Patient experience of medication administration and development of a Patient Experience and Preference Questionnaire (PEPQ) for patients with advanced or metastatic cancer

Introduction: A better understanding of patient experience of intravenous (IV) or subcutaneous (SC) routes of administration is fundamental to providing optimal administration of medical therapies to oncology patients. The objective of this study was to examine patient experiences of IV and SC treatment with nivolumab and confirm the relevance of item concepts in the Patient Experience and Preference Questionnaire (PEPQ). The PEPQ is a clinical outcomes’ assessment instrument developed to obtain patient-centric data and understand the experience with IV and SC treatment administration.Methods: Embedded qualitative interviews were conducted with a subset of participants from three treatment cohorts with metastatic non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), unresectable or advanced metastatic melanoma, hepatocellular carcinoma (HCC), or colorectal cancer (CRC) from the CA209-8KX clinical trial. Concept elicitation interviews were conducted within 14 days of the initial treatment cycle and patient experiences with IV and SC treatment administration were assessed. Concepts from interviews were mapped to the PEPQ version 1.0 questions to assess relevance and convergence of concepts.Results: Interviews were conducted with 43 trial participants from clinical sites opting to participate from six countries (Argentina, France, the Netherlands, Poland, Spain, and New Zealand). The mean age of sub-study participants was 66 ± 11.3 years (range 24–80 years), and 67.4% (N = 29) were male. Sub-study participants with experience of SC most frequently reported symptoms or signs of injection-related redness (27.9%), itching (14.0%), and pain (of needle), and described the pain as pricking, stinging, or tingling (11.0% each). The amount of pain and time burden were widely endorsed as important factors for satisfaction and related to the route of medication administration. For 11 sub-study participants with experience with both IV and SC treatments, 10 (90.9%) preferred SC over IV treatment administration.Conclusion: This study summarizes the experience and satisfaction of receiving IV or SC treatment and confirms the relevance of the PEPQ in a subgroup of CA209-8KX clinical trial participants with metastatic NSCLC, RCC, melanoma, HCC, and CRC. Participant treatment experience and satisfaction with the route of medication mapped to the PEPQ question content support the relevance of PEPQ v2.0 in clinical trials as a self-report measure

Nivolumab plus ipilimumab versus chemotherapy as first-line treatment in advanced non-small-cell lung cancer with high tumour mutational burden: Patient-reported outcomes results from the randomised, open-label, phase III CheckMate 227 trial

BACKGROUND: In the phase III CheckMate 227 study, first-line nivolumab + ipilimumab significantly prolonged progression-free survival (co-primary end-point) versus chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) and high tumour mutational burden (TMB; ≥10 mutations/megabase). AIM: To evaluate patient-reported outcomes (PROs) in this population. METHODS: Disease-related symptoms and general health status were assessed using the validated PRO questionnaires Lung Cancer Symptom Scale (LCSS) and EQ-5D, respectively. LCSS average symptom burden index (ASBI) and three-item global index (3-IGI) and EQ-5D visual analogue scale (VAS) and utility index (UI) scores and changes from baseline were analysed descriptively. Longitudinal changes were assessed by mixed-effect model repeated measures (MMRMs) and time to first deterioration/improvement analyses. RESULTS: In the high TMB population, PRO questionnaire completion rates were ∼90% at baseline and \u3e80% for most on-treatment assessments. During treatment, mean changes from baseline with nivolumab + ipilimumab showed early, clinically meaningful improvements in LCSS ASBI/3-IGI and EQ-5D VAS/UI; with chemotherapy, symptoms and health-related quality of life remained stable (LCSS ASBI/3-IGI, EQ-5D UI) or improved following induction (EQ-5D VAS). MMRM-assessed changes in symptom burden were improved with nivolumab + ipilimumab versus chemotherapy. Symptom deterioration by week 12 was lower with nivolumab + ipilimumab versus chemotherapy (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% confidence interval 2.4-22.5]), irrespective of discontinuation. Time to first deterioration was delayed with nivolumab + ipilimumab versus chemotherapy across LCSS and EQ-5D summary measures. CONCLUSION: First-line nivolumab + ipilimumab demonstrated early, sustained improvements in PROs versus chemotherapy in patients with advanced NSCLC and high TMB. CLINICAL TRIAL REGISTRATION: NCT02477826

