Ipilimumab with Nivolumab in molecular-Selected patients with castration-resistant PRostate cancer: primary analysis of the Phase 2 INSPIRE trial.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) typically exhibits resistance to immune checkpoint inhibitors (ICIs). However, a subset of mCRPC patients displays a more immunogenic profile. This study examines efficacy and safety of dual ICI therapy in molecularly selected mCRPC. PATIENTS AND METHODS: This single-arm, phase II trial, included 69 molecularly selected mCRPC patients with mismatch repair deficiency (MMRd), non-synonymous tumour mutational burden ≥7.1 muts/Mb (hTMB), a BRCA2 mutation (BRCAm), or biallelic CDK12 inactivation (CDK12i). Efficacy was assessed in ICI-naïve patients (cohort A) with RECIST1.1 (A1) and PCWG3 (A2) measurable disease. Safety was evaluated in cohorts A and B (prior ICI monotherapy). Treatment included nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for 4 cycles, followed by nivolumab 480 mg every 4 weeks for up to 1 year. The primary endpoint was disease control rate beyond 6 months (DCR>6), aiming to surpass a DCR>6 of 22%. RESULTS: Patients initiated treatment between January 2021 and February 2024. Cohort A included 65 patients. Of these, 21 had MMRd (32%), 8 hTMB (12%), 20 BRCAm (31%), and 16 CDK12i (25%). DCR>6 was achieved in 38% (95% CI 27-51), and was highest in MMRd (81%), followed by hTMB (25%), CDK12i (19%), and BRCAm (15%). Objective and PSA50 response rates in cohort A were 38% (95% CI 22-55) and 47% (95% CI 34-60), respectively. Median progression-free survival was 4.0 months (95% CI 3.5-12.0) in cohort A, and 32.7 months (95% CI 21.8-NR) in MMRd patients. Treatment-related adverse events (TRAEs) led to permanent discontinuation in 14 of 69 patients (20%). Grade ≥3 TRAEs occurred in 48% of patients, with diarrhoea and elevated transaminases each in 10%. There was one treatment-related death due to a bowel perforation and a second following euthanasia after grade 4 toxicity. CONCLUSIONS: This trial of dual ICIs in molecularly selected mCRPC met its primary endpoint, showing DCR>6 in 40% of patients. Dual ICIs exhibited modest responses in the hTMB, BRCAm and CDK12i subgroups, but demonstrated exceptional efficacy in MMRd.

Real-world data on the management of pazopanib-induced liver toxicity in routine care of renal cell cancer and soft tissue sarcoma patients.

PURPOSE: Pazopanib is known to cause liver toxicity. A relationship between pazopanib exposure and alanine transaminase elevations has been described in clinical trials. This study investigated the relation between pazopanib exposure and liver toxicity in real-world patients and evaluated the management of pazopanib-induced liver toxicity in routine care. METHODS: A retrospective observational cohort study was performed in patients treated with pazopanib in whom pazopanib exposure was measured. The percentage of patients with and without liver toxicity during treatment with pazopanib was calculated as well as the average pazopanib exposure in both groups. Furthermore, the management of patients with liver toxicity was evaluated. RESULTS: Liver toxicity was observed in 25 out of the 133 patients included (19%). Pazopanib exposure was comparable in patients with or without liver toxicity (27.7 mg/L versus 28.1 mg/L). Seven patients permanently discontinued pazopanib after the occurrence of liver toxicity. Of the remaining 18 patients, continuation or restart of pazopanib after liver toxicity was successful in 16 patients and half of these patients were able to safely continue pazopanib at the same dose as prior to liver toxicity for the remaining duration of treatment. CONCLUSION: Our study did not demonstrate a clear relationship between pazopanib exposure and the occurrence of pazopanib-induced liver toxicity. Half of the patients were able to safely continue or restart pazopanib treatment after liver toxicity and received the same dose as prior to drug withdrawal. Successful interventions to address pazopanib-induced toxicity in the clinic led to an algorithm for the management of pazopanib-induced liver toxicity.

Case Report: Imaging immune checkpoint inhibitor-induced yin-yang effects in the brain.

Background: Treatment with immune checkpoint inhibitors (ICI) can induce durable responses in cancer patients, but it is commonly associated with serious immune-related side effects. Both effects are suggested to be mediated by CD8+ T-cell infiltration. Whole body CD8+ T-cell distribution can be visualized by PET imaging of a 89Zr-labeled anti-humanCD8a minibody, currently investigated in a phase 2b trial. Main body: An adult patient diagnosed with metastatic melanoma developed ICI-related hypophysitis after two courses of combined immunotherapy (ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) at 3 weeks interval). On a [89Zr]Zr-crefmirlimab berdoxam PET/CT scan, made 8 days before clinical symptoms occurred, increased CD8+ T-cell infiltration in the pituitary gland was detected. Simultaneously, tracer uptake in a cerebral metastasis was increased, indicating ICI-induced tumor infiltration by CD8+ T-cells. Conclusions: The observations in this case report underscore the role of CD8+ T-cell in non-tumor tissues in ICI-related toxicity. In addition, it illustrates a potential role for molecular imaging by PET/CT for investigation and monitoring of ICI-induced effects.

Health-related quality of life analysis in stage III melanoma patients treated with adjuvant dendritic cell therapy.

BACKGROUND: Health-related quality of life (HRQoL) is an important issue in the rapidly evolving field of adjuvant treatment for stage III melanoma. Dendritic cell vaccination is one of the adjuvant forms of therapy currently investigated. METHODS: We enrolled adults with stage III melanoma to receive adjuvant dendritic cell vaccination after a complete radical lymph node dissection. HRQoL assessment was one of the secondary endpoints of this trial and investigated with the EORTC-QLQ-C30 questionnaire at baseline and week 26. RESULTS: Fifteen patients with a median age of 50 years were included in the study, with twelve evaluable patients on study at time of the second questionnaire. Global health status and role functioning improved clinically relevant with a mean difference of 15 (p = 0.010) and 26 points (p = 0.005), respectively. DISCUSSION: Despite the small number of patients, we found a clinically relevant improved global health status. Besides, compared to the other investigated therapies, toxicity of dendritic cell vaccination is low, which supports our finding. CONCLUSION: This is the first description of HRQoL in melanoma patients receiving dendritic cell vaccination. We show the expected improvement in global health status after surgical treatment of stage III melanoma. Thus, adjuvant dendritic cell vaccination does not seem to hamper this improvement, as shown in our small explorative study.

Gebruik van comedicatie tijdens palliatieve sedatie.

- Palliative sedation is a treatment option for patients in the terminal stage of their disease who have one or more refractory symptoms.- In giving palliative sedation it is important to take into account the pharmacokinetic and pharmacodynamic properties of medications that contribute to good palliation: this covers both medication used in palliative sedation and continued chronic medication.- This article provides tools for clinical practice to deal with the difficulties concerning stopping or continuing chronic medication and on interaction between medications in palliative sedation.