RATIONALE 208: ‘Durable Clinical Activity’ Reported With Tislelizumab in Advanced Liver Cancer

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With the investigational checkpoint inhibitor tislelizumab, durable responses were achieved by some patients with previously treated advanced hepatocellular carcinoma, regardless of the number of prior lines of therapy, in the phase II RATIONALE 208 trial. These findings were presented during the European Society for Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer 2021 by Ghassan K. Abou-Alfa, MD, MBA, of Memorial Sloan Kettering Cancer Center, New York.1

Tislelizumab is an anti–PD-1 antibody engineered to minimize Fc-gamma receptor binding on macrophages. This limits antibody-dependent phagocytosis, a mechanism of T-cell clearance and a potential mechanism of resistance to anti–PD-1 therapy. The drug is approved in China and has been licensed by Novartis from BeiGene for development in North America, Europe, and Japan.

Ghassan K. Abou-Alfa, MD, MBA

Ghassan K. Abou-Alfa, MD, MBA

“Tislelizumab demonstrated encouraging and durable clinical activity in patients with hepatocellular carcinoma who had received at least one prior therapy,” Dr. Abou-Alfa said. The results indicate clinical activity and efficacy for tislelizumab in a group of patients with high unmet medical needs, “despite the lack of randomization against a standard of care,” he said.

Ongoing responses at data cutoff were observed in 66.7% of patients, and 79.2% of patients were event-free at 13 months. The median duration of response was not reached at a median follow-up of about 1 year. Median overall survival was 13.2 months. Survival and tolerability were similar between patients with one prior line of therapy and those with two or more, Dr. Abou-Alfa noted.


The phase II study included 249 patients with advanced hepatocellular carcinoma. They were previously treated with at least one prior line of therapy that did not include a checkpoint inhibitor; 138 had received at least one treatment, and 111 had received at least two treatments.

Patient characteristics were “standard” for this disease, according to Dr. Abou-Alfa. Hepatitis B was the underlying cause in about half the cases, 14% were due to hepatitis C, and 36% had no viral cause. Approximately 90% of patients had Barcelona Clinic Liver Cancer stage C disease, and 80% had extrahepatic spread. PD-L1 expression was positive in 6% of patients; negative in 58%; and for 36%, PD-L1 expression status was unknown.

Patients were treated with intravenous tislelizumab at 200 mg every 3 weeks. Radiologic assessments were performed every 6 weeks for the first 18 weeks and then every 9 weeks. The primary endpoint was objective response rate by independent review.

Key Results

Across the patient cohort, the objective response rate was 13.3% (13.8% in patients with one prior line and 12.6% for those with two or more prior lines). The disease control rate was 53.0%, and the clinical benefit rate (response ≥ 24 weeks) was 24.1%. A response duration of at least 12 months was observed in 79.2% overall; in 82.6% after one prior line; and in 73.0% after two or more lines. Investigator assessment of antitumor activity was similar.

“Of note, the median duration of response was not reached despite a median response follow-up of 11.7 months,” Dr. Abou-Alfa said. At data cutoff (February 27, 2020), 22 of 33 patients (66.7%) were still responding.

Subgroup analysis showed that responses were also comparable regardless of patient gender, geographic region, performance status, prognosis, PD-L1 expression, and extrahepatic spread, among other factors.

“Independent of one or two lines of prior treatment exposure, 35.6% had a reduction in the sum of the target lesion diameters from baseline,” he added.

Overall Survival by Treatment Line

Regarding overall survival, Dr. Abou-Alfa noted: “It’s nice to see the three Kaplan-Meier curves matching.” Median overall survival was 13.2 months in the whole population, 13.8 months for patients with one prior line of treatment, and 12.4 months for those with two or more prior lines. Overall survival at 12 months was 52.6%, 54.3%, and 50.7%, respectively. Median progression-free survival was also similar for the groups, approximately 2.7 months. Dr. Abou-Alfa said the relatively high median overall survival “within the context of a phase II trial” is “very encouraging.”

Grade ≥ 3 treatment-related adverse events occurred in 14.5% of patients; for 6.8%, these side effects led to treatment discontinuation and for 17.3%, dose delays. Toxicities were similar to those reported for other anti–PD-1 agents, he said.

Ongoing Phase III Trial

A global, randomized phase III trial comparing tislelizumab with sorafenib as a first-line treatment for adults with advanced hepatocellular carcinoma is ongoing. According to Dr. Abou-Alfa, this study “will at least establish tislelizumab in comparison with a standard of care,” which will be followed by further “fine-tuning.” 

DISCLOSURE: Dr. Abou-Alfa has received grant support from Arcus, Agios, AstraZeneca, Bayer, BioNtech, BMS, Celgene, Flatiron, Genentech/Roche, Genoscience, Incyte, Polaris, Puma, QED, Silenseed, and Yiviva; and has served as a consultant to Adicet, AstraZeneca, Alnylam, Autem, Bayer, BeiGene, Berry Genomics, Cend, Celgene, CytomX, Eisai, Eli Lilly, Exelixis, Flatiron, Genentech/Roche, Genoscience, Helio, Incyte, Ipsen, Legend Biotech, Merck, Nerviano, QED, Redhill, Rafael, Servier, Silenseed, Sillajen, Sobi, Surface Oncology, Therabionics, Vector, and Yiviva.


1. Ducreux M, Abou-Alfa GK, Ren Z, et al: Results from a global phase 2 study of tislelizumab, an investigational PD-1 antibody, in patients with previously treated advanced hepatocellular carcinoma. ESMO World Congress on Gastrointestinal Cancer 2021. Abstract O-1. Presented July 1, 2021.


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