22 Background: In preliminary analyses from the randomized phase 2, open-label CheckMate 650 tria... more 22 Background: In preliminary analyses from the randomized phase 2, open-label CheckMate 650 trial, nivolumab (NIVO) 1 mg/kg (N1) plus ipilimumab (IPI) 3 mg/kg (I3) Q3W × 4 doses showed clinical activity in patients (pts) with post-chemotherapy (post-CT) mCRPC, particularly those with high tumor mutational burden (TMB), but early toxicity contributed to treatment discontinuations. Here, we report results from pts with post-CT mCRPC receiving alternative NIVO+IPI dosing regimens vs IPI alone vs cabazitaxel (CABA) in CheckMate 650. Methods: Newly enrolled pts previously treated with docetaxel for mCRPC were randomized 2:2:1:2 to cohorts D1 (NIVO 3 mg/kg [N3] + IPI 1 mg/kg [I1] Q3W × 4 doses then NIVO 480 mg Q4W), D2 (N1 Q3W × 8 doses + I3 Q6W × 4 doses then NIVO 480 mg Q4W), D3 (I3 Q3W × 4 doses), or D4 (CABA 20 or 25 mg/m2 Q3W + prednisone 10 mg × 10 doses). Crossover from cohorts D3 and D4 to cohort D1 was allowed after radiographic progressive disease. Outcomes included safety, obj...
Chromatin accessibility is essential in regulating gene expression and cellular identity, and alt... more Chromatin accessibility is essential in regulating gene expression and cellular identity, and alterations in accessibility have been implicated in driving cancer initiation, progression and metastasis1–4. Although the genetic contributions to oncogenic transitions have been investigated, epigenetic drivers remain less understood. Here we constructed a pan-cancer epigenetic and transcriptomic atlas using single-nucleus chromatin accessibility data (using single-nucleus assay for transposase-accessible chromatin) from 225 samples and matched single-cell or single-nucleus RNA-sequencing expression data from 206 samples. With over 1 million cells from each platform analysed through the enrichment of accessible chromatin regions, transcription factor motifs and regulons, we identified epigenetic drivers associated with cancer transitions. Some epigenetic drivers appeared in multiple cancers (for example, regulatory regions of ABCC1 and VEGFA; GATA6 and FOX-family motifs), whereas others ...
19 Background: Docetaxel is a treatment option following disease progression on a next-generation... more 19 Background: Docetaxel is a treatment option following disease progression on a next-generation hormonal agent (NHA) for patients with mCRPC, but there is an urgent need for more efficacious treatments. The randomized, double-blind, phase 3 KEYNOTE-921 study (NCT03834506) evaluated the efficacy and safety of pembrolizumab + docetaxel vs placebo + docetaxel for participants (pts) with mCRPC who had received prior NHA therapy. Methods: Eligible pts were ≥18 years old, had mCRPC that progressed on androgen deprivation therapy, had received 1 prior NHA, and had an ECOG performance status of 0 or 1. Pts were randomized 1:1 to receive 200 mg pembrolizumab Q3W or placebo for ≤35 cycles (~2 years) in combination with 75 mg/m2 docetaxel Q3W for ≤10 cycles and 5 mg prednisone BID. The dual primary endpoints were radiographic progression-free survival (rPFS; tested at first interim analysis) per PCWG-modified RECIST 1.1 by blinded independent central review and overall survival (OS; tested a...