Nivolumab plus ipilimumab versus chemotherapy as first-line treatment in advanced non-small-cell lung cancer with high tumour mutational burden: Patient-reported outcomes results from the randomised, open-label, phase III CheckMate 227 trial

BACKGROUND: In the phase III CheckMate 227 study, first-line nivolumab + ipilimumab significantly prolonged progression-free survival (co-primary end-point) versus chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) and high tumour mutational burden (TMB; ≥10 mutations/megabase). AIM: To evaluate patient-reported outcomes (PROs) in this population. METHODS: Disease-related symptoms and general health status were assessed using the validated PRO questionnaires Lung Cancer Symptom Scale (LCSS) and EQ-5D, respectively. LCSS average symptom burden index (ASBI) and three-item global index (3-IGI) and EQ-5D visual analogue scale (VAS) and utility index (UI) scores and changes from baseline were analysed descriptively. Longitudinal changes were assessed by mixed-effect model repeated measures (MMRMs) and time to first deterioration/improvement analyses. RESULTS: In the high TMB population, PRO questionnaire completion rates were ∼90% at baseline and \u3e80% for most on-treatment assessments. During treatment, mean changes from baseline with nivolumab + ipilimumab showed early, clinically meaningful improvements in LCSS ASBI/3-IGI and EQ-5D VAS/UI; with chemotherapy, symptoms and health-related quality of life remained stable (LCSS ASBI/3-IGI, EQ-5D UI) or improved following induction (EQ-5D VAS). MMRM-assessed changes in symptom burden were improved with nivolumab + ipilimumab versus chemotherapy. Symptom deterioration by week 12 was lower with nivolumab + ipilimumab versus chemotherapy (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% confidence interval 2.4-22.5]), irrespective of discontinuation. Time to first deterioration was delayed with nivolumab + ipilimumab versus chemotherapy across LCSS and EQ-5D summary measures. CONCLUSION: First-line nivolumab + ipilimumab demonstrated early, sustained improvements in PROs versus chemotherapy in patients with advanced NSCLC and high TMB. CLINICAL TRIAL REGISTRATION: NCT02477826

T cell-inflamed gene expression profile and PD-L1 expression and pembrolizumab efficacy in advanced esophageal cancer

Aim: Investigate the relationship between response to pembrolizumab and expression of the 18-gene T cell-inflamed gene expression profile (TcellinfGEP) or PD-L1 combined positive score (CPS) in esophageal cancer. Materials & methods: This analysis included heavily pretreated patients with advanced/metastatic esophageal/gastroesophageal junction adenocarcinoma or squamous cell carcinoma who received pembrolizumab in the single-arm, phase II study KEYNOTE-180. PD-L1 CPS was evaluated with PD-L1 IHC 22C3 pharmDx. Results: In patients with squamous cell carcinoma, trends toward enrichment for responders were observed for patients with PD-L1 CPS ≥10 tumors. In patients with adenocarcinoma, a trend was observed for TcellinfGEP but not for PD-L1. Conclusion: TcellinfGEP and PD-L1 CPS may enrich for responders to pembrolizumab in patients with esophageal cancer. Clinical Trial Registration: NCT02559687 (ClinicalTrials.gov

Effets du cisplatine sur la sensibilité des cancers bronchiques non à petites cellules EGFR sauvage aux inhibiteurs de tyrosine kinase anti EGFR

