Phase 2 Evidence on Serplulimab Plus HLX04 in Advanced HCC Calls for Phase 3 Study

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Treatment with the dual PD-L1 and VEGF targeted therapy,serplulimab (HLX10) in combination with HLX04 demonstrated encouraging anti-tumor efficacy along with a favorable safety profile in patients with previously-treated advanced hepatocellular carcinoma (HCC).¹

Findings come from a phase 2 study conducted in 41 Chinese patients with advanced HCC who progressed onprevious systemic treatment.

Standard treatment options for patients with advanced HCC include systemic therapies like regorafenib (Stivarga), cabozantinib (Cabometyx), and ramucirumab (Cyramza). However, the available therapies offer limited benefit in terms of survival, according to investigators of the phase 2 study of serplulimab plus HLX04.

Thus, the study aimed to test a new approach to advanced HCC treatment by assessing safety as its primary end point. The secondary end points of the study wereoverall response rate (ORR), overall survival (OS), OS rates at 6 and 12 months, progression-free survival (PFS), PFS at months 6 and 12, duration of response (DOR), time to response (TTR), and time to progression (TTP). Investigators also evaluated health-related quality of life (HRQOL) outcomes, pharmacokinetic measures, and immunogenicity as exploratory end points.

Patients in the study were treated at 30 different sites in China.Treatment consisted ofserplulimab 3 mg/kg plus HLX04 5 mg/kg in group A or 10 mg/kg in group B. Therapy was administered intravenously every 2 weeks.

Results by immune-related tumor response (IrRC) assessment showed a confirmed ORR in 6 patients from group A, resulting in a 30.0% ORR (95% CI, 11.9%-54.3%). In group B, 3 patients had a confirmed ORR (14.3%; 95% CI, 3.0%-36.3%). Stable disease was achieved in 10.0% of group A and 33.3% of group B, for disease control rates of 40% (95% CI, 19.8%-63.9%) and 47.6% (95% CI, 25.7%-70.2%), respectively.

The TTR among patients treated in group A was 1.9 months (95% CI, 1.4-2.7 months), and in group B, the TTR was 1.5 months (95% CI, 1.4-1.6 months). Treatment with serplulimab plus HLX04 led to a median DOR of not reached in group A (95% CI, 3.3-not evaluable [NE]) and 9.0 months (95% CI, 7.0-NE). Notably, 66.7% of patients in group A had a response that lasted at least 6 months, as did all 3 of the responders in group B. Progressive disease occurred in 2 of 6 patients treated in group A who had a partial response and 2 of 3 in group B.

In terms of survival, the median PFS observed in group A was 2.2 months (95% CI, 1.4-5.5 months), and 4.1 months (95% CI, 1.5 months-NE) in group B. At 6 months, the PFS rate in groups A and group B were 25.0% (95% CI, 9.1%-44.9%) and 42.9% (95% CI, 21.9%-62.3%), respectively. The 12-month PFS rateswere 25.0% (95% CI, 9.1%-44.9%) and 30.6% (95% CI, 12.2%-51.4%), respectively.

In group A, the 6-month TTP rate was observed to be 25.0% (95% CI, 9.1%-44.9%), and in group B, it was 42.9% (95% CI, 21.9%-62.3%). The 12-month TTP rates were similar to those at month 6.

Patients in group A showed a median OS of 11.6 months (95% CI, 6.4months-NE), and those in group B had a median OS of 14.3 months (95% CI, 8.2 months-NE). At 6 months, the OS rates were 85.0% (95% CI, 60.4%-94.9%) and 85.7% (95% CI, 62.0%-95.2%), respectively. At the 12-month mark, the OS rates were 0.0% (95% CI, 27.1%-69.2%) and 51.9% (95% CI, 29.1%-70.6%), respectively.

For safety, results showed that all patients developed at least 1 treatment-emergent adverse events (TEAE). There was a similar incidence of TEAEs between the 2 cohorts The most common any-grade TEAEs observed in group A and B,respectively, were aspartate aminotransferase increase (60.0% and 61.9%),proteinuria (50.0% and 71.4%), and platelet count decrease (50.0% and 47.6%). Grade 3 or higher TEAEs were observedin 70.0% of group A and57.1% of group B. The most common of these events was hypertension. Thirty percent of patients in group A experienced serious TEAEs, as did 38.1% of group B.

The occurrence of TEAEs led to discontinuation of serplulimab in10.0% of patients in group A, and 19.0% of group B, and TEAEs led to discontinuation of HLX04 in 15.0% and 19.0%, respectively. There werea total of 6 grade 5 TEAEs and 5 deaths in the study. The deaths were determined to have been caused by PD, respiratory failure, and circulatory collapse. Immune-related AEs were observed in 25.0% of patients in group A, and 38.1% in group B, and these events were predominantly grade 3 or higher.

Per the EQ-5D-5L and EORTC QLQ-C30 scores for HRQOL, patients with HRQOL deterioration or QOL were stable throughout treatment. Notably, patients in group B reported poorer HRQOL.

Patients treated in the multicenter, open-label, single-arm, phase 2 clinical trial were treated with serplulimab plus HLX04 for up to 2 years unless clinical benefit was lost, or patients experienced unacceptable toxicity, death, or withdrew from the study. All patients were between the ages of 18 and 75 years oldwith histologically or cytologically confirmed advanced HCC.

Baseline characteristics showed that the majority of patients had Barcelona clinic liver cancer stage C disease and were in the Child-Pugh A class. Only 1 patientwas classified as Child-Pugh B. Most patients were also infected with Hepatitis B virus., Of the prior treatments received by patients in the study, the most common were regorafenib (14.6%) and sorafenib (92.7%). Patients also previously received chemotherapy (12.2%), lenvatinib (Lenvima; 9.8%), and other targeted therapies (7.3%).

According to the study investigators, further research in phase 3 trialsto assessserplulimab plus HLX04 for advanced HCC arewarranted.

REFERENCE:

Ren Z, Shao G, Shen J, et al. Phase 2 study of the PD-1 inhibitor serplulimab plus the bevacizumab biosimilar HLX04 in patients with previously treated advanced hepatocellular carcinoma. Liver Cancer. 2023;12(2):116-128. doi:10.1159/000526638