On December 8, 2022 Jounce Therapeutics, Inc. (NASDAQ: JNCE), a clinical-stage company focused on the discovery and development of novel cancer immunotherapies and predictive biomarkers, reported new clinical data from the INNATE trial with JTX-8064 and pimi and the SELECT trial with vopra and pimi in two poster presentations at the ESMO (Free ESMO Whitepaper)-IO 2022 Annual Congress being held in Geneva, Switzerland (Press release, Jounce Therapeutics, DEC 8, 2022, View Source [SID1234624926]).
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JTX-8064 is a highly selective and potent inhibitor of myeloid-specific Leukocyte Immunoglobulin Like Receptor B2 (LILRB2, also known as ILT4) with the potential to reverse PD-(L)1 inhibitor resistance. JTX-8064 is being studied in the INNATE trial (NCT04669899), a Phase 1/2 dose escalation/expansion trial of two investigational agents, JTX-8064 monotherapy (mono) and combination (combo) with pimi, Jounce’s investigational PD-1 inhibitor. Vopra is an inducible T cell costimulator (ICOS) agonist monoclonal antibody that stimulates CD4 T cells and may amplify anti-tumor activity. The SELECT trial is a randomized Phase 2 trial of vopra combined with pimi versus pimi monotherapy in TISvopra biomarker selected, immunotherapy naïve, 2nd line non-small cell lung cancer (NSCLC) patients.
In the poster titled "Phase 1 Study of JTX-8064, a LILRB2 (ILT4) inhibitor, as monotherapy and combination with pimivalimab (pimi), a PD-1 inhibitor (PD-1i), in patients (pts) with advanced solid tumors" Phase 1 data defining the recommended Phase 2 dose (RP2D) were presented. Patients with advanced solid tumors who progressed after all available therapy were treated at seven dose levels of JTX-8064 mono and two dose levels of JTX-8064 plus pimi 500 mg q3w using a Bayesian design. The study’s primary objectives are safety and determination of the RP2D. Secondary objectives are pharmacokinetics (PK), receptor occupancy (RO), and immunogenicity, and exploratory objectives include evaluation of anti-tumor activity including objective response rate (ORR) by RECIST 1.1 criteria.
Thirty-one patients were treated in dose escalation, 22 JTX-8064 mono, and nine JTX-8064 plus pimi. There were no dose limiting toxicities and maximum tolerated dose was not reached. Eleven monotherapy patients (50%) and six combination patients (66.7%) had treatment-related adverse events (TRAE), most of which were Grade 1 or 2, and there was only one serious TRAE, a tumor flare in the 1200 mg mono cohort. PK was linear. Full RO through 21 days was achieved at ≥ 300 mg resulting in selection of an RP2D of 700 mg q3w for JTX-8064 +/- pimi. Phase 1 efficacy data in the mono cohort (n=22): zero partial response (PR), seven (35%) stable disease (SD) including two durable SD (appendiceal cancer 8.3, ovarian cancer 12.2 months). Phase 1 efficacy data in the combo cohort (n=9): one confirmed PR (6.2 months) at 700 mg in a PD-1i resistant cholangiocarcinoma patient (PD-L1 score of 0) and resolution of both bone pain and cachexia, three (33%) SD with one durable SD of 6 months (PD-1i resistant NSCLC). Enrollment into multiple expansion cohorts is ongoing.
A poster titled "SELECT: A phase II randomized trial evaluating 2 doses of vopratelimab (V) + pimivalimab (P) vs P in TISvopra selected patients (pts)" of the vopra plus pimi SELECT trial included an update to data previously announced on clinical endpoints, including additional durability data for patients who remain on study. SELECT is a randomized Phase 2 trial (NCT04549025) evaluating vopra, Jounce’s ICOS agonist, in combination with pimi versus pimi alone in 69 immunotherapy naïve, second line, non-small cell lung cancer patients. Two hypotheses were tested in the study. First, two different doses were examined, both intended to result in different levels of pulsatile target engagement, which may optimize the dose of an agonist by reducing T cell exhaustion. Second, all patients in the study were selected by TISvopra, an 18 gene RNA tumor inflammation signature, previously associated with improved clinical outcomes in patients treated with vopra +/- nivolumab. Sixty nine (n=69) TISvopra positive patients with metastatic NSCLC after one prior platinum-containing regimen were randomized 2:1:1 to pimi monotherapy 1000 mg (n=36), vopra 0.1 mg/kg (n=18) plus pimi or vopra 0.03 mg/kg (n=15) q6w plus pimi.
