Search

BackgroundNeratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for HER2-positive early-stage and metastatic breast cancer. Diarrhea is the most frequent side effect and the most common reason for early discontinuation. The phase II CONTROL trial investigated antidiarrheal prophylaxis or neratinib dose escalation (DE) for prevention of diarrhea. We present complete study results including final data for two DE strategies.MethodsPatients who completed trastuzumab-based adjuvant therapy received neratinib 240mg/day for 1 year. Early cohorts investigated mandatory prophylaxis with loperamide, then additional budesonide or colestipol. Final cohorts assessed neratinib DE over the first 2 (DE1) or 4 weeks (DE2). The primary endpoint was incidence of grade ≥3 diarrhea. Health-related quality of life (HRQoL) was assessed using FACT-B and EQ-5D-5L.Results563 patients were enrolled into six cohorts. All strategies reduced grade ≥3 diarrhea with the lowest incidence in DE1 (DE1 13%; colestipol+loperamide [CL] 21%, DE2 27%; budesonide+loperamide [BL] 28%; loperamide [L] 31%; colestipol+loperamide as needed [CL-PRN] 33%). Diarrhea-related discontinuations occurred early and were lowest in DE1 (DE1 3%; CL 4%; DE2 6%; CL-PRN 8%; BL 11%; L 20%). More patients stayed on neratinib for the prescribed period versus historical controls. Prior pertuzumab use did not affect rates of grade ≥3 diarrhea, diarrhea-related discontinuations, or treatment duration. Early transient reductions in HRQoL scores were observed.ConclusionsThese complete results from CONTROL show improved neratinib tolerability with proactive management at the start of therapy. Two-week neratinib DE with loperamide as needed was particularly effective.ClinicaltrialsGov registration numberNCT02400476.

Jorge F Maspero,1 Asif H Khan,2 Carl Philpott,3 Peter W Hellings,4 Claire Hopkins,5 Martin Wagenmann,6 Shahid Siddiqui,7 Jérôme Msihid,8 Scott Nash,7 Chien-Chia Chuang,9 Siddhesh Kamat,7 Paul J Rowe,10 Yamo Deniz,7 Juby A Jacob-Nara10 1Allergy & Respiratory Research Unit, Fundación CIDEA, Buenos Aires, Argentina; 2Global Medical Affairs, Sanofi, Chilly-Mazarin, France; 3Rhinology and ENT Research Group, Norwich Medical School, University of East Anglia, Norwich, UK; 4Department of Otorhinolaryngology – Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium; 5Department of Otorhinolaryngology, King’s College London, London, UK; 6Department of Otorhinolaryngology, Düsseldorf University Hospital (UKD), Düsseldorf, Germany; 7Medical Affairs, Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA; 8Health Economics and Value Assessment, Sanofi, Chilly-Mazarin, France; 9Health Economics and Value Assessment, Sanofi, Cambridge, MA, USA; 10Global Medical Affairs, Sanofi, Bridgewater, NJ, USACorrespondence: Jorge F Maspero, Allergy & Respiratory Research Unit, Fundación CIDEA, Paraguay 2035, 2SS, Buenos Aires, Argentina, Tel +54 9 11 4183-7294, Email jorge.maspero@fundacioncidea.org.arPurpose: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammatory disease with a high symptom burden. Data are lacking on the comparative health status of patients with CRSwNP. This analysis compared baseline physical and mental health-related quality of life (HRQoL) and overall health status of patients with severe CRSwNP enrolled in a Phase 3 clinical trial with general population norms and with other chronic diseases.Methods: In this post hoc cross-sectional analysis of baseline data from the SINUS-24 study (NCT02912468), HRQoL was measured using the 36-item Short Form (SF-36) questionnaire and general health status was measured using the EuroQol-5 Dimension visual analog scale (EQ-VAS). Analyses included the intention-to-treat (ITT) population and subgroups defined by prior sinonasal surgery, systemic corticosteroid use, and coexisting asthma or non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD). Scores were compared with published values for population norms (50 for SF-36 physical component summary (PCS) and mental component summary (MCS), 70.4− 83.3 for EQ-VAS) and for rheumatoid arthritis, type 2 diabetes, and asthma.Results: In the ITT population (n=276), mean SF-36 physical component summary (PCS), SF-36 mental component summary (MCS), and EQ-VAS scores were below general population norms (46.4, 48.6, and 66.0, respectively). Mean SF-36 PCS and EQ-VAS scores were below population norms across all subgroups; mean SF-36 MCS scores were below the population norm in all subgroups except no prior surgery. SF-36 PCS and MCS scores from SINUS-24 were generally similar to other chronic diseases, except SF-36 PCS which was lower in rheumatoid arthritis. EQ-VAS scores in SINUS-24 were lower than in other chronic diseases. HRQoL scores weakly correlated with objective measures of disease severity.Conclusion: In patients with severe CRSwNP, including those with coexisting asthma/NSAID-ERD, HRQoL was worse than population norms and as burdensome as diseases such as type 2 diabetes, asthma, and rheumatoid arthritis.Graphical Abstract: Keywords: chronic rhinosinusitis with nasal polyps, health-related quality of life, symptom burden

Andrew J Lloyd,1 Robin Thompson,2 Katy Gallop,1 Megan Teynor3 1Acaster Lloyd Consulting Ltd., London, UK; 2Value and Access, Biogen, Baar, Switzerland; 3Value and Access, Biogen, Cambridge, MA, USACorrespondence: Andrew J LloydAcaster Lloyd Consulting Ltd., 16 Upper Woburn Place, London WC1H0BS, UKTel +44 20 3978 1681Email andrew.lloyd@acasterlloyd.comBackground: Spinal muscular atrophy (SMA) is a rare, genetic, progressive neuromuscular disorder characterized by severe muscle atrophy and weakness and is a leading genetic cause of death in infants and children. Nusinersen was the first treatment targeting the underlying cause of disease approved by the FDA, EMA and other countries for patients with SMA. There are currently very limited data available on the health-related quality of life (HRQoL) burden of SMA suitable for use in a cost-effectiveness analysis.Objective: This study was designed to estimate quality of life weights or utilities for different SMA states.Methods: SMA case studies were developed describing Type I (infantile onset) and Type II (later-onset) patients and different outcomes from treatment. These were developed so that quality of life weights or utilities (where the value of health ranges from 1 – full health to 0 – dead) could be estimated for cost-effectiveness analysis. Clinical experts (n=5) rated each of the case studies using standardized HRQoL instruments – the EQ-5D-Y and PedsQL-NMM (baseline states only).Results: The SMA Type I utilities ranged from −0.33 (requires ventilation) to 0.71 (Type I patient reclassified as Type III following treatment), with quite substantial differences between some states. Most Type I states had a utility score below zero indicating the severity of the states. The SMA Type II utilities ranged from −0.13 (worsened) to 0.72 (stands/walks unaided). In general, the results showed HRQoL improved in line with better health states.Conclusion: The utility scores obtained in this study highlight the very substantial burden experienced by SMA patients. Despite the limitations in the methods used, this study produced data with face validity and is a useful starting point for understanding the burden of SMA Types I and II in cost-effectiveness analysis.Keywords: spinal muscular atrophy, health-related quality of life, utility, EQ-5D, cost-effectiveness analysis