TY - JOUR
T1 - Blocking TIM-3 in treatment-refractory advanced solid tumors
T2 - A phase Ia/b study of LY3321367 with or without an Anti-PD-L1 antibody
AU - Harding, James J.
AU - Moreno, Victor
AU - Bang, Yung Jue
AU - Hong, Min Hee
AU - Patnaik, Amita
AU - Trigo, José
AU - Szpurka, Anna M.
AU - Yamamoto, Noboru
AU - Doi, Toshihiko
AU - Fu, Siqing
AU - Calderon, Boris
AU - De Mendizabal, Nieves Velez
AU - Calvo, Emiliano
AU - Yu, Danni
AU - Gandhi, Leena
AU - Liu, Zhuqing Tina
AU - Galvao, Violeta Regnier
AU - Leow, Ching Ching
AU - De Miguel, Maria J.
N1 - Funding Information:
This work was supported by Eli Lilly and Company, Indianapolis, IN.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/4
Y1 - 2021/4
N2 - Purpose: T-cell immunoglobulin and mucin-domain. containing molecule-3 (TIM-3) blunts anticancer immunity and mediates resistance to programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors. We assessed a novel, first-in-class, TIM-3 mAb, LY3321367, alone or in combination with the anti-PD-L1 antibody, LY300054 in patients with advanced solid tumor. Patients and Methods: This open-label, multicenter, phase Ia/b study aimed to define the safety/tolerability and recommended phase II dose (RP2D) of LY3321367 with or without LY300054. Secondary objectives included pharmacokinetics/pharmacodynamics, immunogenicity, and efficacy. Biomarkers were assessed in exploratory analysis. Results: No dose-limiting toxicities were observed in the monotherapy (N = 30) or combination (N = 28) dose escalation. LY3321367 treatment-related adverse events (≥2 patients) included pruritus, rash, fatigue, anorexia, and infusion-related reactions. Dose-proportional increase in LY3321367 concentrations was not affected by either LY300054 or antidrug antibodies (observed in 50%.70% of patients). Pharmacokinetic/pharmacodynamic modeling indicated 100% target engagement at doses ≥600 mg. LY3321367 RP2D was 1,200 mg biweekly for four doses followed by 600 mg every 2 weeks thereafter. In the non.small cell lung cancer monotherapy expansion cohort, outcomes varied by prior anti-PD-1 therapy response status: anti-PD-1/L1 refractory patients [N = 23, objective response rate (ORR) 0%, disease control rate (DCR) 35%, progression-free survival (PFS) 1.9 months] versus anti-PD-1/L1 responders (N = 14, ORR 7%, DCR 50%, PFS 7.3 months). In combination expansion cohorts (N = 91), ORR and DCR were 4% and 42%; CD8 infiltration in paired biopsies increased in approximately half these patients. Conclusions: LY3321367 exhibited acceptable safety profile with favorable pharmacokinetics/pharmacodynamics but only modest antitumor activity. The therapeutic relevance of TIM-3 blockade requires further investigation.
AB - Purpose: T-cell immunoglobulin and mucin-domain. containing molecule-3 (TIM-3) blunts anticancer immunity and mediates resistance to programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors. We assessed a novel, first-in-class, TIM-3 mAb, LY3321367, alone or in combination with the anti-PD-L1 antibody, LY300054 in patients with advanced solid tumor. Patients and Methods: This open-label, multicenter, phase Ia/b study aimed to define the safety/tolerability and recommended phase II dose (RP2D) of LY3321367 with or without LY300054. Secondary objectives included pharmacokinetics/pharmacodynamics, immunogenicity, and efficacy. Biomarkers were assessed in exploratory analysis. Results: No dose-limiting toxicities were observed in the monotherapy (N = 30) or combination (N = 28) dose escalation. LY3321367 treatment-related adverse events (≥2 patients) included pruritus, rash, fatigue, anorexia, and infusion-related reactions. Dose-proportional increase in LY3321367 concentrations was not affected by either LY300054 or antidrug antibodies (observed in 50%.70% of patients). Pharmacokinetic/pharmacodynamic modeling indicated 100% target engagement at doses ≥600 mg. LY3321367 RP2D was 1,200 mg biweekly for four doses followed by 600 mg every 2 weeks thereafter. In the non.small cell lung cancer monotherapy expansion cohort, outcomes varied by prior anti-PD-1 therapy response status: anti-PD-1/L1 refractory patients [N = 23, objective response rate (ORR) 0%, disease control rate (DCR) 35%, progression-free survival (PFS) 1.9 months] versus anti-PD-1/L1 responders (N = 14, ORR 7%, DCR 50%, PFS 7.3 months). In combination expansion cohorts (N = 91), ORR and DCR were 4% and 42%; CD8 infiltration in paired biopsies increased in approximately half these patients. Conclusions: LY3321367 exhibited acceptable safety profile with favorable pharmacokinetics/pharmacodynamics but only modest antitumor activity. The therapeutic relevance of TIM-3 blockade requires further investigation.
UR - http://www.scopus.com/inward/record.url?scp=85104348198&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85104348198&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-4405
DO - 10.1158/1078-0432.CCR-20-4405
M3 - Article
C2 - 33514524
AN - SCOPUS:85104348198
SN - 1078-0432
VL - 27
SP - 2168
EP - 2178
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 8
ER -