5074 Background: Analysis of phase 3 studies of patients (pts) with mHSPC in the era of ADT, incl... more 5074 Background: Analysis of phase 3 studies of patients (pts) with mHSPC in the era of ADT, including in combination with docetaxel and/or androgen receptor axis targeted therapies have established PSA-7mo as a key prognostic marker. Our objective was to evaluate the association between PSA-3mo, PSA 7-mo and OS measured in the phase 3 S1216 trial in mHSPC comparing ADT + orteronel (treatment arm) vs ADT + bicalutamide (control arm) [NCT01809691]. Methods: Pts enrolled in the S1216 trial with available PSA-3mo & PSA-7mo were included in this analysis. PSA responses were defined as complete response (CR) if PSA ≤ 0.2 ng/mL, partial response (PR) for PSA >0.2 and ≤ 4ng/mL, and no response (NR) as PSA >4 ng/mL at month 3 or 7. Landmark OS was measured and Cox regression model applied adjusting for stratification (performance status, extent of disease, early vs late start of treatment, treatment arm). Results: 1251 pts were alive and evaluable for PSA-3mo and 1231 pts were evaluab...
Supplementary Figure S1. AI-based analysis uncovers differences in stromal distribution using sof... more Supplementary Figure S1. AI-based analysis uncovers differences in stromal distribution using software-generated masks between mpMRI-invisible and -visible PCa. Upper, Middle, quantification of stromal distribution in non-malignant and malignant compartments. Bottom, the kernel density estimations (stromal distribution) between malignant and non-malignant compartments (Wasserstein distance) were calculated for each mpMRI-invisible and -visible PCa tumor.
Supplementary Figure S3. Immune cell populations present in the epithelium and stroma of mpMRI-in... more Supplementary Figure S3. Immune cell populations present in the epithelium and stroma of mpMRI-invisible and -visible PCa. A, Box plots showing the percentage of specific immune cell subsets in the different compartments of mpMRI-invisible and -visible PCa tumors. B, Box plots showing the percentage of stromal cells in the different compartments of relapsed or non-relapsed PCa tumors.
Purpose: The first-in-human phase I/II ICONIC trial evaluated an investigational inducible costim... more Purpose: The first-in-human phase I/II ICONIC trial evaluated an investigational inducible costimulator (ICOS) agonist, vopratelimab, alone and in combination with nivolumab in patients with advanced solid tumors. Patients and Methods: In phase I, patients were treated with escalating doses of intravenous vopratelimab alone or with nivolumab. Primary objectives were safety, tolerability, MTD, and recommended phase II dose (RP2D). Phase II enriched for ICOS-positive (ICOS+) tumors; patients were treated with vopratelimab at the monotherapy RP2D alone or with nivolumab. Pharmacokinetics, pharmacodynamics, and predictive biomarkers of response to vopratelimab were assessed. Results: ICONIC enrolled 201 patients. Vopratelimab alone and with nivolumab was well tolerated; phase I established 0.3 mg/kg every 3 weeks as the vopratelimab RP2D. Vopratelimab resulted in modest objective response rates of 1.4% and with nivolumab of 2.3%. The prospective selection for ICOS+ tumors did not enrich...
Purpose PARP inhibitor (PARPi) therapy is approved for patients with metastatic castration-resist... more Purpose PARP inhibitor (PARPi) therapy is approved for patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) genomic aberrations. However, only a fraction of patients with BRCA1/2 mutations respond to PARPi therapy. In this pilot study, we assess PARP-1 expression in prostate cancer patients with and without HRR genomic alternations using a novel PARP-based imaging agent. Procedures Nine advanced prostate cancer patients were studied with PET/CT and [18F]FluorThanatrace (FTT), an analogue of the PARPi rucaparib. Images were analyzed using maximum standardized uptake values (SUVmax). PARP expression was assessed by immunohistochemistry (IHC) when feasible (n = 4). Results We found great variability in FTT uptake (SUVmax range: 2.3–15.4). Patients with HRR mutations had a significantly higher SUVmax (p = 0.0379) than patients with non-HRR mutations although there was an overlap in FTT uptake between groups. Three patients witho...
490Background: Integrating molecular subtypes, gene transcripts associated with disease recurrenc... more 490Background: Integrating molecular subtypes, gene transcripts associated with disease recurrence (DR), and clinicopathologic features may help risk stratify muscle-invasive bladder cancer (MIBC) ...
