Tepotinib plus osimertinib in patients with EGFR-mutated non-small-cell lung cancer with MET amplification following progression on first-line osimertinib (INSIGHT 2): a multicentre, open-label, phase 2 trial.

BACKGROUND: Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population. METHODS: This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete). FINDINGS: Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea. INTERPRETATION: Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated. FUNDING: Merck (CrossRef Funder ID: 10.13039/100009945).

MET Exon 14 Skipping in NSCLC: A Systematic Literature Review of Epidemiology, Clinical Characteristics, and Outcomes.

INTRODUCTION: MET exon 14 (METex14) skipping is a rare oncogenic driver in non-small-cell lung cancer (NSCLC) for which targeted therapy with MET tyrosine kinase inhibitors (TKIs) was recently approved. Given the heterogeneity in published data of METex14 skipping NSCLC, we conducted a systematic literature review to evaluate its frequency, patient characteristics, and outcomes. METHODS: On June 13, 2022 we conducted a systematic literature review of publications and conference abstracts reporting frequency, patient characteristics, or outcomes of patients with METex14 skipping NSCLC. RESULTS: We included 139 studies reporting frequency or patient characteristics (350,997 patients), and 39 studies reporting clinical outcomes (3989 patients). Median METex14 skipping frequency was 2.0% in unselected patients with NSCLC, with minimal geographic variation. Median frequency was 2.4% in adenocarcinoma or nonsquamous subgroups, 12.0% in sarcomatoid, and 1.3% in squamous histology. Patients with METex14 skipping NSCLC were more likely to be elderly, have adenocarcinoma histology; there was no marked sex or smoking status distribution. In first line of treatment, median objective response rate ranged from 50.7% to 68.8% with targeted therapies (both values correspond to MET TKIs), was 33.3% with immunotherapy, and ranged from 23.1% to 27.0% with chemotherapy. CONCLUSIONS: Patients with METex14 skipping are more likely to have certain characteristics, but no patient subgroup can be ruled out; thus, it is crucial to test all patients with NSCLC to identify suitable candidates for MET inhibitor therapy. MET TKIs appeared to result in higher efficacy outcomes, although no direct comparison with chemotherapy or immunotherapy regimens was found.

Cost-Effectiveness of Tepotinib Versus Capmatinib for the Treatment of Adult Patients With Metastatic Non-Small Cell Lung Cancer Harboring Mesenchymal-Epithelial Transition Exon 14 Skipping.

OBJECTIVES: From the US Medicare perspective, this study compared the cost-effectiveness of tepotinib and capmatinib for treating metastatic non-small cell lung cancer with tumors harboring mesenchymal-epithelial transition factor gene exon 14 skipping. METHODS: A 3-state partitioned survival model assessed outcomes over a lifetime horizon. Parametric survival analysis of the phase 2 VISION trial informed clinical inputs for tepotinib. Capmatinib inputs were captured using hazard ratios derived from an unanchored matching-adjusted indirect comparison study and published literature. National cost databases, trial data, and literature furnished drug, treatment monitoring, and disease/adverse event management expenditures (2021 US dollars) and utility inputs. Outcomes were discounted at 3% annually. RESULTS: In the base case, tepotinib dominated capmatinib in frontline settings (incremental discounted quality-adjusted life-years [QALYs] and costs of 0.2127 and -$47 756, respectively) while realizing an incremental cost-effectiveness ratio of $274 514/QALY in subsequent lines (incremental QALYs and costs of 0.3330 and $91 401, respectively). In a line agnostic context, tepotinib produced an incremental cost-effectiveness ratio of $105 383/QALY (incremental QALYs and costs of 0.2794 and $29 447, respectively). Sensitivity and scenarios analyses for individual lines typically supported the base case, whereas those for the line agnostic setting suggested sensitivity to drug acquisition costs and efficacy inputs. CONCLUSIONS: Tepotinib could be cost-effective versus capmatinib in frontline and line agnostic contexts, considering the range of willingness-to-pay thresholds recommended by the Institute for Clinical and Economic Review ($100 000-$150 000/QALY). Tepotinib could be cost-effective in subsequent lines at higher willingness-to-pay levels. These results are to be interpreted cautiously, considering uncertainty in key model inputs.

Matching-Adjusted Indirect Comparison (MAIC) of Tepotinib with Other MET Inhibitors for the Treatment of Advanced NSCLC with MET Exon 14 Skipping Mutations.

