Editor's Note: China has a high incidence of liver cancer, with most patients being diagnosed at an advanced stage, losing the opportunity for surgical cure. Currently, the treatment for advanced hepatocellular carcinoma (HCC) has transitioned from systemic chemotherapy to targeted therapy, immunotherapy, and combination therapy, offering better survival benefits for liver cancer patients. The "2024 Annual Progress Seminar on Chinese Clinical Oncology (BOC) and Best of ASCO 2024 China" was held in Guangzhou from July 5 to 7, 2024. At the conference, Professor Chen Xun from Nanjing Tianyinshan Hospital shared the latest results of the CheckMate 9DW study. After the conference, Oncology Frontier invited Professor Chen Xun for an in-depth analysis of the study's value for advanced liver cancer patients and to share optimized second-line treatment options.
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Oncology Frontier: Could you briefly summarize the main findings of the CheckMate 9DW study? What advantages does this combination therapy have over lenvatinib or sorafenib?
Professor Chen Xun: The CheckMate 9DW study is the only liver cancer clinical research included in the latest breakthrough abstracts (LBA) oral presentations at this year’s ASCO conference. This international multicenter, randomized controlled phase III clinical trial compared nivolumab combined with ipilimumab to lenvatinib and sorafenib as first-line treatments for advanced liver cancer. The study enrolled liver cancer patients from multiple countries, with 27 centers in China participating. A total of 668 patients were included, randomized 1:1 into the nivolumab plus ipilimumab group (335 patients) or the TKI group (333 patients), with 85% of the TKI group receiving lenvatinib. The primary endpoint was OS, with secondary endpoints including ORR, DoR, and time to symptomatic deterioration (TTSD), and exploratory endpoints of PFS and safety.
The baseline characteristics of the study population were balanced. About one-third of the patients had HBV infection, and approximately three-quarters were in BCLC stage C, indicating advanced liver cancer. The median OS for the nivolumab plus ipilimumab group was 23.7 months (versus 20.6 months for the control group, HR=0.79, P=0.018). As time progressed, the survival curves of the two groups diverged more significantly, with the 2-year OS rate in the treatment group approaching 50% (compared to 39% in the control group).
Although there was no statistical difference in PFS between the two groups, the PFS curves crossed at 9 months and continued to diverge, with the 18-month and 24-month PFS rates being significantly higher in the nivolumab plus ipilimumab group than in the control group.
Previous CheckMate 040 studies showed an ORR of 32% with nivolumab plus ipilimumab, while the CheckMate 9DW study reported an ORR as high as 36%, the highest value in phase III liver cancer studies to date. The DoR for the nivolumab plus ipilimumab group was also high at 30.4 months (compared to 12.9 months in the control group), setting a new record for the duration of response in liver cancer treatment.
In terms of adverse effects, the incidence of treatment-related adverse events (TRAEs) was similar between the two groups. However, serious adverse events (SAEs) appeared to be numerically higher in the nivolumab plus ipilimumab group, particularly liver-related adverse events. The time to symptomatic deterioration favored the nivolumab plus ipilimumab group (2.6 months vs. 2.1 months, P=0.0059), and there was a descriptive improvement in quality of life for patients in this group.
This study has several highlights. Firstly, the treatment efficacy is high, with a 36% ORR, the highest in phase III liver cancer studies. More importantly, this effective ORR translated into improved OS, achieving the primary endpoint. Many patients in the control group received subsequent immunotherapy, highlighting the substantial contribution of dual immunotherapy to overall OS. Secondly, dual immunotherapy provided sustained immune responses, with increasing differences in OS and PFS over time, potentially offering longer-term benefits to patients. The DoR in this study also broke the 30-month barrier for the first time. These survival results from dual immunotherapy are impressive.
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Oncology Frontier: How were the side effects and safety of nivolumab combined with ipilimumab in the CheckMate 9DW study? What clinical aspects need special attention?
Professor Chen Xun: In the earlier phase II CheckMate 040 cohort 4 study, the overall incidence of immune-mediated adverse events (IMAEs) with nivolumab plus ipilimumab was high, with a significant rate of grade 3-4 immune-related adverse events. Although this regimen received conditional approval from the US FDA for patients with advanced liver cancer who had failed prior sorafenib treatment, clinicians remained cautious. In the CheckMate 9DW study presented at ASCO, the overall incidence of IMAEs was 58%, significantly lower than the phase II data. Generally, the safety of the regimen was manageable, with no new unexpected serious adverse events. However, immune-related hepatitis was reported, and among the 12 treatment-related deaths, 9 were related to liver adverse events. Therefore, future use of this regimen should strictly adhere to indications, carefully consider elderly or frail patients, and closely monitor for adverse events, especially liver-related adverse events.
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Oncology Frontier: Immunotherapy has become the standard first-line treatment, with various combination regimens available. For patients who fail first-line immunotherapy, how should second-line treatment be optimized?
Professor Chen Xun: With the continuous advancement of liver cancer research, the treatment of advanced liver cancer is now multifaceted, involving multidisciplinary diagnosis and treatment, opening up new horizons for advanced liver cancer treatment. For second-line treatment after first-line immunotherapy failure, comprehensive consideration should be given to the patient’s physical condition, economic status, previous treatment response, and metastatic characteristics (whether oligometastatic or extensive metastasis). Already approved but previously unused regimens should be selected for targeted treatment.
Since most approved second-line treatments were designed based on failure after first-line TKI therapy, we look forward to clinical studies targeting patients who fail immunotherapy. For example, the ongoing IMbrave251 study, an international, multicenter, phase III study, investigates treatment with atezolizumab plus lenvatinib or sorafenib after failure of the atezolizumab plus bevacizumab regimen. We hope more related studies will provide ideal answers.
