Feasibility and User Experience of Digital Patient Monitoring for Real-World Patients With Lung or Breast Cancer.

BACKGROUND: Digital patient monitoring (DPM) tools can facilitate early symptom management for patients with cancer through systematic symptom reporting; however, low adherence can be a challenge. We assessed patient/healthcare professional (HCP) use of DPM in routine clinical practice. MATERIALS AND METHODS: Patients with locally advanced/metastatic lung cancer or HER2-positive breast cancer received locally approved/reimbursed drugs alongside DPM, with elements tailored by F. Hoffmann-La Roche Ltd, on the Kaiku Health DPM platform. Patient access to the DPM tool was through their own devices (eg, laptops, PCs, smartphones, or tablets), via either a browser or an app on Apple iOS or Android devices. Coprimary endpoints were patient DPM tool adoption (positive threshold: 60%) and week 1-6 adherence to weekly symptom reporting (positive threshold: 70%). Secondary endpoints included experience and clinical impact. RESULTS: At data cutoff (June 9, 2022), adoption was 85% and adherence was 76%. Customer satisfaction and effort scores for patients were 76% and 82%, respectively, and 83% and 79% for HCPs. Patients spent approximately 10 minutes using the DPM tool and completed approximately 1.0 symptom questionnaires per week (completion time 1-4 minutes). HCPs spent approximately 1-3 minutes a week using the tool per patient. Median time to HCP review for alerted versus non-alerted symptom questionnaires was 19.6 versus 21.5 hours. Most patients and HCPs felt that the DPM tool covered/mostly covered symptoms experienced (71% and 75%), was educational (65% and 92%), and improved patient-HCP conversations (70% and 83%) and cancer care (51% and 71%). CONCLUSION: The DPM tool demonstrated positive adoption, adherence, and user experience for patients with lung/breast cancer, suggesting that DPM tools may benefit clinical cancer care.

Assessing the impact of digital patient monitoring on health outcomes and healthcare resource usage in addition to the feasibility of its combination with at-home treatment, in participants receiving systemic anticancer treatment in clinical practice: protocol for an interventional, open-label, multicountry platform study (ORIGAMA).

INTRODUCTION: Digital patient monitoring (DPM) tools can enable more effective clinical care and improved patient outcomes in cancer. However, their broad adoption requires ease of use and demonstration of real-world clinical utility/impact. ORIGAMA (MO42720) is an interventional, open-label, multicountry platform study investigating the clinical utility of DPM tools and specific treatments. ORIGAMA will begin with two cohorts that aim to assess the impact of the atezolizumab-specific Roche DPM Module (hosted on the Kaiku Health DPM platform (Helsinki, Finland)) on health outcomes and healthcare resource usage, and its feasibility to support at-home treatment administration, in participants receiving systemic anticancer treatment. Other digital health solutions may be added to future cohorts. METHODS AND ANALYSIS: In Cohort A, participants with metastatic non-small cell lung cancer (NSCLC), extensive-stage SCLC or Child Pugh A unresectable hepatocellular carcinoma will be randomised to a locally approved anticancer regimen containing intravenous atezolizumab (TECENTRIQ, F. Hoffmann-La Roche Ltd/Genentech) and local standard-of-care support, with/without the Roche DPM Module. Cohort B will assess the feasibility of the Roche DPM Module in supporting administration of three cycles of subcutaneous atezolizumab (1875 mg; Day 1 of each 21-day cycle) in the hospital, followed by 13 cycles at home by a healthcare professional (ie, flexible care), in participants with programmed cell-death ligand 1-positive, early-stage NSCLC. The primary endpoints are the mean difference in change of the participant-reported Total Symptom Interference Score at Week 12 from baseline (Cohort A) and flexible care adoption rate at Cycle 6 (Cohort B). ETHICS AND DISSEMINATION: This study will be conducted according to the Declaration of Helsinki, and/or the applicable laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the individual. The study received its first Ethics Committee approval in Spain in October 2022. Participants will provide written informed consent in a face-to-face setting. The results of this study will be presented at national and/or international congresses and disseminated via publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05694013.

