A recent article reported a trial of a combination of a MET inhibitor and a PD-1 inhibitor in the second-line treatment of advanced HCC after sorafenib.
Since 2020, multi-kinase inhibitors and monoclonal antibodies have been approved for use in patients with hepatocellular carcinoma after treatment failure of sorafenib. Among them, MET mutations are thought to be oncogenic drivers of hepatocellular carcinoma and are associated with resistance to sorafenib and lenvatinib treatments.
Capmatinib: a potent and selective MET inhibitor that has demonstrated anti-tumor activity in preclinical models of hepatocellular carcinoma.
Spartalizumab: A humanized monoclonal antibody against PD-1 that prevents its binding to PD-L1 and PD-L2, thereby restoring effector T cell function and ultimately improving anti-tumor responses.
Previous studies have found that MET inhibitors and PD-1 inhibitors have some activity as monotherapy in advanced hepatocellular carcinoma, and early clinical studies of MET inhibitors tivantinib and tepotinib have achieved positive results. This provides a theoretical basis for the treatment of advanced hepatocellular carcinoma with PD-1 combined with MET inhibitors.
Objectives: To determine the safety and recommended Phase 2 dose (RP2D) of the combination of capmatinib and spartalizumab, and to further evaluate the safety and clinical activity of this combination in patients with advanced hepatocellular carcinoma who have failed or are intolerant to sorafenib.
Study Design: This is an open-label, randomized, multicenter Phase 1b/2 clinical trial conducted across 18 centers worldwide, including China (mainland China, Hong Kong, and Taiwan), South Korea, France, Germany, Italy, and Canada. The study was divided into two parts, conducted sequentially. The Phase 1b dose escalation part is designed to determine the recommended dose (RP2D) for the combination of capmatinib and spartalizumab. A phase 2 randomized trial was followed to evaluate the safety and efficacy of capmatinib in combination with spartalizumab or spartalizumab alone.
Treatment: During the phase 1b study, 27 patients were treated with capmatinib in combination with a fixed dose of spartalizumab until the RP2D was determined. Capmatinib is administered continuously twice daily (bid) in the form of oral tablets at a fixed daily milligram dose, not individually adjusted for body weight or body surface area. Spartalizumab 300 mg is administered by intravenous infusion once every 3 weeks (q3w).
Study endpoints: The primary endpoints included the incidence and severity of adverse events (AEs), serious adverse events (SAEs), and dose-limiting toxicities (DLTs) (Phase 1b) and overall response rate (ORR) as assessed by the investigator according to RECIST v1.1 (Phase 2). Secondary endpoints of Phase 2 included best overall response (BOR), duration of response (DOR), time to response (TTR), progression-free survival (PFS), time to progression (TTP), and safety and tolerability.
Findings:
First Evaluation of MET Inhibitor and PD-1 Targeted Drug Combination: This is the first study to evaluate the combination of MET inhibitor and PD-1 targeted drug for the treatment of advanced hepatocellular carcinoma. In Phase 1b, the RP2D of capmatinib in combination with spartalizumab 300 mg q3w was determined to be 400 mg bid.
Objective response rate (ORR): Preliminary clinical activity was observed in Phase 1b (ORR 14.8%), but the primary efficacy endpoint was not met in Phase 2. The ORR of combination therapy was 9.4%, compared to 10.0% with spartalizumab alone.
Disease control rate (DCR): 51.9% in stage 1b. In Phase 2, the DCR was 46.9% in the combination group and 40.0% in the spartalizumab alone group.
Progression-free survival (PFS) and overall survival (OS): median PFS was 3.35 months and median OS was 13.73 months in stage 1b. In Phase 2, median PFS was 2.79 months in both the combination treatment arm and the spartalizumab alone arm. Median OS was 14.88 months in the combination treatment group compared to 9.79 months in the spartalizumab alone group.
Best overall response (BOR): In Phase 2, the BOR for the combination arm included 3 partial responses (PR), 12 stable disease (SD), and 13 progressive disease (PD), compared with 3 PR, 9 SD, and 15 PD in the spartalizumab arm alone.
Drug safety and tolerability: Overall, treatment-related adverse events (TRAEs) were more common in the combination therapy group. The most common TRAEs include nausea, weakness, vomiting, and diarrhea.
Pharmacokinetic (PK) analysis: In Phase 1b, the exposure to capmatinib increases with increasing doses. In phase 2, exposure to capmatinib and spartalizumab was similar from cycle 2.
Biomarker analysis: There was no significant change in CD8 and PD-L1 protein expression before and after treatment. RNA expression analysis showed an increase in non-significant IFNg and T cell expression signatures.
Comparison with other studies of hepatocellular carcinoma
Cross-trial comparisons with other second-line HCC studies involving PD-1 antibodies (KEYNOTE-224 and CheckMate 040) showed that single-agent pembrolizumab and nivolumab performed better in median overall response rates (ORRs) (17% vs. 14%, respectively). Median overall survival (OS) in the combination treatment arm (14.88 months) and spartalizumab alone (9.79 months) appeared to be similar to those reported in KEYNOTE-224 (12.9 months) and CheckMate 040 (13.2 months).
METcapmatinib
To date, no single targeted drug has shown promising efficacy results in pivotal HCC trials. MET inhibitors such as tivantinib and tepotinib have shown limited anti-tumor activity in previous studies. Due to the limited number of tumor samples collected in the study, PD data (CD8 and PD-L1 protein expression) did not show significant changes before and after treatment.
conclusion
The overall safety and tolerability results showed manageable toxicity and did not pose new significant safety concerns for patients enrolled in the study. Although capmatinib 400 mg bid in combination with spartalizumab 300 mg q3w was identified as RP2D, the combination did not show better clinical activity than spartalizumab alone.
Source: International Hepatobiliary Information