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ICONIC: Biologic and clinical activity of first in class ICOS agonist antibody JTX-2011 +/- nivolumab (nivo) in patients (pts) with advanced cancers.

2018; Lippincott Williams & Wilkins; Volume: 36; Issue: 15_suppl Linguagem: Inglês

10.1200/jco.2018.36.15_suppl.3000

1527-7755

Timothy A. Yap, Howard A. Burris, Shivaani Kummar, Gerald S. Falchook, Russell K. Pachynski, Patricia LoRusso, Scott S. Tykodi, Geoffrey T. Gibney, Justin F. Gainor, Osama E. Rahma, Tanguy Y. Seiwert, Funda Meric‐Bernstam, Mariela A. Blum Murphy, Jennifer K. Litton, Ellen Hooper, Heather A. Hirsch, Christopher J. Harvey, Myles Clancy, Ty McClure, Margaret K. Callahan,

Inflammatory mediators and NSAID effects

3000 Background: ICOS is a costimulatory molecule expressed on the surface of activated T cells. JTX-2011 is an ICOS agonist designed to stimulate CD4 T effector (T eff) cells and deplete intratumoral T regulatory (Treg) cells. Preclinical efficacy was seen with mouse JTX-2011 monotherapy (mono) and combination (combo) with anti-PD-1 in ICOS+ tumors. Methods: Relapsed/refractory cancer pts received escalating doses of JTX-2011 mono or combo with nivo in Phase 1 (P1), and the recommended P2 dose (RP2D) in P2, based on safety, target engagement (TE), immunophenotyping and cytokines. P2 gastric (GC) and triple negative breast (TNBC) combo cohorts completed enrollment. ICOS was assessed by IHC in archival (arch) and fresh pre-treatment tumor biopsies (bx) or by flow in peripheral blood. Results: 164 pts had ≥1 dose of JTX-2011; 71 P1 (40 mono, 31 combo); 93 P2 (25 mono, 68 combo) including 7 GC mono, 24 GC and 16 TNBC combo. Pts ≥3 prior therapies: 57% GC mono, 48% GC combo, 56% TNBC combo. JTX-2011 RP2D: 0.3mg/kg q3w mono and combo with nivo 240 mg q3w. DLTs: raised AST/ALT and pleural effusion at 1 mg/kg mono. At 0.3mg/kg: TE > 70% sustained through 3wks; no substantial change in # of peripheral T eff or Tregs; dose dependent increase in IFN-γ at 1-6 hrs. P2 adverse events (AEs): drug-related G3-4 8% mono, 13% combo; immune-related 4% mono, 21% combo; infusion related 12% mono, 19% combo. Of 13 GC combo pts with paired arch and fresh bx, 6 were ICOS hi on both, 5 changed from low to hi. Of 7 TNBC combo pts with paired bx, 5/7 archival were ICOS hi, 4/7 fresh were ICOS hi. RECIST antitumor activity: JTX-2011 mono: 1/7 partial response (PR) in GC; 2/5 stable disease (SD) in P1 TNBC. JTX-2011 combo: 2 PRs (0.1, 0.3mg/kg) and 2 ongoing SD in 19 P1/2 GC; 1 PR in 15 P2 TNBC. Of 17 evaluable pts, 4 had emergence of peripheral CD4 T cell ICOS hi subsets during JTX-2011 therapy, including 1 PR mono, 2 PR combo and 1 SD; none were seen in pts with progressive disease. Conclusions: JTX-2011 mono and combo with nivo were well tolerated with antitumor responses in heavily pre-treated GC and TNBC pts. Emergence of peripheral blood CD4 ICOS hi T cell subsets may be a surrogate biomarker of response. Further trials of JTX-2011 are planned. Clinical trial information: NCT02904226.