Evolving regulatory perspectives on digital health technologies for medicinal product development.

Digital health technology tools (DHTTs) present real opportunities for accelerating innovation, improving patient care, reducing clinical trial duration and minimising risk in medicines development. This review is comprised of four case studies of DHTTs used throughout the lifecycle of medicinal products, starting from their development. These cases illustrate how the regulatory requirements of DHTTs used in medicines development are based on two European regulatory frameworks (medical device and the medicinal product regulations) and highlight the need for increased collaboration between various stakeholders, including regulators (medicines regulators and device bodies), pharmaceutical sponsors, manufacturers of devices and software, and academia. As illustrated in the examples, the complexity of the interactions is further increased by unique challenges related to DHTTs. These case studies are the main examples of DHTTs with a regulatory assessment thus far, providing an insight into the applicable current regulatory approach; they were selected by a group of authors, including regulatory specialists from pharmaceutical sponsors, technology experts, academic researchers and employees of the European Medicines Agency. For each case study, the challenges faced by sponsors and proposed potential solutions are discussed, and the benefit of a structured interaction among the different stakeholders is also highlighted.

A multicentre analytical comparison study of inter-reader and inter-assay agreement of four programmed death-ligand 1 immunohistochemistry assays for scoring in triple-negative breast cancer.

AIMS: Studies in various cancer types have demonstrated discordance between results from different programmed death-ligand 1 (PD-L1) assays. Here, we compare the reproducibility and analytical concordance of four clinically developed assays for assessing PD-L1-positivity in tumour-infiltrating immune cells in the tumour area (PD-L1-IC-positivity) in triple-negative breast cancer (TNBC). METHODS AND RESULTS: Primary TNBC resection specimens (n = 30) were selected based on their PD-L1-IC-positivity per VENTANA SP142 (<1%: 15 cases; 1-5%: seven cases; >5%: eight cases). Serial histological sections were stained for PD-L1 using VENTANA SP142, VENTANA SP263, DAKO 22C3 and DAKO 28-8. PD-L1-IC-positivity and tumour cell expression (≥1 versus <1%) were scored by trained readers from seven sites using online virtual microscopy. The adjusted mean of PD-L1-IC-positivity for SP263 (7.8%) was significantly higher than those for the other three assays (3.7-4.9%). Differences in adjusted means were statistically significant between SP263 and the other three assays (P < 0.0001) but not between the three remaining assays when excluding SP263 (P = 0.0961-0.6522). Intra-class correlation coefficients revealed moderate-to-strong inter-reader agreement for each assay (0.460-0.805) and poor-to-strong inter-assay agreement for each reader (0.298-0.678) on PD-L1-IC-positivity. CONCLUSIONS: In this first multicentre study of different PD-L1 assays in TNBC, we show that PD-L1-IC-positivity for SP142, 22C3 and 28-8 was reproducible and analytically concordant, indicating that these three assays may be analytically interchangeable. The relevance of the higher PD-L1-IC-positivity for SP263 should be further investigated.

Digital Monitoring and Management of Patients With Advanced or Metastatic Non-Small Cell Lung Cancer Treated With Cancer Immunotherapy and Its Impact on Quality of Clinical Care: Interview and Survey Study Among Health Care Professionals and Patients.