Docetaxel has immunostimulatory effects that may promote an immunoresponsive prostate tumour micr... more Docetaxel has immunostimulatory effects that may promote an immunoresponsive prostate tumour microenvironment, providing a rationale for combination with nivolumab (programmed death-1 inhibitor) for metastatic castration-resistant prostate cancer (mCRPC). In the non-randomised, multicohort, global phase II CheckMate 9KD trial, 84 patients with chemotherapy-naive mCRPC, ongoing androgen deprivation therapy and ≤2 prior novel hormonal therapies (NHTs) received nivolumab 360 mg and docetaxel 75 mg/m2 every 3 weeks with prednisone 5 mg twice daily (≤10 cycles) and then nivolumab 480 mg every 4 weeks (≤2 years). The co-primary end-points were objective response rate (ORR) and prostate-specific antigen response rate (PSA50-RR; ≥50% decrease from baseline). The confirmed ORR (95% confidence interval [CI]) was 40.0% (25.7-55.7), and the confirmed PSA50-RR (95% CI) was 46.9% (35.7-58.3). The median (95% CI) radiographic progression-free survival (rPFS) and overall survival (OS) were 9.0 (8.0-11.6) and 18.2 (14.6-20.7) months, respectively. In subpopulations with versus without prior NHT, the ORR was 38.7% versus 42.9%, the PSA50-RR was 39.6% versus 60.7%, the median rPFS was 8.5 versus 12.0 months and the median OS was 16.2 months versus not reached. Homologous recombination deficiency status or tumour mutational burden did not appear to impact efficacy. The most common any-grade and grade III-IV treatment-related adverse events were fatigue (39.3%) and neutropenia (16.7%), respectively. Three treatment-related deaths occurred (1 pneumonitis related to nivolumab; 2 pneumonias related to docetaxel). Nivolumab plus docetaxel has clinical activity in patients with chemotherapy-naïve mCRPC. Safety was consistent with the individual components. These results support further investigation in the ongoing phase III CheckMate 7DX trial. CLINICALTRIALS. NCT03338790.
14 Background: ICOS is a costimulatory molecule upregulated on activated T cells. Vopra is an inv... more 14 Background: ICOS is a costimulatory molecule upregulated on activated T cells. Vopra is an investigational ICOS agonist antibody that results in activation and proliferation of primed CD4 T effector cells. Vopra was assessed in heavily pretreated patients with advanced solid tumors as monotherapy (mono) or in combination with nivolumab (nivo) in the Phase 1/2 ICONIC trial (NCT02904226). Emergence of a distinct ICOS high (hi) population of peripheral CD4 T effector cells, not seen with PD-1 inhibitors alone, was associated with improved ORR, PFS and OS with vopra mono and combo therapy (AACR 2019). Baseline tumor and blood biomarkers were assessed for ability to predict ICOS hi CD4 T cell emergence and clinical outcomes. Methods: Fresh pre-treatment tumor biopsies were assessed by RS, a gene signature describing immune cell infiltration, and other biomarkers, including PD-L1 TPS by IHC. Pts were classified as RS1 and RS2 based on medium and high cutoffs. Associations between poten...
