Novocure (United States)

Post-stroke spasticity (PSS) affects up to 48% of stroke survivors, with disabling forms in about 18%. In the upper limb, 95% of cases show a flexor-dominant pattern. Botulinum toxin A (BoNT-A) is the treatment of choice, but adjunctive strategies such as serial casting may be used to enhance outcomes. To evaluate whether serial casting prior to abobotulinumtoxinA (AboBoNT-A) injections improves the reduction of wrist and finger flexor spasticity in subacute stroke survivors. In this prospective, randomized, two-center trial, 27 stroke patients with moderate wrist and finger flexor spasticity were allocated to one of two groups: SC + BoNT-A group (Group 1): serial casting for two weeks prior to AboBoNT-A injection (n = 14). BoNT-A group (Group 2): standard treatment with AboBoNT-A alone (n = 13). Both groups participated in an eight-week inpatient neurorehabilitation program. Spasticity and joint stiffness were assessed using the Modified Ashworth Scale (MAS) and the Modified Tardieu Scale (MTS). Additional validated outcome measures for stroke rehabilitation were also employed, including the passive Range of Motion (PROM), Wolf Motor Function Test (WMFT), Grip Strength, Barthel Index, Visual Analogue Scale for pain (VAS), and Stroke Impact Scale (SIS). Both groups showed improvements after BoNT-A. In the SC + BoNT-A group, MAS scores decreased and remained stable during follow-up. In the BoNT-A group, a recurrence of muscle stiffness was observed at week 6. Serial casting prior to BoNT-A was associated with a trend toward more sustained reduction of spasticity, but superiority over BoNT-A alone was not statistically confirmed.

Tumor Treating Fields (TTFields) therapy is an approved cancer treatment modality, based on non-invasive application of electric fields to the tumor region. Proteomic and cell biology methods revealed a versatile mechanism of action to be involved in the response to TTFields. In the current research we performed whole transcriptome analysis across tumor types to identify pan-cancer responses to TTFields. For this we collected samples from control and TTFields-treated human cancer cell lines of gastric cancer, pancreatic cancer, ovarian cancer, non-small cell lung carcinoma, pleural mesothelioma, and glioblastoma. The transcriptomic analysis supported previous reported effects: downregulation of pathways associated with cell cycle, cell growth, and proliferation; downregulation of DNA replication and the FA-BRCA DNA repair pathway; and upregulation of cellular responses to stress—senescence, autophagy, and apoptosis. Notably, previously unrecognized downstream effects of TTFields were revealed on cellular metabolism, with downregulation of protein and RNA metabolism, and upregulation of steroid biosynthesis. Additional DNA repair pathways were also found to be downregulated, including nucleotide excision repair, base excision repair, and mismatch repair. In conclusion, this study revealed similar response patterns to TTFields across different tumor types, re-enforcing some already pinpointed mechanisms, while revealing new mechanisms. Unlocking these new mechanisms may allow identification of potential new cancer treatments for application together with TTFields based on mechanistical compatibility.