BACKGROUND: Cancer immunotherapy (CIT), as a monotherapy or in combination with chemotherapy, has been shown to extend overall survival in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). However, patients experience treatment-related symptoms that they are required to recall between hospital visits. Digital patient monitoring and management (DPMM) tools may improve clinical practice by allowing real-time symptom reporting. OBJECTIVE: This proof-of-concept pilot study assessed patient and health care professional (HCP) adoption of our DPMM tool, which was designed specifically for patients with advanced or metastatic NSCLC treated with CIT, and the tool's impact on clinical care. METHODS: Four advisory boards were assembled in order to co-develop a drug- and indication-specific CIT (CIT+) module, based on a generic CIT DPMM tool from Kaiku Health, Helsinki, Finland. A total of 45 patients treated with second-line single-agent CIT (ie, atezolizumab or otherwise) for advanced or metastatic NSCLC, as well as HCPs, whose exact number was decided by the clinics, were recruited from 10 clinics in Germany, Finland, and Switzerland between February and May 2019. All clinics were provided with the Kaiku Health generic CIT DPMM tool, including our CIT+ module. Data on user experience, overall satisfaction, and impact of the tool on clinical practice were collected using anonymized surveys-answers ranged from 1 (low agreement) to 5 (high agreement)-and HCP interviews; surveys and interviews consisted of closed-ended Likert scales and open-ended questions, respectively. The first survey was conducted after 2 months of DPMM use, and a second survey and HCP interviews were conducted at study end (ie, after ≥3 months of DPMM use); only a subgroup of HCPs from each clinic responded to the surveys and interviews. Survey data were analyzed quantitatively; interviews were recorded, transcribed verbatim, and translated into English, where applicable, for coding and qualitative thematic analysis. RESULTS: Among interim survey respondents (N=51: 13 [25%] nurses, 11 [22%] physicians, and 27 [53%] patients), mean rankings of the tool's seven usability attributes ranged from 3.2 to 4.4 (nurses), 3.7 to 4.5 (physicians), and 3.7 to 4.2 (patients). At the end-of-study survey (N=48: 19 [40%] nurses, 8 [17%] physicians, and 21 [44%] patients), most respondents agreed that the tool facilitated more efficient and focused discussions between patients and HCPs (nurses and patients: mean rating 4.2, SD 0.8; physicians: mean rating 4.4, SD 0.8) and allowed HCPs to tailor discussions with patients (mean rating 4.35, SD 0.65). The standalone tool was well integrated into HCP daily clinical workflow (mean rating 3.80, SD 0.75), enabled workflow optimization between physicians and nurses (mean rating 3.75, SD 0.80), and saved time by decreasing phone consultations (mean rating 3.75, SD 1.00) and patient visits (mean rating 3.45, SD 1.20). Workload was the most common challenge of tool use among respondents (12/19, 63%). CONCLUSIONS: Our results demonstrate high user satisfaction and acceptance of DPMM tools by HCPs and patients, and highlight the improvements to clinical care in patients with advanced or metastatic NSCLC treated with CIT monotherapy. However, further integration of the tool into the clinical information technology data flow is required. Future studies or registries using our DPMM tool may provide insights into significant effects on patient quality of life or health-economic benefits.

Multicentric Analytical and Inter-observer Comparability of Four Clinically Developed Programmed Death-ligand 1 Immunohistochemistry Assays in Advanced Clear-cell Renal Cell Carcinoma.

BACKGROUND: Previous studies have suggested increased clinical benefit with inhibition of programmed death-ligand 1 (PD-L1)/programmed death-1 in patients with PD-L1-positive locally advanced/metastatic renal cell carcinoma (RCC). We examined the analytical and inter-observer comparability of PD-L1-positivity across 4 clinically developed immunohistochemistry assays in clear-cell RCC (CCRCC). MATERIALS AND METHODS: Randomly selected archived, formalin-fixed, paraffin-embedded nephrectomy specimens from 201 patients with locally advanced CCRCC were screened using VENTANA SP142. From these, 30 cases were selected based on their tumor-infiltrating immune cell (IC) PD-L1 status (PD-L1-IC-positivity of < 1%, 1%-5%, or > 5%; 10 cases each). These cases were stained for PD-L1 using VENTANA SP142 and SP263, and DAKO 22C3 and 28-8, and scored for PD-L1 expression on IC and tumor cells (TC) by trained readers at 5 sites. RESULTS: Adjusted mean percentages of PD-L1-IC-positivity and PD-L1-TC-positivity varied from 4.0% to 4.9% and from 1.3% to 10.7%, respectively, between assays. Inter-assay differences in PD-L1-IC-positivity were small and non-significant (P = .1938 to .9963); for PD-L1-TC-positivity, significant differences were observed between VENTANA SP142 and the other assays (P ≤ .0001) and between VENTANA SP263 and DAKO 28-8 (P = .0248). Intra-class correlation values showed moderate-to-high inter-reader agreement for each assay for PD-L1-IC-positivity and for 3 assays for PD-L1-TC-positivity. CONCLUSIONS: In this first multicenter analytical comparison study of PD-L1 assays in CCRCC, PD-L1-positivity could be assessed reproducibly using all 4 assays for IC and for 3 of the 4 assays for TC.

