Efficacy and immune-related adverse event associations in avelumab-treated patients.

BACKGROUND: Adverse events (AEs) of special interest that arise during treatment with immune checkpoint inhibitors, including immune-related AEs (irAEs), have been reported to be associated with improved clinical outcomes. We analyzed patients treated with avelumab from the JAVELIN Solid Tumor and Merkel 200 trials, examining the association between AEs and efficacy while adjusting for confounding factors such as treatment duration and event order. METHODS: We analyzed efficacy and safety data from 1783 patients treated with the programmed death ligand 1 inhibitor avelumab who were enrolled in expansion cohorts of the JAVELIN Solid Tumor and Merkel 200 trials. To analyze the association between irAEs and efficacy with regard to survival, we used a time-dependent Cox model with time-varying indicators for irAEs, as well as multistate models that accounted for competing risks and time inhomogeneity. RESULTS: 295 patients (16.5%) experienced irAEs and 454 patients (25.5%) experienced infusion-related reactions. There was a reduced risk of death in patients who experienced irAEs compared with those who did not (HR 0.71, 95% CI 0.59 to 0.85) using the time-dependent Cox model. The multistate model did not suggest that the occurrence of irAEs could predict response; however, it predicted a higher chance of irAEs occurring after a response. No association was observed between response and infusion-related reactions. CONCLUSIONS: Patients who experience irAEs showed improved survival. Although irAEs are not predictors for response to immune checkpoint inhibitors, increased vigilance for irAEs is needed after treatment with avelumab. TRIAL REGISTRATION NUMBERS: NCT01772004 and NCT02155647.

The TRUST (EvaluaTion of Bladder Function in Relapsing-Remitting MUltiple Sclerosis Patients Treated with Natalizumab) Observational Study.

BACKGROUND: Bladder dysfunction is a common symptom of multiple sclerosis (MS). This study was designed to evaluate effects of natalizumab on bladder function in patients with relapsing-remitting MS. METHODS: The TRUST (EvaluaTion of Bladder Function in Relapsing-Remitting MUltiple Sclerosis Patients Treated with Natalizumab) study was an open-label, single-arm, two-center study. Natalizumab-naive MS patients with disabling bladder dysfunction and initiating natalizumab were enrolled and followed for 6 months. The primary endpoint was change in the Urogenital Distress Inventory short form (UDI-6) score from baseline. Change in Incontinence Impact Questionnaire short form (IIQ-7) score from baseline was a secondary endpoint. RESULTS: Thirty patients were enrolled. Mean baseline characteristics were age 49.9 years, Expanded Disability Status Scale score 4.6, number of relapses in previous year 2.4, UDI-6 score 10.4, and IIQ-7 score 12.3. Mean changes in UDI-6 and IIQ-7 scores were significantly improved from baseline beginning at week 4 and up to week 24; mean improvements at 24 weeks were 4.4 (P < .0001) and 4.9 (P = .0005) points, respectively. At week 24, 85.7% and 78.6% of patients demonstrated improvements from baseline in UDI-6 and IIQ-7 scores, respectively. CONCLUSIONS: Incontinence-related quality of life as measured by UDI-6 and IIQ-7 scores improved significantly during natalizumab treatment.

Effect of neutralizing antibodies on biomarker responses to interferon beta: the INSIGHT study.

BACKGROUND: Interferon beta (IFNbeta) effectively reduces disease activity in patients with multiple sclerosis (MS). Neutralizing antibodies (NAbs) can diminish or abolish the clinical efficacy of IFNbeta therapies. Biomarkers of the IFNbeta response, such as myxovirus resistance protein A (MxA), viperin, and interferon-induced protein with tetratricopeptide repeats 1 (IFIT-1), may be used to measure the in vivo effects of NAbs on IFNbeta bioactivity. METHODS: In this multicenter, open-label study, antibody status was measured at screening, and then antibody status, levels of MxA, viperin, and IFIT-1 were measured at baseline (< or =8 weeks after screening) and 6 months after baseline in patients with relapsing forms of MS treated with IM IFNbeta-1a, subcutaneous (SC) IFNbeta-1a, or IFNbeta-1b. RESULTS: Treatment with IM IFNbeta-1a was associated with a lower rate of NAb formation among 718 patients screened (p < 0.0001 vs SC IFNbeta-1a 22 microg, 44 microg, and IFNbeta-1b). At baseline, patients who were binding antibody positive (BAb+)/neutralizing antibody positive (NAb+) had lower MxA, viperin, and IFIT-1 response compared with BAb-negative (BAb-)/NAb-negative (NAb-) patients (all p < 0.0001). Analyses stratified by NAb titer level among BAb+/NAb+ patients showed diminished biomarker response in patients with NAb titers from 20 to 99 tenfold reduction units (TRU) and abolished response in patients with NAb titers > or =100 TRU compared with BAb-/NAb- patients. A majority of patients BAb+/NAb+ at screening remained BAb+/NAb+ throughout the study, and biomarker responses remained consistently depressed in these patients at month 6. CONCLUSIONS: These data provide evidence that high titers of neutralizing antibodies abolish the in vivo response to interferon beta.