First-in-Human Phase I/II ICONIC Trial of the ICOS Agonist Vopratelimab Alone and with Nivolumab: ICOS-High CD4 T-Cell Populations and Predictors of Response.

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 for responses. A vopratelimab-specific peripheral blood pharmacodynamic biomarker, ICOS-high (ICOS-hi) CD4 T cells, was identified in a subset of patients who demonstrated greater clinical benefit versus those with no emergence of these cells [overall survival (OS), P = 0.0025]. A potential genomic predictive biomarker of ICOS-hi CD4 T-cell emergence was identified that demonstrated improvement in clinical outcomes, including OS (P = 0.0062). CONCLUSIONS: Vopratelimab demonstrated a favorable safety profile alone and in combination with nivolumab. Efficacy was observed only in a subset of patients with a vopratelimab-specific pharmacodynamic biomarker. A potential predictive biomarker of response was identified, which is being prospectively evaluated in a randomized phase II non-small cell lung cancer trial. See related commentary by Lee and Fong, p. 3633.

The relationship among symptoms, sleep disturbances and quality of life in patients with interstitial cystitis.

PURPOSE: We conducted a retrospective analysis to determine associations among symptoms, sleep disturbances and quality of life in responder and nonresponder groups of patients with interstitial cystitis. MATERIALS AND METHODS: Patients in a multidose pentosan polysulfate sodium clinical trial with a diagnosis of interstitial cystitis who were randomized to 300 mg pentosan polysulfate sodium per day (128) completed the Interstitial Cystitis Symptom Index, an adapted Medical Outcomes Study Sleep scale and the Medical Outcomes Study Short Form-12 Health Survey at baseline, and at weeks 8, 16, 24 and 32. Responders were defined as those achieving a 30% or greater reduction in Interstitial Cystitis Symptom Index score from baseline to study end point (week 32 or last observation carried forward). RESULTS: A positive correlation at baseline was observed between sleep scores and Short Form-12 physical and mental components (r = 0.43 and 0.37, respectively, p <0.0001). Patients showed statistically significant improvement in Interstitial Cystitis Symptom Index and sleep scores by week 32. Responders (48, 43%) had a mean change in sleep score of 11.8 +/- 22.4 while nonresponders (64, 57%) had a mean change of 1.6 +/- 15.7 (p = 0.0055 between groups). The reduction in Interstitial Cystitis Symptom Index score correlated with improvement in sleep score from baseline to study end point (r = -0.33, p = 0.0003). At the study end point responders demonstrated a significant improvement in the Short Form-12 physical component compared with baseline (p <0.0001). CONCLUSIONS: Reduction in interstitial cystitis symptoms may be associated with patient reported improvement in sleep and quality of life.

Improvement in sexual functioning in patients with interstitial cystitis/painful bladder syndrome.

INTRODUCTION: Sexual functioning is one of the strongest predictors of poorer quality of life (QOL) in patients diagnosed with interstitial cystitis/painful bladder syndrome (IC/PBS). AIMS: To examine the relationship between symptom reduction and sexual functioning in patients with IC/PBS. METHODS: Patients with IC/PBS were treated with 300 mg/day pentosan polysulfate sodium for 32 weeks. MAIN OUTCOME MEASURES: Patients completed the O'Leary-Sant Interstitial Cystitis Symptom Index, Short Form-12 QOL, and Medical Outcomes Study Sexual Functioning Scale at baseline, and at 8, 16, 24, and 32 weeks. Treatment responders were defined as those achieving a >/=30% reduction in symptom index from baseline. RESULTS: A total of 128 patients were included in the analyses. At baseline, mean symptom index, QOL (physical and mental), and sexual functioning scores were 12.3, 41.7, 45.9, and 56.1, respectively. Patients showed statistically significant improvement in symptom and sexual functioning scores at weeks 8, 16, 24, and 32. At week 32, the mean change in symptom index score from baseline was -2.97 (standard deviation [SD] = 4.66, P < 0.0001), and the mean change in sexual functioning score from baseline was 8.9 (SD = 32.9, P = 0.0054). Reduction in symptom index score was moderately correlated with improvement in sexual functioning score at the end of study (r = -35, P = 0.0002). Positive correlation was observed at the end of the study between the mean change scores of sexual functioning score and physical and mental QOL components (r = 0.46, P < 0.0001 and r = 0.29, P = 0.0023, respectively). Patients achieving a >/=30% reduction in symptom index (responder, N = 47; 44%) had an adjusted mean change in sexual functioning score of 19.8 (standard error [SE] = 4.69), while nonresponders (N = 59, 56%) had an adjusted mean change -0.49 (SE = 4.17) (between groups, P = 0.0020). CONCLUSIONS: Sexual dysfunction is moderate to severe in patients with IC/PBS and impacts significantly on QOL. Reduction in symptoms was associated with improvement in the patient-reported outcomes of sexual function.