Phase 2 Trials Currently Filling Unmet Needs in Advanced HCC

Chris Verslype, MD, PhD

A phase 2 trial of tislelizumab (BGB-A317) and another trial of Tumor Treating Fields (TTFields) accompanied by sorafenib (Nexavar) are filling unmet needs in advanced hepatocellular carcinoma (HCC), although more data are still needed in this space according to a discussion at the 2021 European Society for Medical Oncology World Congress on Gastrointestinal Cancer.

Up until recently, the HCC landscape has been dominated by tyrosine kinase inhibitors. The first-line standard of atezolizumab (Tecentrig) and bevacizumab (Avastin) has been available since 2020 after demonstrating a 6.9-month progression-free survival (PFS), 19.2-month overall survival (OS), and 30% overall response rate (ORR). However, there is still uncertainty for using this therapy in the second or later line settings.

Additionally, there is a need for predictive markers to help guide the selection and sequencing of therapy, and for innovative options to overcome primary and secondary resistance to treatment.

“Tislelizumab is an active and safe investigational PD-1 antibody, in second and third line, comparable to other PD-1 agents,” Chris Verslype, MD, PhD, a digestive oncologist at the University Hospitals Leuven, Belgium, said in his presentation. The global, single-arm, phase 2 RATIONALE 208 study (NCT03419897) of the investigational agent tislelizumab at 200 mg intravenously every 3 weeks was evaluated in 249 patients with previously treated advanced HCC.

This trial had a 13.3% ORR, a PFS of 2.7, and an OS of 13.2 months. Patients number of prior lines of therapy did not affect the results. The treatment-related adverse events of grade 3 or more occurred in 14.5% of patients, and 4.8% discontinued treatment.

In this group of patients, 80% had metastatic disease, 36% had non-viral etiology, and 90% had Barcelona-Clinic Liver Cancer (BCLC) stage C. They could not have prior PD-1 or PD-L1 inhibitors.

Verslype compared these data with the phase 3 KEYNOTE-240 trial (NCT02702401) of pembrolizumab (Keytruda) versus placebo in 413 patients with pretreated advanced HCC, randomized 2:1. Seventy percent had metastatic disease, 80% had BCLC stage C, 58.6% had non-viral etiology, and 87% had progressive disease after receiving sorafenib. The results of this trial showed an 18.3% ORR, 3-month PFS, and 13.9-month OS. Grade 3 or more events of interest occurred in 7.2%.

The results from RATIONALE-208 and KEYNOTE-240 are comparable. Currently, there is a phase 3 trial of tislelizumab versus sorafenib in the first line setting for patients with unresectable HCC, though they are unlikely to yield clinically relevant results, according to Verslype’s discussion.

Subsequently, Verslype went over the phase 2 HEPANOVA trial (NCT03606590) of TTFields at 150 kHz for 18 or more hours a day plus daily sorafenib at 400 mg twice daily. The 27 patients on this trial were diagnosed with advanced HCC by biopsy or imaging plus alpha-fetoprotein, had BCLC stage 0-C, 5 to 8 Child-Pugh score, and could not receive surgery or local therapy.

In this trial, the ORR was 9.5%, the PFS was 5.8 months, and the OS rate at 1 year was 30%. There were 67% of patients with grade 1 or 2 TTFields-related skin toxicity, and 1 patient had grade 3 toxicity.

“For TTFields, there are no new safety concerns. [These are the] first good data in HCC, but more data are needed to appreciate the efficacy of TTFields in advanced HCC,” Verslype said.

Treatment for this trial started 7 days or less after enrollment, and TTFields start more or less than 7 days from starting sorafenib. Follow-ups occurred every 4 weeks and CT/MRI scans were scheduled for every 12 weeks. TTFields and follow-ups continued until progressive disease per RECIST. Follow-up visits after patients experienced progressive disease were 30 days after discontinuation. Survival follow-ups were every 8 weeks until death. Verslype also noted that there were 78% of patients with BCLC stage C, 51% with Child-Pugh B, and 22% with an ECOG performance status of 2 recently.

“Updated results from the IMbrave150 [NCT03434379] study evaluating atezolizumab/bevacizumab versus sorafenib [showed] that you can have with sorafenib…11% ORR and even a very high overall survival at 1 year,” Verslype explained during his presentation. “So in my opinion, recent studies with sorafenib as the control have shown better results than historical controls used in [HEPANOVA]. Is this really showing more efficacy than sorafenib? I doubt it.”

_Reference:

_{Verslype C. Discussion O-1, O-16. Slides presented at: 2021 European Society for Medical Oncology World Congress on Gastrointestinal Cancer; June 30-July 3, 2021; virtual. LBA-2. doi:}