Posted: Monday, April 24, 2023
The combination of the MET inhibitor capmatinib in vitro and the anti–PD-1 checkpoint inhibition in vivo appeared to limit tumor growth in hepatocellular carcinoma and may improve survival across three preclinical hepatocellular carcinoma models. Additionally, Ricardo A. de Azevedo, PhD, of The University of Texas MD Anderson Cancer Center, Houston, and colleagues reported that the drugs increased proliferating and central memory CD8 T cells and protected against relapse better than PD-1 blockade alone. These findings, which were presented at the American Association for Cancer Research (AACR) Annual Meeting 2023 (Abstract 5745), highlight the potential of known MET and PD-1 inhibitors to inform combination strategies for future clinical trials.
The study evaluated the capmatinib combined with anti–PD-1 checkpoint inhibitors. First, the study authors validated that both MET-selective (capmatinib and tivantinib) and -nonselective (cabozantinib) inhibitors induced PD-L1 on hepatocellular carcinoma cell lines in vitro. Then, capmatinib and cabozantinib alone were compared with PD-1 immune-checkpoint blockade in vivo in the immune-checkpoint blockade–sensitive Hepa1–6 and HCA-1 models of hepatocellular carcinoma. Finally, the serially passaged, αPD-1-refractory DEN hepatocellular carcinoma model was reviewed.
In HCA-1, there was a statistically significant benefit with the combination based on the limitation of tumor growth and extension of survival. In each case, the capmatinib combination had better outcomes with PD-1 blockade. Mechanistically, the capmatinib and αPD-1 combination decreased tumor Treg cells while promoting increased accumulation of activated, nonexhausted, proliferating CD8 T cells. In animal models, those treated with the capmatinib and αPD-1 combination seemed to be better protected against subsequent rechallenge than those cured by αPD-1 alone. The MET inhibitor and αPD-1 combination appeared to significantly extend survival and inhibit tumor growth. Overall, in a hepatocellular carcinoma model resistant to anti–PD-1 alone, the combination demonstrated significant and durable therapeutic benefit, according to the investigators.
Disclosure: The study authors reported no conflicts of interest.