Statistical modelling of HER2-positivity in breast cancer: Final analyses from two large, multicentre, non-interventional studies in Germany.

BACKGROUND: The German NIU HER2 model was developed based on five variables found to have statistically significant influences on HER2-positivity, to allow exploration of deviations between model-predicted and actual HER2-positivity rates as a measure of testing quality. The prospective, non-interventional EPI HER2 BC study (NCT02666261) compared NIU and EPI data, aiming to validate the NIU model. METHODS: HER2 status and patient-/tumour-related information were collected from eligible patients with invasive breast cancer. The influence of variables on HER2-positivity was compared between studies and the NIU model validated using EPI data with cut-off and variable coefficients from the NIU study. The influences of additional variables, centre effects and laboratory-specific parameters were also explored. RESULTS: The study included 14,729 EPI and 15,281 NIU samples; HER2-positivity rates were comparable (13.5% versus 14.2%). The five covariates from NIU were shown to significantly affect HER2-positivity using EPI data. The Youden Index for the NIU model refitted to EPI data (0.3632) and the NIU model for prediction of HER2-positivity in EPI (0.3552) was close to that for the NIU model fitted to NIU data (0.3888), validating the NIU model. Replacing hormone receptor status with progesterone and oestrogen receptor expression, and adding method of sample extraction as a variable improved the model's predictive strength (ROC AUC 0.7402; Youden Index 0.3935). CONCLUSIONS: Reliable, high-quality HER2-testing methods are essential for selection of patients with HER2-positive breast cancer for HER2-tageted treatment. Integration of our model into a locally used software or website may improve its viability for use in clinical practice.

Multicentric analytical comparability study of programmed death-ligand 1 expression on tumor-infiltrating immune cells and tumor cells in urothelial bladder cancer using four clinically developed immunohistochemistry assays.

Programmed death-ligand 1 (PD-L1) expression on tumor cells (TC) or tumor-infiltrating immune cells (IC) correlated in several studies with PD-L1/programmed death-1 (PD-1) checkpoint inhibitor efficacy. Since June 2018, a positive PD-L1 status is required for atezolizumab or pembrolizumab treatment of patients with advanced or metastasized urothelial bladder cancer, who are ineligible for cisplatin-containing therapy. We examined technical comparability and inter-reader agreement of four clinically developed PD-L1 assays in locally advanced disease. Archived, formalin-fixed, paraffin-embedded sections from 30 patients (73.3% cystectomies, 26.7% transurethral resections) were stained by PD-L1 immunohistochemistry using VENTANA SP142, VENTANA SP263, DAKO 22C3, and DAKO 28-8 at two sites per manufacturers' protocols and scored blinded at five sites for PD-L1 expression on IC (% per tumor area) and TC (%). Small, non-significant inter-assay differences were observed for IC. For TC, SP142 showed significantly lower staining percentages. Pairwise comparisons revealed - 0.3 to 1.6% differences in adjusted means between assays for IC, and for TC, - 10.5 to - 7.8% (SP142 versus others) and - 1.9 to 2.7% (other comparisons). Inter-reader and inter-assay agreement was moderate to high for both IC and TC. Allocation to binary cutoffs (1%, 5%, 10%) showed substantial to high Kappa agreement scores (0.440-0.923) for IC and TC between assays for each reader. This first multicenter study, with five independent readers blinded with respect to the assay used, suggests that all four currently clinically relevant assays are analytically similar for evaluation of PD-L1-stained IC and three (SP263, 22C3, and 28-8) for PD-L1-stained TC. Inter-observer agreement for trained readers in scoring of both IC and TC positivity was generally high.