Background: ICOS is a costimulatory molecule upregulated on activated T cells. JTX-2011 is an ICO... more Background: ICOS is a costimulatory molecule upregulated on activated T cells. JTX-2011 is an ICOS agonist antibody intended to stimulate primed CD4 T effector cells. JTX-2011 was assessed in pts with advanced solid tumors as monotherapy (mono) and combination (combo) with nivolumab (nivo) in the Phase I/II ICONIC trial (NCT02904226). Peripheral T cell phenotyping in ICONIC demonstrated emergence of an ICOS high (hi) subset of CD4 T cells associated with tumor reductions in mono and combo pts. In ex vivo studies, soluble JTX-2011 stimulated a polyfunctional cytokine response only in ICOS hi cells. Methods: Ad hoc flow cytometry phenotyping on PBMCs from a subset of pts with evaluable samples (n=50) was initiated retrospectively in early 2018 in ongoing pts, then prospectively on newly enrolled pts. Clinical characteristics and outcomes were analyzed, including unadjusted p-values for post-hoc statistical analyses. Phenotyping was also done on samples from pts treated with PD-1/L1 inhibitor (PD-1/L1i) mono collected outside of ICONIC. Results: Emergence of ICOS hi CD4 T effector cells (all FoxP3-, subset Tbet+ Ki67+) was observed in all pts with ≥30% target lesion tumor reduction by investigator assessment on mono and combo therapy (n=7). Emergence was seen in pts with stable target lesions (n=11/23) including loss of these cells with disease progression. ICOS hi cells were not seen in ICONIC pts with target lesion increase ≥20% (n=14), or in pts treated with PD-1/L1i mono, including responders. Emergence of ICOS hi CD4 T cells correlated with improved PFS and OS (Table). Conclusion: Emergence of a distinct ICOS hi population of peripheral CD4 T cells is associated with improved PFS and OS with JTX-2011 mono and combo therapy. Two JTX-2011 development paths are planned: (1) combo with agents that induce ICOS hi CD4 T cells; (2) use of potential putative biomarkers predictive of emergence of this T cell population and JTX-2011 response. Citation Format: Timothy Anthony Yap, Justin F. Gainor, Margaret K. Callahan, Gerald S. Falchook, Russell Kent Pachynski, Patricia LoRusso, Shivaani Kummar, Geoffrey Thomas Gibney, Howard A. Burris, Scott S. Tykodi, Osama E. Rahma, Tanguy Seiwert, Kyriakos P. Papadopoulos, Ellen Hooper, Christopher J. Harvey, Amanda Hanson, Sean Lacey, Rachel McComb, Courtney Hart, Haley Laken, Ty McClure, Elizabeth Trehu. Improved progression-free and overall survival (PFS/OS) in patients (pts) with emergence of JTX-2011 associated biomarker (ICOS high CD4 T cells) on the ICONIC trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT189.
22 Background: In preliminary analyses from the randomized phase 2, open-label CheckMate 650 tria... more 22 Background: In preliminary analyses from the randomized phase 2, open-label CheckMate 650 trial, nivolumab (NIVO) 1 mg/kg (N1) plus ipilimumab (IPI) 3 mg/kg (I3) Q3W × 4 doses showed clinical activity in patients (pts) with post-chemotherapy (post-CT) mCRPC, particularly those with high tumor mutational burden (TMB), but early toxicity contributed to treatment discontinuations. Here, we report results from pts with post-CT mCRPC receiving alternative NIVO+IPI dosing regimens vs IPI alone vs cabazitaxel (CABA) in CheckMate 650. Methods: Newly enrolled pts previously treated with docetaxel for mCRPC were randomized 2:2:1:2 to cohorts D1 (NIVO 3 mg/kg [N3] + IPI 1 mg/kg [I1] Q3W × 4 doses then NIVO 480 mg Q4W), D2 (N1 Q3W × 8 doses + I3 Q6W × 4 doses then NIVO 480 mg Q4W), D3 (I3 Q3W × 4 doses), or D4 (CABA 20 or 25 mg/m2 Q3W + prednisone 10 mg × 10 doses). Crossover from cohorts D3 and D4 to cohort D1 was allowed after radiographic progressive disease. Outcomes included safety, obj...
Chromatin accessibility is essential in regulating gene expression and cellular identity, and alt... more Chromatin accessibility is essential in regulating gene expression and cellular identity, and alterations in accessibility have been implicated in driving cancer initiation, progression and metastasis1–4. Although the genetic contributions to oncogenic transitions have been investigated, epigenetic drivers remain less understood. Here we constructed a pan-cancer epigenetic and transcriptomic atlas using single-nucleus chromatin accessibility data (using single-nucleus assay for transposase-accessible chromatin) from 225 samples and matched single-cell or single-nucleus RNA-sequencing expression data from 206 samples. With over 1 million cells from each platform analysed through the enrichment of accessible chromatin regions, transcription factor motifs and regulons, we identified epigenetic drivers associated with cancer transitions. Some epigenetic drivers appeared in multiple cancers (for example, regulatory regions of ABCC1 and VEGFA; GATA6 and FOX-family motifs), whereas others ...