Les inhibiteurs de tyrosine kinase (ITK) anti EGFR ont très nettement amélioré la survie des patients atteints de cancers bronchiques non à petites cellules (CBNPC) métastatiques porteurs d’une mutation activatrice d’EGFR. En l’absence de mutation activatrice, le bénéfice de ces traitements est marginal et semble conditionné par l’utilisation préalable de la chimiothérapie. Dans cette étude, l’exposition préalable de cellules de CBNPC EGFR sauvage à des doses sub-léthales de cisplatine induit une augmentation de la phosphorylation d’EGFR augmentant la sensibilité de ces cellules à l’erlotinib, ITK anti-EGFR, in vitro et in vivo, contrairement à l’effet observé sur des cellules EGFR mutées. Cette activation d’EGFR est liée à la transactivation du récepteur par Src selon un mécanisme indépendant des ligands d’EGFR mais impliquant l’IL6. Cette activation d’EGFR ligand indépendante est corrélée à l’activation de la voie interféron de type 1 en particulier de TBK1, IRF3 et l’augmentation de l’expression de deux de leurs gènes cible IFIT1 et IFI27. L’augmentation de l’expression d’IFIT1 et d’IFI27 ainsi que de l’IL6 sont des marqueurs robustes de la sensibilisation aux ITK induite par le cisplatine in vitro et in vivo. Enfin les résultats de notre étude suggèrent un rôle important dans cette sensibilisation de la localisation mitochondriale d’EGFR possiblement induite par la phosphorylation de la tyrosine 845, cible privilégiée de Src. Cette sensibilisation pourrait être liée au rôle joué par l’EGFR mitochondrial dans la dynamique et la morphologie mitochondriale ainsi que dans le métabolisme cellulaire.Anti-EGFR tyrosine kinase inhibitors (ITKs) have markedly improved the overall survival of patients with metastatic non-small cell lung cancer (NSCLC) with an EGFR activating mutation. In the absence of activating mutation, the benefit of these treatments is marginal and seems conditioned by the prior use of chemotherapy. In this study, prior exposure of wild-type EGFR NSCLC cells to sub-lethal doses of cisplatin induces an increase in EGFR phosphorylation increasing the sensitivity of these cells to erlotinib, anti-EGFR TKI, in vitro and in vivo, contrary to the effect observed on mutated EGFR cells. This activation of EGFR is related to the transactivation of the receptor by Src according to an independent mechanism of the EGFR ligands but involving IL6. This independent ligand activation of EGFR is correlated with the activation of the type 1 interferon pathway, in particular TBK1, IRF3, and the increase in the expression of two of their targeted genes IFIT1 and IFI27. Increasing expression of IFIT1 and IFI27 as well as IL6 are robust markers of cisplatin-induced ITK sensitization in vitro and in vivo. Finally the results of our study suggest an important role in this sensitization of the mitochondrial localization of EGFR, possibly induced by the phosphorylation of tyrosine 845, tyrosine target of Src. This sensitization could be related to the role played by the mitochondrial EGFR in the dynamics and the mitochondrial morphology as well as in the cellular metabolism

Impact de la chimiothérapie de première ligne sur la survie des cancers du sein métastatiques au cours du temps

La prise en charge du cancer du sein métastatique a évolué ces 20 dernières années avec le développement de nouveaux traitements de chimiothérapie dont l'impact sur la survie n'est pas clairement établi. Nous avons analysé l'impact de la 1ère ligne de chimiothérapie sur la survie au cours du temps en comparant deux populations de patientes suivies pour un cancer du sein métastatique à l'Institut de Cancérologie de l'Ouest entre 1992 et 1995 (période I n=185) et entre 2001 et 2004 (période II n=196). Il n'y a pas de différence significative en survie globale entre les deux périodes (26 vs 29 mois p=0.12). Il existe une augmentation significative de la survie sans progression au cours du temps pour la population globale (10.2 vs 12 mois p=0.08) et dans le sous-groupe des patientes traitées par une 1ère ligne de chimiothérapie (8.4 vs 11.8 mois p=0.022). Le délai sans rechute > 24 mois, la positivité des récepteurs aux œstrogènes et la période II sont des facteurs pronostiques favorables sur la survie globale. Les nouveaux agents de chimiothérapie améliorent la survie sans progression mais ne semblent pas améliorer la survie globale.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Opportunities and Obstacles to the Development of Health Data Warehouses in Hospitals in France: The Recent Experience of Comprehensive Cancer Centers