INTRODUCTION: MET exon 14 skipping in patients with advanced non-small cell lung cancer (aNSCLC), can be targeted with MET inhibitors including tepotinib, capmatinib, savolitinib, and crizotinib. Matching-adjusted indirect comparison (MAIC) methodology was used to compare outcomes data between agents and to address bias from differences in baseline characteristics. METHODS: Patient-level data from the VISION study (tepotinib) were weighted for comparison with aggregate data from the GEOMETRY mono-1 (capmatinib), NCT02897479 (savolitinib) and PROFILE 1001 (crizotinib) studies in patients with aNSCLC, using baseline characteristics prognostic for overall survival (OS) in VISION. Overall response rate (ORR), OS, progression-free survival (PFS), and duration of response (DOR) were compared. Patients were stratified by line of therapy: overall (all lines), previously treated, and treatment-naïve. RESULTS: Improvements in ORR and all time-to-event endpoints were predicted for tepotinib compared with crizotinib and savolitinib in the different populations, although comparisons with savolitinib were hindered by considerable differences in baseline patient populations. Tepotinib appeared to be associated with prolonged PFS and OS compared with capmatinib in previously treated patients (PFS HR 0.54; 95% CI 0.36-0.83; OS HR 0.66; 95% CI 0.42-1.06) and the overall populations (PFS HR 0.60; 95% CI 0.43-0.86; OS HR 0.72; 95% CI 0.49-1.05), with smaller improvements in DOR. The ORR comparisons between tepotinib and capmatinib identified a swing of up to ± 6 percentage points in the weighted tepotinib ORR depending on the population studied (treatment-naïve vs. previously treated patients). CONCLUSIONS: The MAIC identified potential differences in efficacy endpoints with the different MET inhibitors, and predicted prolonged PFS and OS with tepotinib compared with capmatinib and crizotinib. Although MAIC cannot balance for unobserved factors, it remains an informative method to contextualize single-arm studies, where head-to-head trials are unlikely to be feasible.

Evaluation of Meal Carbohydrate Counting Errors in Patients with Type 1 Diabetes.

AIM: Correct estimation of meal carbohydrate content is a prerequisite for successful intensified insulin therapy in patients with diabetes. In this survey, the counting error in adult patients with type 1 diabetes was investigated. METHODS: Seventy-four patients with type 1 diabetes estimated the carbohydrate content of 24 standardized test meals. The test meals were categorized into 1 of 3 groups with different carbohydrate content: low, medium, and high. Estimation results were compared with the meals' actual carbohydrate content as determined by calculation based on weighing. A subgroup of the participants estimated the test meals for a second (n=35) and a third time (n=22) with a mean period of 11 months between the estimations. RESULTS: During the first estimation, the carbohydrate content was underestimated by -28% (-50, 0) of the actual carbohydrate content. Particularly meals with high mean carbohydrate content were underestimated by -34% (-56, -13). Median counting error improved significantly when estimations were performed for a second time (p<0.001). CONCLUSIONS: Participants generally underestimated the carbohydrate content of the test meals, especially in meals with higher carbohydrate content. Repetition of estimation resulted in significant improvements in estimation accuracy and is important for the maintenance of correct carbohydrate estimations. The ability to estimate the carbohydrate content of a meal should be checked and trained regularly in patients with diabetes.

Do Surrogate Endpoints Better Correlate with Overall Survival in Studies That Did Not Allow for Crossover or Reported Balanced Postprogression Treatments? An Application in Advanced Non-Small Cell Lung Cancer.

BACKGROUND: In previous studies, correlation between overall survival (OS) and surrogate endpoints like objective response rate (ORR) or progression-free survival (PFS) in advanced non-small cell lung cancer (NSCLC) was poor. This can be biased by crossover and postprogression treatments. OBJECTIVES: To evaluate the relationship between these two surrogate endpoints and OS in advanced NSCLC studies that did not allow for crossover or reported balanced post-progression treatments. METHODS: A systematic review in patients with advanced NSCLC receiving second- and further-line therapy was performed. The relationship between the absolute difference in ORR or median PFS (mPFS) and the absolute difference in median OS (mOS) was assessed using the correlation coefficient (R) and weighted regression models. The analysis was repeated in predefined data cuts based on crossover and balance of postprogression treatments. When the upper limit of R's 95% confidence interval (CI) was more than 0.7, the surrogate threshold effect (STE) was estimated. RESULTS: In total, 146 randomized clinical trials (43,061 patients) were included. The mean ORR, mPFS, and mOS were 12.2% ± 11.2%, 3.2 ± 1.3 months, and 9.6 ± 4.1 months, respectively. The correlation coefficients of ORR and mPFS were 0.181 (95% CI 0.016-0.337) and 0.254 (95% CI 0.074-0.418), respectively, with mOS. Nevertheless, in trials that did not allow crossover and reported balanced postprogression treatments, the correlation coefficients of ORR and mPFS were 0.528 (95% CI 0.081-0.798) and 0.778 (95% CI 0.475-0.916), respectively, with mOS. On the basis of STE estimation, in trials showing significant treatment effect size of 41.0% or more ORR or 4.15 or more mPFS months, OS benefit can be expected with sufficient certainty. CONCLUSIONS: Crossover and postprogression treatments may bias the relationship between surrogate endpoints and OS. Presented STE calculation can be used to interpret treatment effect on either ORR or PFS when used as primary endpoints.