19 Background: Docetaxel is a treatment option following disease progression on a next-generation... more 19 Background: Docetaxel is a treatment option following disease progression on a next-generation hormonal agent (NHA) for patients with mCRPC, but there is an urgent need for more efficacious treatments. The randomized, double-blind, phase 3 KEYNOTE-921 study (NCT03834506) evaluated the efficacy and safety of pembrolizumab + docetaxel vs placebo + docetaxel for participants (pts) with mCRPC who had received prior NHA therapy. Methods: Eligible pts were ≥18 years old, had mCRPC that progressed on androgen deprivation therapy, had received 1 prior NHA, and had an ECOG performance status of 0 or 1. Pts were randomized 1:1 to receive 200 mg pembrolizumab Q3W or placebo for ≤35 cycles (~2 years) in combination with 75 mg/m2 docetaxel Q3W for ≤10 cycles and 5 mg prednisone BID. The dual primary endpoints were radiographic progression-free survival (rPFS; tested at first interim analysis) per PCWG-modified RECIST 1.1 by blinded independent central review and overall survival (OS; tested a...
5074 Background: Analysis of phase 3 studies of patients (pts) with mHSPC in the era of ADT, incl... more 5074 Background: Analysis of phase 3 studies of patients (pts) with mHSPC in the era of ADT, including in combination with docetaxel and/or androgen receptor axis targeted therapies have established PSA-7mo as a key prognostic marker. Our objective was to evaluate the association between PSA-3mo, PSA 7-mo and OS measured in the phase 3 S1216 trial in mHSPC comparing ADT + orteronel (treatment arm) vs ADT + bicalutamide (control arm) [NCT01809691]. Methods: Pts enrolled in the S1216 trial with available PSA-3mo & PSA-7mo were included in this analysis. PSA responses were defined as complete response (CR) if PSA ≤ 0.2 ng/mL, partial response (PR) for PSA >0.2 and ≤ 4ng/mL, and no response (NR) as PSA >4 ng/mL at month 3 or 7. Landmark OS was measured and Cox regression model applied adjusting for stratification (performance status, extent of disease, early vs late start of treatment, treatment arm). Results: 1251 pts were alive and evaluable for PSA-3mo and 1231 pts were evaluab...
Supplementary Figure S1. AI-based analysis uncovers differences in stromal distribution using sof... more Supplementary Figure S1. AI-based analysis uncovers differences in stromal distribution using software-generated masks between mpMRI-invisible and -visible PCa. Upper, Middle, quantification of stromal distribution in non-malignant and malignant compartments. Bottom, the kernel density estimations (stromal distribution) between malignant and non-malignant compartments (Wasserstein distance) were calculated for each mpMRI-invisible and -visible PCa tumor.
Supplementary Figure S3. Immune cell populations present in the epithelium and stroma of mpMRI-in... more Supplementary Figure S3. Immune cell populations present in the epithelium and stroma of mpMRI-invisible and -visible PCa. A, Box plots showing the percentage of specific immune cell subsets in the different compartments of mpMRI-invisible and -visible PCa tumors. B, Box plots showing the percentage of stromal cells in the different compartments of relapsed or non-relapsed PCa tumors.