Both doses of vopra demonstrated distinct patterns of pulsatile target engagement while vopra 0.03 mg/kg achieved a shorter duration of target engagement and a meaningful rest period from receptor saturation and signaling was observed. The low dose vopra combination trended favorably for the primary endpoint (percent change from baseline of all measurable lesions averaged over 9 and 18 weeks), ORR, and progression free survival (PFS). ORR was 40% (95% confidence intervals [CI]16.34, 67.71) for low dose vopra combination cohort, 27.8% (CI 14.20, 45.19) for pimi alone, and 16.7% (CI 3.58, 41.42) for high dose vopra combination cohort. Six month landmark PFS was 80% (CI 50, 93) for low dose vopra combination, 36% (CI 20, 53) for pimi monotherapy, and 31% (CI 11, 52) for high dose vopra combination. Benchmarks for approved PD-1 inhibitors in second line IO naïve NSCLC are ORR 18-20% and 6 month landmark PFS 30-38%. PD-L1 was evenly distributed across TISvopra patients and not associated with efficacy, suggesting TISvopra may select for patients who respond independent of PD-L1. Study treatment was well tolerated with 7.2% of patients reporting Grade ≥3 TRAEs. Most common TRAEs were Grade 1/2 hyperthyroidism and hypothyroidism.
Preclinical data demonstrating that a shorter period of target engagement with vopra in vitro stimulates T cells without the exhaustion seen with longer treatment was also summarized in the poster. This data provides a scientific rationale that clinical outcomes obtained with lower doses of vopra may be improved relative to doses that result in continuous target engagement, as the SELECT clinical data suggests. Jounce plans to pursue a partnership to enable further development of vopra 0.03 mg/kg in combination with a PD-1 inhibitor.
The posters will be available on the "Our Pipeline" section of the Jounce Therapeutics website after presentation at www.jouncetx.com.
About JTX-8064
JTX-8064 is a humanized IgG4 monoclonal antibody designed to specifically bind to Leukocyte Immunoglobulin Like Receptor B2 (LILRB2/ILT4) and block interactions with its ligands. JTX-8064 is the first tumor-associated macrophage candidate developed from Jounce’s Translational Science Platform. Preclinical data presented at the 2020 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s Annual Meeting and the 2019 and 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meetings support the development of JTX-8064 as a novel immunotherapy to reprogram immune-suppressive macrophages and enhance anti-tumor immunity. A Phase 1/2 clinical trial named INNATE (NCT04669899) of JTX-8064 as a monotherapy and in combination with Jounce’s internal anti-PD-1 inhibitor, pimivalimab (formerly JTX-4014) is currently enrolling patients with advanced solid tumors.
About Vopratelimab
Vopratelimab is a clinical-stage monoclonal antibody that binds to and activates ICOS, the Inducible T cell CO-Stimulator, a protein on the surface of certain T cells commonly found in many solid tumors. Vopratelimab is being assessed in the SELECT Phase 2 clinical trial (NCT04549025) in combination with Jounce’s internal investigational PD-1 inhibitor, pimivalimab (formerly JTX-4014), compared to pimivalimab alone. The SELECT trial completed enrollment of 69 immunotherapy naïve NSCLC patients who have been pre-selected with the TISvopra predictive biomarker, an 18 gene RNA tumor inflammation signature which predicted the emergence of ICOS hi CD4 T cells and clinical benefit in the ICONIC trial of vopratelimab alone and in combination with a PD-1 inhibitor.
About Pimivalimab
Pimivalimab (formerly JTX-4014) is a well-characterized fully human IgG4 monoclonal antibody designed to block binding to PD-L1 and PD-L2. Pimivalimab demonstrated a 17% durable overall response rate in a Phase 1 trial of 18 heavily pre-treated PD-(L)1 inhibitor naïve patients, which excluded all tumor types for which PD-(L)1 inhibitors were approved. In this Phase 1 trial, pimivalimab was shown to have an acceptable safety profile. Pimivalimab is currently being assessed in the INNATE Phase 1/2 trial (NCT04669899) in combination with JTX-8064, a LILRB2 (ILT4) inhibitor. Pimivalimab is also being assessed in the SELECT Phase 2 clinical trial (NCT04549025) in combination with vopratelimab.