Phase Ib KEYNOTE-200: A study of an intravenously delivered oncolytic virus, coxsackievirus A21 in combination with pembrolizumab in advanced NSCLC and bladder cancer patients

Abstract

Background: Coxsackievirus A21 (CVA21, CAVATAK) is a naturally occurring ICAM-1 targeted oncolytic immunotherapeutic virus. Pembrolizumab (pembro) is a human programmed death receptor-1 (PD-1) blocking mAb. Active CVA21 replication mediates a cellular RIG-I response increasing levels of immune-checkpoint (CPK) molecules namely PD-L1 and immune-cell infiltration in the tumor microenvironment of treated human melanoma and bladder cancer lesions. IV delivery of CVA21 results in tumor targeting evidenced by detection of CVA21 viral RNA in tumor biopsies at study Day 8. The combination of IV CVA21+pembro may provide combinatorial benefit in the clinic. Methods: KEYNOTE-200 is an on-going Phase Ib study with primary objectives to assess the safety and preliminary efficacy of IV CVA21 +pembro. Secondary objectives are to assess ORR by irRECIST, PFS, and OS. In the expansion cohort, 78 pts were given IV CVA21 + pembro, with IV CVA21 dose 1x109 TCID50 on study days 1, 3, 5, 8, 29 and Q3W for 6 additional infusions. Pembro was given at 200 mg IV Q3W from Day 8 for up to 2 years. Results: The combination of IV CVA21 and pembro was generally well tolerated with no DLT's and 12.8% (10/78 pts) G3 TRAE's. No G4/5 TRAE's have been observed. The ORR in evaluable CKP naïve NSCLC pts is currently 23% (7/31, 2CR+5PR) and 33% (7/21) in pts not harbouring EGFR or ALK mutations. In CPK naïve bladder cancer pts, most of whom were second line, the ORR is 31% (8/26, 3CR+5PR). Of note, was an ORR of 30% (3/10) in CPK naïve bladder cancer pts with neg PD-L1 tumor staining at baseline. Preliminary IHC staining of paired biopsies from evaluable CPK naïve pts with neg/low baseline PD-L1 revealed a notable increase in PD-L1+ tumor cells at Day 15 of 62% (8/13) of pts following treatment with CVA21 and pembro. The current median OS for CPK naïve NSCLC and bladder cancer pts is 9.5 and 11.2 mos, respectively. Prolonged SD was the best ORR observed in pts previously treated with CKP (n=17). Conclusions: Systemic CVA21 with pembro has been well tolerated and has mediated encouraging clinical signals of activity in parallel with notable increases in PD-L1 tumor levels within these pt populations.