Purpose: The first-in-human phase I/II ICONIC trial evaluated an investigational inducible costim... more Purpose: The first-in-human phase I/II ICONIC trial evaluated an investigational inducible costimulator (ICOS) agonist, vopratelimab, alone and in combination with nivolumab in patients with advanced solid tumors. Patients and Methods: In phase I, patients were treated with escalating doses of intravenous vopratelimab alone or with nivolumab. Primary objectives were safety, tolerability, MTD, and recommended phase II dose (RP2D). Phase II enriched for ICOS-positive (ICOS+) tumors; patients were treated with vopratelimab at the monotherapy RP2D alone or with nivolumab. Pharmacokinetics, pharmacodynamics, and predictive biomarkers of response to vopratelimab were assessed. Results: ICONIC enrolled 201 patients. Vopratelimab alone and with nivolumab was well tolerated; phase I established 0.3 mg/kg every 3 weeks as the vopratelimab RP2D. Vopratelimab resulted in modest objective response rates of 1.4% and with nivolumab of 2.3%. The prospective selection for ICOS+ tumors did not enrich...
Purpose PARP inhibitor (PARPi) therapy is approved for patients with metastatic castration-resist... more Purpose PARP inhibitor (PARPi) therapy is approved for patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) genomic aberrations. However, only a fraction of patients with BRCA1/2 mutations respond to PARPi therapy. In this pilot study, we assess PARP-1 expression in prostate cancer patients with and without HRR genomic alternations using a novel PARP-based imaging agent. Procedures Nine advanced prostate cancer patients were studied with PET/CT and [18F]FluorThanatrace (FTT), an analogue of the PARPi rucaparib. Images were analyzed using maximum standardized uptake values (SUVmax). PARP expression was assessed by immunohistochemistry (IHC) when feasible (n = 4). Results We found great variability in FTT uptake (SUVmax range: 2.3–15.4). Patients with HRR mutations had a significantly higher SUVmax (p = 0.0379) than patients with non-HRR mutations although there was an overlap in FTT uptake between groups. Three patients witho...
490Background: Integrating molecular subtypes, gene transcripts associated with disease recurrenc... more 490Background: Integrating molecular subtypes, gene transcripts associated with disease recurrence (DR), and clinicopathologic features may help risk stratify muscle-invasive bladder cancer (MIBC) ...
Docetaxel has immunostimulatory effects that may promote an immunoresponsive prostate tumour micr... more Docetaxel has immunostimulatory effects that may promote an immunoresponsive prostate tumour microenvironment, providing a rationale for combination with nivolumab (programmed death-1 inhibitor) for metastatic castration-resistant prostate cancer (mCRPC). In the non-randomised, multicohort, global phase II CheckMate 9KD trial, 84 patients with chemotherapy-naive mCRPC, ongoing androgen deprivation therapy and ≤2 prior novel hormonal therapies (NHTs) received nivolumab 360 mg and docetaxel 75 mg/m2 every 3 weeks with prednisone 5 mg twice daily (≤10 cycles) and then nivolumab 480 mg every 4 weeks (≤2 years). The co-primary end-points were objective response rate (ORR) and prostate-specific antigen response rate (PSA50-RR; ≥50% decrease from baseline). The confirmed ORR (95% confidence interval [CI]) was 40.0% (25.7-55.7), and the confirmed PSA50-RR (95% CI) was 46.9% (35.7-58.3). The median (95% CI) radiographic progression-free survival (rPFS) and overall survival (OS) were 9.0 (8.0-11.6) and 18.2 (14.6-20.7) months, respectively. In subpopulations with versus without prior NHT, the ORR was 38.7% versus 42.9%, the PSA50-RR was 39.6% versus 60.7%, the median rPFS was 8.5 versus 12.0 months and the median OS was 16.2 months versus not reached. Homologous recombination deficiency status or tumour mutational burden did not appear to impact efficacy. The most common any-grade and grade III-IV treatment-related adverse events were fatigue (39.3%) and neutropenia (16.7%), respectively. Three treatment-related deaths occurred (1 pneumonitis related to nivolumab; 2 pneumonias related to docetaxel). Nivolumab plus docetaxel has clinical activity in patients with chemotherapy-naïve mCRPC. Safety was consistent with the individual components. These results support further investigation in the ongoing phase III CheckMate 7DX trial. CLINICALTRIALS. NCT03338790.
