Combining PARP inhibition with PD-1 inhibitors
Mené sur 49 patients atteints d'une tumeur solide de stade avancé (âge médian : 63 ans), cet essai de phase IA/B évalue la dose maximale tolérée du pamiparib (un inhibiteur de PARP 1/2) dispensé en combinaison avec le tislélizumab (un anticorps anti-PD-1)
In The Lancet Oncology, Michael Friedlander and colleagues report the findings of a phase 1a/b trial of the combination of poly (ADP-ribose) polymerase (PARP) inhibition and checkpoint inhibitors in patients with previously treated, advanced solid tumours. The authors hypothesise that tumours responding to PARP inhibition might have enhanced sensitivity to the combination of PARP inhibition and anti-PD-1 therapy. There is a strong rationale for combining PARP inhibitors with checkpoint inhibitors. Genomic instability and DNA damage repair pathway mutations have been shown to induce neoantigens and DNA damage upregulates PD-L1 via multiple mechanisms, including interferon expression and activation of the innate immune pathway by the stimulator of interferon genes molecule (STING). Furthermore, DNA damage repair pathway deficiency in at least one gene other than the classic mismatch repair genes ( MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, and PMS2) has been shown to result in better response to checkpoint inhibitors compared with patients with normal DNA damage repair pathway (80% vs 19%).
The Lancet Oncology , commentaire, 2018