Big Data and Artificial Intelligence can profoundly transform medical practices, particularly in oncology. Comprehensive Cancer Centers have a major role to play in this revolution. With the purpose of advancing our knowledge and accelerating cancer research, it is urgent to make this pool of data usable through the development of robust and effective data warehouses. Through the recent experience of Comprehensive Cancer Centers in France, this article shows that, while the use of hospital data warehouses can be a source of progress by taking into account multisource, multidomain and multiscale data for the benefit of knowledge and patients, it nevertheless raises technical, organizational and legal issues that still need to be addressed. The objectives of this article are threefold: 1. to provide insight on public health stakes of development in Comprehensive Cancer Centers to manage cancer patients comprehensively; 2. to set out a challenge of structuring the data from within them; 3. to outline the legal issues of implementation to carry out real-world evidence studies. To meet objective 1, this article firstly proposed a discussion on the relevance of an integrated approach to manage cancer and the formidable tool that data warehouses represent to achieve this. To address objective 2, we carried out a literature review to screen the articles published in PubMed and Google Scholar through the end of 2022 on the use of data warehouses in French Comprehensive Cancer Centers. Seven publications dealing specifically with the issue of data structuring were selected. To achieve objective 3, we presented and commented on the main aspects of French and European legislation and regulations in the field of health data, hospital data warehouses and real-world evidence

Adenosine Methylation Level of miR-125a-5p Promotes Anti-PD-1 Therapy Escape through the Regulation of IGSF11/VSIG3 Expression

Background: Despite encouraging anti-tumour activity in lung cancer, anti-PD-1 therapy has encountered increasing resistance to treatment. Several companion diagnostic assays have been performed to identify patients who may benefit from this immunotherapy and to adapt this therapy in case of acquired resistance. Methods: A large panel of methods was used for the analysis of expression and methylation levels of miRNAs (qPCR, MemiRIP, …), protein/miRNA interactions (CLIP, oligo pull-down, …), and protein–protein interactions (CoIP) in cells and/or blood samples. Results: Our work highlights that the saturation of PD-1 by anti-PD1 therapies induces an immune escape phenomenon due to the overexpression of IGSF11 following adenosine methylation of miR-125a-5p. Mechanistically, we identify METTL3/KHDRBS3 and HuR as two crucial players in the methylation and the loss of the repressive function of this miRNA. Finally, our work shows that the adenosine methylation of miR-125a-5p is analyzable from EVs/exosomes from longitudinal blood samples and that such EVs/exosomes modulate the IGSF11/VSIG3 expression in lung cancer cells to promote an immune escape phenomenon. Conclusions: Our data provide a biomarker (m6A-miR-125a-5p level) and two therapeutic solutions (anti-IGSF11 antibody and METTL3 inhibitor) that could potentially address the anti-PD1 therapy failure in the context of precision and personalized medicine

Prognostic Impact of TP53 Mutations in Metastatic Nonsquamous Non–small-cell Lung Cancer

International audienceBackground: The prognostic impact of TP53 mutations in advanced or metastatic nonsquamous non-small-cell lung cancer (nsNSCLC) patients treated with chemotherapy and/or immune checkpoint inhibitors (ICI) remains unclear.Materials and methods: We retrospectively collected data from patients with nsNSCLC treated in the first line from January 2018 to May 2021. The patient was separated into 2 groups according to their TP53 mutation status (wt vs. mut). Survival was estimated through the Kaplan-Meier method and compared by log-rank test.Results: Of 220 patients included, 126 were in the mutTP53 group, and 94 were in the wtTP53wt group. Median OS (mOS) was not significantly different between the mutTP53 and wtTP53 groups [17.5 months (95% confidence interval (CI), 11.3-21.5) vs. 9.5 months (95% CI, 7.4-14.2), (P = .051)]. In subgroup analyses, the mutTP53 group treated with ICI had a significantly improved mOS compared to the wtTP53 group [(24.7 months (95% CI, 20.8-not reach) vs. 12.0 months (95% CI, 4.7-not reach), (P = .017)] and mPFS [(9.6 months (95% CI, 5.8-not reach) vs. 3.2 months (95% CI, 1.3-13.8) (P = .048)]. There was no difference in terms of mOS and mPFS between the mutTP53 and the wtTP53 group treated by chemotherapy alone or combined with ICI.Conclusion: TP53 mutation had no survival impact in the overall population, but is associated with better outcomes with ICI alone. These results suggest that patients with TP53 mutations could be treated with ICI alone, and wild-type patients could benefit from the addition of chemotherapy