On August 30, 2022 Jounce Therapeutics, Inc. (NASDAQ: JNCE), a clinical-stage company focused on the discovery and development of novel cancer immunotherapies and predictive biomarkers, reported top line data from the randomized Phase 2 SELECT trial evaluating vopratelimab (vopra), Jounce’s inducible costimulator (ICOS) agonist, in combination with pimivalimab (pimi) versus pimivalimab alone in immunotherapy naïve, TISvopra biomarker-selected, second line non-small cell lung cancer (NSCLC) patients (Press release, Jounce Therapeutics, AUG 30, 2022, View Source [SID1234618774]). The trial tested two pulsatile and differentiated doses of vopra in the combination groups against pimi monotherapy, using as the primary endpoint the mean percent change from baseline in tumor size in all measurable lesions, averaged over 9 and 18 weeks as assessed by central independent radiology review. As the study was powered to detect a 20% absolute difference of the pooled combo doses compared to pimi monotherapy, and the actual difference was 7%, SELECT did not meet its primary endpoint. In the combination dose cohort with the lowest dose of vopra (0.03mg/kg), interesting trends were observed in both the primary endpoint, with an absolute mean change of 15%, and in the prespecified secondary endpoints of overall response rate (ORR), which was 40% compared to 25% in pimi alone, and landmark six month progression free survival (PFS) of 80% compared to 33% with pimi alone. Consistent with these clinical outcomes, recent mechanistic data in primary human immune cells in vitro supports shorter duration pulsatile dosing of ICOS agonism, with general implications for T cell agonist dosing. Data from SELECT is summarized as follows:

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JTX-4014 (pimi) (N=36) Pooled pimi + vopra doses (N=33) pimi + vopra 0.1 mg/kg (N=18) pimi + vopra 0.03 mg/kg (N=15)
Primary Endpoint, mean % change from baseline1(95% CI) 7.33 (-12.46, 27.12) 0.23 (-20.10, 20.56) 8.35 (-19.94, 36.65) -7.89 (-37.15, 21.37)
Difference in primary endpoint between combo and pimi monotherapy, absolute %1(95% CI) NA -7.10 (-35.42, 21.22) 1.02 (-33.46, 35.51) -15.22 (-50.51,20.06)
Complete Response (CR), n (%) 1 (2.8) 1 (3.0) 0 1 (6.7)
Partial Response (PR), n (%) 8 (22.2) 8 (24.2) 3 (16.7) 5 (33.3)
Stable Disease (SD), n (%) 13 (36.1) 15 (45.5) 8 (44.4) 7 (46.7)
Progressive Disease (PD), n (%) 10 (27.8) 6 (18.2) 5 (27.8) 1 (6.7)
Not Reported / Not Evaluable / Early Termination, n (%) 4 (11.1) 3 (9.1) 2 (11.1) 1 (6.7)
Overall Response Rate (ORR), n (%) 9 (25.0) 9 (27.3) 3 (16.7) 6 (40.0)
Disease Control Rate (DCR), n (%)2 22 (61.1) 24 (72.7) 11 (61.1) 13 (86.7)
Landmark 6 month Progression Free Survival3(PFS), % (95% CI) 33 (16,50) 54 (35, 69) 29 (10, 52) 80 (50, 93)
Data cutoff: July 7, 2022, central radiology review
1 Means, 95% CIs, difference between means, 95% CIs of difference are based on a mixed-model repeated measures (MMRM) analysis;2best overall response of CR, PR, or SD (duration of at least 9 weeks);3landmark PFS data is mature only for the 0.03 mg/kg cohort; CI: confidence interval;
Safety and Biomarkers
Vopra continued to be well tolerated, and the frequency and types of adverse events in the combination cohorts were comparable to those in the pimi monotherapy cohort. Most adverse events were mild to moderate, and there were few treatment related serious adverse events.

Target engagement achieved the expected pulsatile patterns, with the 0.03 mg/kg dose providing a shorter duration of receptor occupancy compared to the 0.1 mg/kg dose. There was no association found between baseline PD-L1 score and overall response rate, suggesting that TISvopra may be used to select patients for potential benefit from PD-1 containing therapy independently of PD-L1 score. The distribution of PD-L1 scores within the TISvopra positive patients was similar to what would be expected for an unselected patient population.

"The team did an outstanding job executing on a complex biomarker selected trial impacted by both the pandemic and the war in Ukraine. Although we are intrigued by the preliminary efficacy trends, particularly the landmark PFS and ORR in the lower vopra dose combination arm, the SELECT results do not support moving into registration studies as had been our previous goal. We will re-evaluate the vopra program in the context of our broader pipeline in the coming months," said Richard Murray, Ph.D., chief executive officer and president of Jounce Therapeutics. "We continue to be pleased with pimi’s activity, which supports its continued use in our ongoing and future combination trials. We plan to submit a clinical abstract to present the entire SELECT study, including more mature data, at the ESMO (Free ESMO Whitepaper) Immuno-Oncology Congress in December 2022. We remain focused on our mission of delivering meaningful and long-lasting benefit to cancer patients through the discovery and pursuit of therapies that target new mechanisms of immune suppression across different types of immune cells, and bringing the right immunotherapies to the right patients."

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 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.

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. SELECT is powered to demonstrate the statistical superiority of the combination of vopratelimab plus pimivalimab compared to pimivalimab.