Disruption of intercellular communication within tumors is emerging as a novel potential strategy for cancer-directed therapy. Tumor-Treating Fields (TTFields) therapy is a treatment modality that has itself emerged over the past decade in active clinical use for patients with glioblastoma and malignant mesothelioma, based on the principle of using low-intensity alternating electric fields to disrupt microtubules in cancer cells undergoing mitosis. There is a need to identify other cellular and molecular effects of this treatment approach that could explain reported increased overall survival when TTFields are added to standard systemic agents. Tunneling nanotube (TNTs) are cell-contact-dependent filamentous-actin-based cellular protrusions that can connect two or more cells at long-range. They are upregulated in cancer, facilitating cell growth, differentiation, and in the case of invasive cancer phenotypes, a more chemoresistant phenotype. To determine whether TNTs present a potential therapeutic target for TTFields, we applied TTFields to malignant pleural mesothelioma (MPM) cells forming TNTs in vitro. TTFields at 1.0 V/cm significantly suppressed TNT formation in biphasic subtype MPM, but not sarcomatoid MPM, independent of effects on cell number. TTFields did not significantly affect function of TNTs assessed by measuring intercellular transport of mitochondrial cargo via intact TNTs. We further leveraged a spatial transcriptomic approach to characterize TTFields-induced changes to molecular profiles in vivo using an animal model of MPM. We discovered TTFields induced upregulation of immuno-oncologic biomarkers with simultaneous downregulation of pathways associated with cell hyperproliferation, invasion, and other critical regulators of oncogenic growth. Several molecular classes and pathways coincide with markers that we and others have found to be differentially expressed in cancer cell TNTs, including MPM specifically. We visualized short TNTs in the dense stromatous tumor material selected as regions of interest for spatial genomic assessment. Superimposing these regions of interest from spatial genomics over the plane of TNT clusters imaged in intact tissue is a new method that we designate Spatial Profiling of Tunneling nanoTubes (SPOTT). In sum, these results position TNTs as potential therapeutic targets for TTFields-directed cancer treatment strategies. We also identified the ability of TTFields to remodel the tumor microenvironment landscape at the molecular level, thereby presenting a potential novel strategy for converting tumors at the cellular level from 'cold' to 'hot' for potential response to immunotherapeutic drugs.

Abstract Tumor Treating Fields (TTFields) are alternating electric fields generated by a wearable medical device (NovoTTF-200A), delivered to the tumor target by arrays placed on the skin. These fields have multiple biological effects on tumor cells, including mitotic disruption, dysregulated DNA repair, antimigratory effects, and stimulation of antitumor immune response. TTFields therapy was approved for recurrent and newly diagnosed glioblastoma, based on the randomized, pivotal EF-11 and EF-14 studies, respectively. Data from both studies demonstrated favorable outcomes, sustained quality of life, and tolerable safety profile. Side effects are limited to mostly manageable, mild to moderate skin reactions with no increased systemic toxicity. TTFields therapy is also approved for pleural mesothelioma and has met the primary endpoint in the pivotal LUNAR study for metastatic non-small cell lung cancer patients. Despite extensive preclinical data, positive clinical study outcomes, and favorable real-world evidence, adoption of TTFields therapy remains tepid. Here we discuss potential causes and possible solutions to treatment barriers. Based on extensive surveys in the field, we have identified several potential reasons. The first challenge is the perception that open-label studies are less rigorous since sham devices are not used per protocol. The purpose of sham treatments in trials is to minimize placebo effects and/or investigator bias, but RANO criteria is designed to guard against just that. Secondly, dissemination of knowledge underlying innovative therapies often takes time. Unlike chemotherapy and radiotherapy, the mechanistic aspects of TTFields are not typically included in oncology training. Lastly, the benefits of TTFields therapy may be difficult to appreciate due to the required chronic use during maintenance. Therefore, education, additional bench research, and future clinical studies are important for a better adoption of this increasingly important oncological option.