Assessing HER2 testing quality in breast cancer: variables that influence HER2 positivity rate from a large, multicenter, observational study in Germany.

Despite >10 years of routine human epidermal growth factor receptor 2 (HER2) testing in breast cancer, testing quality is still an issue. Guidelines recommend assessing HER2 positivity rates as a quality indicator; however, the extent to which patient- or tumor-related factors influence HER2 positivity is still unknown. The present study analyzed these influences to identify pathology centers with HER2 positivity rates unexplained by patient- or tumor-related factors. This observational, prospective study monitored routine HER2 testing at 57 institutes of pathology in Germany (January 2013-August 2014). Data collected included HER2 test result, patient- and tumor-related factors, sample source, and method of sample retrieval. Factors influencing HER2 positivity rates were identified by multiple logistic regression. Individual center effects were assessed in an extended multiple logistic regression model by their statistical significance after adjusting for the combined effect of patient- or tumor-related covariates and multiple testing. Analyses included 15 332 invasive breast cancer samples. Histologic grade showed the strongest influence on HER2 positivity, followed by hormone receptor status, histologic subtype, age, and nodal status (all P<0.0001). The overall HER2 positivity rate across centers was 14.4% (range 7.1-27.3%). A statistically significant center effect on the HER2 positivity rate was identified for three centers (P<0.05), with a trend toward a center effect for a further three (P<0.2). This study, the first of its kind, highlights that assessing HER2 testing quality with HER2 positivity rates should include standardized assessment of patient- or tumor-related characteristics to identify centers with HER2 testing quality issues more effectively. As treatment options for HER2-positive breast cancer continue to evolve, identifying the right patients is key.

Development and use of IgM/J-chain fusion proteins for characterization of immunoglobulin superfamily ligand-receptor interactions.

Discovery of binding partners for immunoglobulin molecules expressed by cells of the immune system is an important topic of current research. However, many ligand-receptor interactions are of low affinity, and hence detection is refractory to most established protocols. We evaluated fusion proteins based on human IgM as high avidity probes to screen for ligand-receptor binding. We describe methods for cloning, expression, and quantification of IgM fusion proteins with J-chain. Furthermore, we outline protocols to assess binding of IgM fusion proteins to cells and to plate-bound proteins. Compared to standard IgG-fusion proteins, IgM + J chain increased binding of a test interaction, PD-L1 to PD-1, up to 1000-fold.

Butyrophilin Btn2a2 inhibits TCR activation and phosphatidylinositol 3-kinase/Akt pathway signaling and induces Foxp3 expression in T lymphocytes.

The butyrophilin-related protein Btn2a2 was upregulated on murine APC including CD19(+) B cells, CD11b(+)F4/80(+) peritoneal macrophages, and CD11c(+) bone marrow-derived dendritic cells after activation with LPS or Pam3CysK4, suggesting a role in modulation of T lymphocytes. Consistent with this, binding of mouse Btn2a2-Fc to CD3(+) primary mouse T cells stimulated with anti-CD3 and anti-CD28 reduced the number of proliferating cells and entry of cells into the cell cycle. Binding of Btn2a2-Fc to anti-CD3-stimulated T cells inhibited CD3ε, Zap70, and subsequent Erk1/2 activation. It also interfered with activation of the regulatory subunit of PI3K, p85, and activation of Akt in T cells stimulated with both anti-CD3 and anti-CD28. Inhibition of Akt activation by Btn2a2-Fc was, in contrast to inhibition by programmed death ligand-1-Fc, not overcome by anti-CD28 costimulation. Using Foxp3-GFP-transgenic, naive T cells, Btn2a2-Fc induced de novo expression of Foxp3 in a dose-dependent manner, and Btn2a2-Fc-induced CD4(+)CD25(+)Foxp3(+) T cells had inhibitory properties. The data indicate an important physiological role for Btn2a2 in inhibiting T cell activation and inducing Foxp3(+) regulatory T cells.