14 Background: ICOS is a costimulatory molecule upregulated on activated T cells. Vopra is an inv... more 14 Background: ICOS is a costimulatory molecule upregulated on activated T cells. Vopra is an investigational ICOS agonist antibody that results in activation and proliferation of primed CD4 T effector cells. Vopra was assessed in heavily pretreated patients with advanced solid tumors as monotherapy (mono) or in combination with nivolumab (nivo) in the Phase 1/2 ICONIC trial (NCT02904226). Emergence of a distinct ICOS high (hi) population of peripheral CD4 T effector cells, not seen with PD-1 inhibitors alone, was associated with improved ORR, PFS and OS with vopra mono and combo therapy (AACR 2019). Baseline tumor and blood biomarkers were assessed for ability to predict ICOS hi CD4 T cell emergence and clinical outcomes. Methods: Fresh pre-treatment tumor biopsies were assessed by RS, a gene signature describing immune cell infiltration, and other biomarkers, including PD-L1 TPS by IHC. Pts were classified as RS1 and RS2 based on medium and high cutoffs. Associations between poten...
Background: ICOS is a costimulatory molecule upregulated on activated T cells. JTX-2011 is an ICO... more Background: ICOS is a costimulatory molecule upregulated on activated T cells. JTX-2011 is an ICOS agonist antibody intended to stimulate primed CD4 T effector cells. JTX-2011 was assessed in pts with advanced solid tumors as monotherapy (mono) and combination (combo) with nivolumab (nivo) in the Phase I/II ICONIC trial (NCT02904226). Peripheral T cell phenotyping in ICONIC demonstrated emergence of an ICOS high (hi) subset of CD4 T cells associated with tumor reductions in mono and combo pts. In ex vivo studies, soluble JTX-2011 stimulated a polyfunctional cytokine response only in ICOS hi cells. Methods: Ad hoc flow cytometry phenotyping on PBMCs from a subset of pts with evaluable samples (n=50) was initiated retrospectively in early 2018 in ongoing pts, then prospectively on newly enrolled pts. Clinical characteristics and outcomes were analyzed, including unadjusted p-values for post-hoc statistical analyses. Phenotyping was also done on samples from pts treated with PD-1/L1 inhibitor (PD-1/L1i) mono collected outside of ICONIC. Results: Emergence of ICOS hi CD4 T effector cells (all FoxP3-, subset Tbet+ Ki67+) was observed in all pts with ≥30% target lesion tumor reduction by investigator assessment on mono and combo therapy (n=7). Emergence was seen in pts with stable target lesions (n=11/23) including loss of these cells with disease progression. ICOS hi cells were not seen in ICONIC pts with target lesion increase ≥20% (n=14), or in pts treated with PD-1/L1i mono, including responders. Emergence of ICOS hi CD4 T cells correlated with improved PFS and OS (Table). Conclusion: Emergence of a distinct ICOS hi population of peripheral CD4 T cells is associated with improved PFS and OS with JTX-2011 mono and combo therapy. Two JTX-2011 development paths are planned: (1) combo with agents that induce ICOS hi CD4 T cells; (2) use of potential putative biomarkers predictive of emergence of this T cell population and JTX-2011 response. Citation Format: Timothy Anthony Yap, Justin F. Gainor, Margaret K. Callahan, Gerald S. Falchook, Russell Kent Pachynski, Patricia LoRusso, Shivaani Kummar, Geoffrey Thomas Gibney, Howard A. Burris, Scott S. Tykodi, Osama E. Rahma, Tanguy Seiwert, Kyriakos P. Papadopoulos, Ellen Hooper, Christopher J. Harvey, Amanda Hanson, Sean Lacey, Rachel McComb, Courtney Hart, Haley Laken, Ty McClure, Elizabeth Trehu. Improved progression-free and overall survival (PFS/OS) in patients (pts) with emergence of JTX-2011 associated biomarker (ICOS high CD4 T cells) on the ICONIC trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT189.
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