KEYNOTE-022: Pembrolizumab with trametinib in patients with BRAF wild-type melanoma or advanced solid tumours irrespective of BRAF mutation
Mené sur 42 patients atteints d'un mélanome sans mutation BRAF ou d'une tumeur solide de stade avancé, cet essai de phase I/II évalue la dose maximale tolérée du pembrolizumab en combinaison avec le tramétinib
Objectives : Parts 4 and 5 of the phase 1/2 KEYNOTE-022 study investigated the maximum tolerated dose (MTD), safety, and efficacy of pembrolizumab plus trametinib in solid tumours and BRAF wild-type melanoma. Patients and methods : Patients received intermittent or concurrent dosing of pembrolizumab plus trametinib.Concurrent dosing was 2 or 4 weeks of trametinib run-in followed by concurrent pembrolizumabevery 3 weeks (Q3W) plus trametinib once daily (QD). Intermittent dosing was 2 weeksof trametinib run-in followed by pembrolizumab plus intermittent trametinib (1 weekoff/2 weeks on). A 3 + 3 dose escalation was used, followed by dose confirmation. Results : Forty-two patients were enrolled. No dose-limiting toxicities (DLTs) occurred at initial dose levels (DL). At subsequent DLs, 10 of 38 evaluable patients had DLTs. For concurrentdosing, MTD was pembrolizumab 200 mg Q3W plus trametinib 1.5 mg QD, with a 2-weektrametinib 1.5 mg QD run-in (concurrent DL2a); in concurrent DL2a group, five (31%)patients had grade 3/4 treatment-related adverse events (TRAEs); the objective responserate (ORR) was 0%. ORR was 40% in concurrent DL1 and 0% in concurrent DL2b. For intermittentdosing, MTD was pembrolizumab 200 mg Q3W plus trametinib 2 mg QD with a 2-week trametinib2 mg QD run-in (intermittent DL2); in the intermittent DL2 group, seven (47%) patientshad grade 3/4 TRAEs; ORR was 27%. ORR in intermittent DL1 was 33%. Conclusions : MTDs for concurrent and intermittent dosing of pembrolizumab with trametinib wereidentified. The combination had limited antitumour activity, numerically higher ORRwith intermittent versus concurrent dosing, and manageable safety.