The invited discussant of the RATIONALE 208 trial, Chris Verslype, MD, PhD, Professor of Medicine at University Hospitals Leuven in Belgium, said tislelizumab is an “active and safe” investigational PD-1 antibody, “comparable to other PD-1 agents.” In particular, he noted, the results of RATIONALE 208 reflect those achieved with pembrolizumab in the phase III KEYNOTE-240 trial in terms of response, progression-free survival, overall survival, and tolerability in a similar patient population.1
In KEYNOTE-240, the objective response rate was 18.3%, median progression-free survival was 3.0 months, and median overall survival was 13.9 months. “This is quite in line with what we have seen for tislelizumab,” noted Dr. Verslype.
Chris Verslype, MD, PhD
Changing Treatment Paradigm
With PD-1 inhibitors, the treatment of advanced hepatocellular carcinoma has clearly changed. Until recently, tyrosine kinase inhibitors “dominated” the treatment algorithm. However, in 2020, atezolizumab plus bevacizumab yielded a median progression-free survival of 6.9 months and a median overall survival of 19.2 months in the first-line setting, changing the guidelines.2
Current European Society for Medical Oncology guidelines now list atezolizumab plus bevacizumab as the standard first-line option, with sorafenib and lenvatinib representing good options for patients not fit enough for the former. A variety of second-line regimens follow, but they are backed by low-quality evidence and are therefore more “difficult” choices, especially when atezolizumab plus bevacizumab is given first line, he said.
“So, there is uncertainty regarding treatment in the second line and beyond,” Dr. Verslype noted. “There is a need for predictive markers to guide treatment and sequencing and for innovative options that overcome primary and secondary resistance.”
It is possible that tislelizumab may be suited for this, based on its interesting mechanism of action. “We know that Fc-gamma receptor binding is important because it may keep T cells in better shape—they are not phagocytized by macrophages,” he explained. “This is an innovative strategy that potentially offers less T-cell clearance.”
Key Questions
Dr. Verslype posed several key questions that arise when considering a novel agent in this field. What is the added value when compared with similar drugs? This question has been answered by the results that are “comparable to other classic PD-1 agents such as pembrolizumab,” he said.
In addition, Dr. Verslype also questioned whether the ongoing phase III study with tislelizumab will “yield new clinical insights.” The drug has already been found to be comparable to other PD-1 inhibitors, and “and we know that anti–PD-1 agents do not yield benefits vs sorafenib in an unselected population, so it’s unlikely to change the field.”
Translational Studies
Translational studies would be important to identify patients most likely to benefit from this second-line approach. Recently, investigators evaluated 111 samples of hepatocellular carcinoma tissue in patients before initiating treatment with an anti–PD-1 agent.3 They identified an 11-gene signature that was able to predict response and progression-free survival in patients who had not received (but not in those who had received) a tyrosine kinase inhibitor; the signature encompassed genes associated with interferon and antigen presentation.
“This highlights the need for fresh tissue biopsy prior to treatment with immunotherapy,” Dr. Verslype said. “We can’t predict the effect by this gene signature, but it may be worthwhile to have additional translational studies in this field.”
DISCLOSURE: Dr. Verslype has served as a consultant or advisor to Bayer, Ipsen, Novartis, and Roche; has participated in a speakers bureau for Bayer; has received institutional research funding from Bayer; and has been reimbursed for travel, accommodations, or other expenses by Bayer and Ipsen.
REFERENCES
1. Finn RS, Ryoo BY, Merle P, et al: Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: A randomized, double-blind, phase III trial. J Clin Oncol 38:193-202, 2020.
2. Galle PR, Finn RS, Qin S, et al: Patient-reported outcomes from the phase III IMbrave150 trial of atezolizumab plus bevacizumab vs sorafenib as first-line treatment for patients with unresectable hepatocellular carcinoma. 2020 ASCO Gastrointestinal Cancers Symposium. Abstract 476. Presented January 24, 2020.
3. Haber PK, Torres-Martin M, Dufour JF, et al: Molecular markers of response to anti-PD1 therapy in advanced hepatocellular carcinoma. International Liver Congress 2021. Abstract PO-1420. Presented June 23, 2021.