BTN1A1, the mammary gland butyrophilin, and BTN2A2 are both inhibitors of T cell activation.

Butyrophilin (BTN) genes encode a set of related proteins. Studies in mice have shown that one of these, BTN1A1, is required for milk lipid secretion in lactation, whereas butyrophilin-like 2 is a coinhibitor of T cell activation. To understand these disparate roles of BTNs, we first compared the expression and functions of mouse Btn1a1 and Btn2a2. Btn1a1 transcripts were not restricted to lactating mammary tissue but were also found in virgin mammary tissue and, interestingly, spleen and thymus. In confirmation of this, BTN1A1 protein was detected in thymic epithelial cells. By contrast, Btn2a2 transcripts and protein were broadly expressed. Cell surface BTN2A2 protein, such as the B7 family molecule programmed death ligand 1, was upregulated upon activation of T cells. We next examined the potential of both BTN1A1 and BTN2A2 to interact with T cells. Recombinant Fc fusion proteins of murine BTN2A2 and, surprisingly BTN1A1, bound to activated T cells, suggesting the presence of one or more receptors on these cells. Immobilized BTN-Fc fusion proteins, but not MOG-Fc protein, inhibited the proliferation of CD4 and CD8 T cells activated by anti-CD3. BTN1A1 and BTN2A2 also inhibited T cell metabolism, IL-2, and IFN-gamma secretion. Inhibition of proliferation was not abrogated by exogenous IL-2 but could be overcome following costimulation with high levels of anti-CD28 Ab. These data are consistent with a coinhibitory role for mouse BTNs, including BTN1A1, the BTN expressed in the lactating mammary gland and on milk lipid droplets.

Sensitization of neuroblastoma cells for TRAIL-induced apoptosis by NF-kappaB inhibition.

The transcription factor nuclear factor-kappaB (NF-kappaB) plays a central role in stress-induced transcriptional activation and has been implicated in chemoresistance of cancers. In the present study, we investigated the role of NF-kappaB in inducible chemoresistance of neuroblastoma. Doxorubicin, VP16 and the cytotoxic ligand TRAIL trigger NF-kappaB activation, whereas cisplatin and taxol have no impact on NF-kappaB activity. Specific inhibition of NF-kappaB activation by overexpression of dominant-negative mutant IkappaBalpha-super-repressor does not alter cell death upon doxorubicin or VP16 treatment, although it prevents doxorubicin- or VP16-mediated NF-kappaB activation. By comparison, inhibition of TRAIL-stimulated NF-kappaB activation by IkappaBalpha-superrepressor or the small molecule NF-kappaB inhibitor BMS-345541 significantly enhances TRAIL-induced apoptosis, pointing to an antiapoptotic function of NF-kappaB in TRAIL-mediated apoptosis. Analysis of signaling pathways reveals that NF-kappaB inhibition prevents TRAIL-triggered up-regulation of Mcl-1, promoting TRAIL-induced cytochrome c release and activation of caspases. Accordingly, knockdown of Mcl-1 by RNA interference significantly enhances TRAIL-induced apoptosis and also increases sensitivity of neuroblastoma cells to CD95- or chemotherapy-induced apoptosis. In conclusion, NF-kappaB regulates apoptosis in a stimulus-specific manner in neuroblastoma cells and confers protection against TRAIL-induced apoptosis. By demonstrating that NF-kappaB inhibition sensitizes neuroblastoma cells for TRAIL-induced apoptosis, our findings have important implications. Thus, NF-kappaB inhibitors may open new perspectives to potentiate the efficacy of TRAIL-based protocols in the treatment of neuroblastoma.