Abstract BACKGROUND TTFields therapy is a noninvasive, locoregional anticancer treatment approved for newly diagnosed and recurrent GBM based on efficacy and safety results in 2 global, randomized pivotal studies, supported by real-world evidence. METHODS In 2022, 2 questionnaires (mail or online) surveyed the real-world experiences of patients with GBM receiving TTFields therapy (NovoTTF-200A; Novocure®, GmBH) and their caregivers in Germany, Austria, and Switzerland (DACH), and the USA. RESULTS 545/1197 surveys were returned in DACH (46%); 1332/5031 in the USA (26%). Most respondents indicated satisfaction/high satisfaction with TTFields (in patients starting therapy, 82% [DACH] and 58% [USA]; in patients with >6 months use, 67% [DACH] and 72% [USA]). The following data pertain to patients with >6 months of TTFields use (n = 114 DACH; n = 375 USA). 63% in DACH reported that daily life was changed “much”/“very much”, and 35% “hardly at all”; in the USA, 17% indicated they were able to live as they did before therapy, 61% had to make adjustments but had returned to a normal routine, and 23% said therapy had markedly impacted daily life. 74% (DACH) and 73% (USA) would recommend to other patients. Common reasons for low satisfaction included skin irritation and device handling. To assess any impact of age, responses from patients aged ≥70 years ( >6 months use) from the USA (n = 82 [22%]) were analyzed (there were not enough elderly patients with >6 months use in DACH [n = 8] to analyze). As with the overall population, elderly patients in the USA reported they were satisfied/very satisfied (67%). 66% of elderly patients (USA) were very likely to recommend TTFields to someone else. CONCLUSIONS Surveys of patient/caregivers in DACH and the USA who used TTFields for GBM identified a high degree of satisfaction, including elderly patients. Most respondents would recommend TTFields to others.

Introduction/BackgroundPlatinum-resistant or -refractory ovarian cancer (PROC) confers a substantial symptom burden and cost. Health state utility values (HSUVs) provide summary measures of health-related quality of life (HRQoL) and are used in economic analyses. We aimed to comprehensively characterize HSUVs in PROC.MethodologyTwo systematic literature reviews (SLRs) were conducted to characterize the economic burden and HRQoL in PROC recurring within 6 months of platinum-based chemotherapy. The original SLRs and SLR updates identified studies reporting HSUVs published between January 2010 and March 2, 2023, according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. MEDLINE®, Embase®, EconLit, Cochrane, relevant conference proceedings, and health technology assessments were searched.ResultsOverall, 13 studies reporting HSUVs in patients with PROC met the inclusion criteria. Among them, four were HRQoL studies and nine were economic analyses. The studies occurred in the United States (n=8), multiple countries (n=2), and the United Kingdom, Thailand, and Belgium (n=1 each). Reported HSUVs were heterogeneous, ranging from a high of 0.81 pre-progression to a low of 0.07 in hospitalized patients receiving end-of-life care. Mean HSUV for progressed PROC was 0.62 (n=7; range 0.40–0.78; figure 1). Among HSUVs reported with treatment regimens (range 0.56–0.84), paclitaxel or doxorubicin alone and vistusertib + paclitaxel had the lowest and highest values, respectively. Gastrointestinal perforation and bowel obstruction were associated with HSUVs of 0.50. #805 Figure 1Reported utility values in patients with PROCConclusionReported HSUVs within health states were heterogeneous; however, they declined following disease progression. Gastrointestinal complications and end-stage disease were associated with the lowest HSUVs. Well-tolerated treatments that extend progression-free survival are crucial in PROC.DisclosuresMI and MP are employees and shareholders of Novocure. ZC is employed under contract by Novocure.

Tumor Treating Fields (TTFields) are electric fields, delivered via wearable arrays placed on or near the tumor site, that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. As a first-in-class treatment, TTFields therapy is approved for use in newly diagnosed glioblastoma, recurrent glioblastoma, and pleural mesothelioma. Additionally, TTFields therapy is being investigated in non-small cell lung cancer (NSCLC), brain metastases from NSCLC, pancreatic cancer, ovarian cancer, hepatocellular carcinoma, and gastric adenocarcinoma. Because TTFields therapy is well tolerated and delivery is locoregional, there is low risk of additive systemic adverse events (AEs) when used with other cancer treatment modalities. The most common AE associated with TTFields therapy is mild-to-moderate skin events, which can be treated with topical agents and may be managed without significant treatment interruptions. Currently, there are no guidelines for oncologists regarding the management of TTFields therapy-related skin AEs in the thoracic region, applicable for patients with pleural mesothelioma or NSCLC. This publication aims to provide guidance on preventing, minimizing, and managing dermatologic AEs in the thoracic region to help improve patient quality of life and reduce treatment interruptions that may impact outcomes with TTFields therapy.