.0% vs. 18.1%), it showed better 18-month and 24-month PFS rates (18 months: 16.1% vs. 9.5%; 24 months: 13.9% vs. 6.1%). Tislelizumab had lower rates of grade ≥3 TRAEs (22.2% vs. 53.4%) and fewer treatment discontinuations and dose adjustments (discontinuation: 6.2% vs. 10.2%; dose adjustment: 20.1% vs. 57.7%).
HIMALAYA Study
The HIMALAYA study is an international, multicenter, open-label, phase III randomized controlled trial that evaluated the efficacy and safety of the STRIDE regimen (Tremelimumab + Durvalumab) and Durvalumab monotherapy compared to Sorafenib as first-line treatments for unresectable HCC[4]. Patients were randomized to receive the STRIDE regimen (n=393), Durvalumab monotherapy (n=389), or Sorafenib monotherapy (n=389). The study data showed median OS of 16.43, 16.56, and 13.77 months for the STRIDE, Durvalumab, and Sorafenib groups, respectively; the 36-month OS rates were 30.7%, 24.7%, and 20.2%.
The 4-year OS data from the study[5] as of January 23, 2023, reported median follow-up times of 49.12, 48.46, and 47.31 months for the STRIDE, Durvalumab, and Sorafenib groups, respectively. The 4-year OS rate remained high for the STRIDE group at 25.2% compared to 15.1% for the Sorafenib group.
Summary and Outlook
With the widespread use of immune checkpoint inhibitors (ICIs), liver cancer treatment has entered the “immune +” era. Combination therapy models, including immunotherapy combined with targeted therapy and dual immunotherapy, have become the new trend in systemic treatment for liver cancer. However, the field still faces numerous challenges, such as selecting the right patient populations, developing post-resistance treatment strategies, and managing adverse reactions.
Looking ahead, liver cancer treatment will rely on continuous scientific innovation, including the exploration of new-generation ICIs, breakthroughs in liver cancer omics, and the close integration of clinical and basic research. We hope these research outcomes can be rapidly translated into clinical practice to bring more survival benefits to liver cancer patients.
