With the novel immunotherapy tislelizumab, durable responses are achieved for patients with advanced hepatocellular carcinoma (HCC), regardless of the number of prior lines of therapy, show results from a phase 2, open-label trial.

RATIONALE 208 involved almost 250 patients with advanced HCC who were treated with the drug. Of those patients, 67% demonstrated ongoing responses at the data cutoff, and 79% were event free after 12 months.

With an objective response rate of 13% and a median overall survival of 13 months, the results are “encouraging,” commented lead author Ghassan K. Abou-Alfa MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York City.

Tislelizumab showed “clinical activity and efficacy…in patients with HCC with a high unmet medical need,” he said, “despite the lack of randomization against a standard of care.”

He presented the data at the World Congress on Gastrointestinal Cancers 2021 (WCGC 2021) on July 1.

Tislelizumab is an anti-PD-1 antibody engineered to minimize Fc-gamma receptor binding on macrophages, which is a mechanism of T-cell clearance and potential anti-PD-1 resistance, he noted.

The drug is approved in China and has been licensed by Novartis from BeiGene for development in North America, Europe, and Japan.

Abou-Alfa noted that a large, global, randomized phase 3 study comparing tislelizumab with sorafenib as a first-line treatment for adults with advanced HCC is ongoing.

There is a “need for innovative options” to overcome primary and secondary resistance in HCC, commented Chris Verslype, MD, PhD, Digestive Oncology, University Hospitals Leuven, Leuven, Belgium, who was not involved in the study.

There is also “a need for predictive markers to guide therapy and sequencing,” he added.

But the main question that arises when considering a novel agent in this field, he went on, is, “what is the added value” when compared to similar drugs.

He noted that KEYNOTE-240, a phase 3 trial of pembrolizumab vs placebo in a similar cohort of patients with HCC, suggests that in terms of response rates, progression-free survival, overall survival, and adverse events, the outcomes were “in line with” those seen with tislelizumab.

However, he questioned whether the ongoing phase 3 study with tislelizumab is “likely to yield new clinical insights,” because the drug is comparable to other PD-1 inhibitors, and previous studies have shown that anti-PD-1 agents do not offer any benefits over sorafenib.

In the post-presentation discussion, Abou-Alfa said he agreed with Verslype that comparison between tislelizumab and other anti-PD-1 agents is important but that the “first step” in taking the drug forward is the ongoing phase 3 trial.

He said this “will at least establish tislelizumab in comparison with a standard of care…and then the other steps will be further fine-tuning.”

Abou-Alfa emphasized that the current results “remain very encouraging,” especially in consideration of the relatively high median overall survival “within the context of a phase 2 trial.”

For the phase 2 study, patients with advanced HCC were included if they had received at least one prior line of systemic therapy that did not include a checkpoint inhibitor and had good performance status and a relatively good prognosis.

They were treated with intravenous tislelizumab every 3 weeks until intolerable toxicity, withdrawal of consent, or the patient was deemed to be no longer benefiting from the study therapy.

A total of 249 patients were included in the analysis. The vast majority (80.3%) had extrahepatic spread.

The majority of HCC cases were due to hepatitis B (51.4%); 14.5% were caused by hepatitis C; and 36.1% were nonviral. PD-L1 expression on tumor cells was ≥1% in 6.0% of patients.

All patients had received prior systemic therapy; 138 patients had received one line of therapy, and 111 patients had received at least two lines.

Radiologic assessments were performed every 6 weeks for the first 18 weeks and then every 9 weeks.

On the basis of these assessments, across the patient cohort, the objective response rate was 13.3%, the disease control rate was 53.0%, and the clinical benefit rate was 24.1%.

The team also found that 79.2% of patients had a response to tislelizumab that lasted at least 12 months; 66.7% of responses were ongoing at the time of data cutoff on February 27, 2020.

The median duration of response was not reached.

Abou-Alfa noted that the response to tislelizumab in patients who had received at least two prior lines of therapy was comparable to that seen in those who had previously been treated with one line of therapy.

The disease control rate was 53.2% among patients who had received at least two prior therapies, vs 52.9% among patients who were less heavily pretreated. The clinical benefit rate was 21.6% vs 26.1%; 73.0% had a response that lasted at least 12 months, vs 82.6% among patients who were less heavily pretreated.

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

Interestingly, there was a signal for a greater objective response rate among patients with HCC associated with hepatitis C, at 22.6%.

Overall survival was 13.2 months across the whole cohort; 54.3% of patients were alive at 12 months.

Over a median follow-up of 16.4 months, median progression-free survival was 2.7 months, and 79.2% of patients were event free at 12 months.

Grade ≥3 treatment-emergent adverse events occurred in 48.6% of patients; 14.5% had grade ≥3 treatment-related adverse events.

The most common treatment-related adverse events of any grade were as follows: increased aspartate aminotransferase levels, in 12.9% of patients; increased alanine aminotransferase levels, in 9.2%; asethenia, in 7.6%; and hypothyroidism, in 7.6%.

For both survival outcomes and in terms of adverse events, patients who had received at least two prior lines of systemic therapy performed as well as those who had received only one prior therapy before treatment with tislelizumab.

The study was sponsored by BeiGene, Ltd. Abou-Alfa reports relationships with Arcus, Agios, Astra Zeneca, Bayer, BeiGene, Berry Genomics, BioNtech, BMS, Celgene, CytomX, Eisai, Eli Lilly, Exelixis, Flatiron, Genentech/Roche, Genoscience, Helio, Incyte, Ipsen, Legend Biotech, Loxo, Merck, MINA, Polaris, Puma, QED, Redhill, Rafael, Silenseed, Sillajen, Sobi, Surface Oncology, Therabionics, Twoxar, Vector, and Yiviva. Verslype reports relationships with Roche, Bayer, Ipsen, Lilly. No other relevant financial relationships have been disclosed.

World Congress on Gastrointestinal Cancers 2021 (WCGC 2021): Abstract: O-1. Presented July 1, 2021.

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