A phase Ia/Ib study of an anti-TIM-3 antibody (LY3321367) monotherapy or in combination with an anti-PD-L1 antibody (LY3300054): Interim safety, efficacy, and pharmacokinetic findings in advanced cancers.

12 Background: Combined targeting of both the TIM-3 and PD-L1 immune checkpoint pathways may improve efficacy. LY3321367 mAb targets TIM-3 on immune cells and LY3300054 mAb targets PD-L1 on tumor cells and tumor-infiltrating immune cells. This analysis presents safety, efficacy, pharmacokinetic (PK) and pharmacodynamics/soluble target engagement (TE) results from LY3321367 (anti-TIM-3) monotherapy and in combination with LY3300054 (anti-PD-L1) in patients (pts) with advanced cancer. Methods: This ongoing, open-label phase 1a/1b, dose escalation and expansion study enrolled pts with histologically confirmed advanced relapsed/refractory solid tumors. Pts received IV infusions of 3mg-1200mg LY3321367 Q2W monotherapy (Arm A) or 70mg-1200mg LY3321367 + 200mg-700mg LY3300054 Q2W combination therapy (Arm B). Primary objectives assessed safety and tolerability and determined the RP2D. PK, soluble target TE, anti-drug antibodies (ADAs), and clinical efficacy (RECIST v1.1) were also evaluated. Results: At data cutoff (3 August 2018), LY3321367 monotherapy was administered to 23 pts (Arm A); 18 pts received LY3321367 combination therapy (Arm B) as phase 1a dose escalation (3 mths median follow-up). Treatment-related AEs observed in Arms A and B were mild (Gr ≤2), except for 1 pt with Gr 3 anemia in Arm B (200 mg LY3321367 + 700 mg LY3300054). No dose limiting toxicities, dose limiting-equivalent toxicities, treatment-related SAEs, or deaths were observed in Arm A or B. For LY3321367, 68.2% (Arm A) and 88.2% (Arm B) of pts were positive for treatment-emergent ADAs. Despite ADAs, no effect on PK was noted; ADA titers were low, except for 1 pt with an infusion-related reaction. LY3321367 t 1/2 was ~22 days. Full TE was maintained 2 wks after 1200 mg dose; 600 mg Q2W maintained TE at steady-state. In Arm A, 2 pts had > 20% tumor regression, 1 of which was later confirmed as a PR in a post-PD-1 SCLC pt. Conclusions: LY3321367 is well tolerated as a monotherapy and in combination with LY3300054. The RP2D for LY3321367 combination therapy is 1200 mg IV infusions Q2W for cycles 1-2; 600 mg infusions Q2W starting at cycle 3 onward. Clinical trial information: NCT03099109.