Series: Pragmatic trials and real world evidence: Paper 4. Informed consent.

The GetReal consortium of the Innovative Medicines Initiative aims to develop strategies to incorporate real-world evidence earlier into the drug life cycle to better inform health care decision makers on the comparative risks and benefits of new drugs. Pragmatic trials are currently explored as a means to generate such evidence in routine care settings. The traditional informed consent model for randomized clinical trials has been argued to pose substantial hurdles to the practicability of pragmatic trials: it would lead to recruitment difficulties, reduced generalizability of the results, and selection bias. The present article analyzes these challenges and discusses four proposed alternative informed consent models: integrated consent, targeted consent, broadcast consent, and a waiver of consent. These alternative consent models each aim at overcoming operational and methodological challenges, while still providing patients all the relevant information they need to make informed decisions. Each consent model, however, relies on different attitudes toward the principle of respect for persons and the related duty to inform patients as well as represents different views on whether the common good demands moral duties from patients. Such normative consequences of modifying consent requirements should be at least acknowledged and ought to be assessed in light of the validity of empirical claims.

Impact of modified-release prednisone on functional ability in patients with rheumatoid arthritis.

This observational study assessed functional ability in patients treated with modified-release prednisone under conditions of normal clinical practice. Patients treated with modified-release prednisone were observed over 9 months. The primary outcome measure was the change from baseline total score using the Questionnaire on Activity Status (QAS); total QAS score ranges from 0 (severely impaired) to 100 (completely unimpaired). Other measures included Visual Analogue Scale (VAS) from 0 to 10 (where 10 = full daily performance) and Health Assessment Questionnaire Disability Index (HAQ-DI). There were no restrictions on dose of modified-release prednisone or use of concomitant therapy. A total of 1,733 patients were included in the study, with valid observations at baseline and study end for 1,185 patients (thereof 74 % female, median age 59 years, median disease duration 5 years). Mean total QAS score improved significantly after 9 months of treatment with modified-release prednisone from 54.3 to 70.2 (p < 0.001). There were also significant (p < 0.001) improvements in all three QAS dimensions (occupational performance: 66.6-78.9; household duties: 55.6-70.9; leisure activities: 51.6-69.4), daily performance (mean VAS 5.1-7.0; p < 0.001) and mean HAQ-DI score (1.35-1.00; p < 0.001). Dose of modified-release prednisone was significantly reduced (from 5.0 to 4.4 mg/day, p < 0.001) and fewer patients required biological rheumatoid arthritis (RA) treatments, analgesia and gastroprotectants. Functional ability in patients with RA improved significantly from baseline after 9 months of treatment with modified-release prednisone. This observational study, conducted under daily-practice conditions, confirms the beneficial effects of modified-release prednisone shown previously in randomised controlled trials.

A prospective multi-center cohort study of acute non-displaced fractures of the scaphoid: operative versus non-operative treatment [NCT00205985].

BACKGROUND: Acute scaphoid fractures are common in active adults and do lead to reasonable time lost to work. One important goal of treatment is early return to work or sport. On this background, the adequate treatment of non-displaced acute scaphoid fractures is still under discussion. The aim of this study is to compare time to return to previous activity level comparing surgical versus non-surgical treatment of non-displaced acute scaphoid fractures. METHODS/DESIGN: The study is designed as a non-randomized multiple center cohort study including 12 sites in Germany and Austria. The inclusion period is planned to be 12 months with a follow up of 6 months. Allocation to operative or non-operative treatment is chosen by the patient together with his treating surgeon. The primary outcome is time to return to previous activity level adapted for loading of the wrist in daily life as measured by a newly developed questionnaire (PLDL-wrist). Factors identified a priori to be associated with the outcome, e.g., poverty status, age, education, smoking status, gender, and occupation, are measured to ensure adequate control for their potential confounding effects. DISCUSSION: The rationale and the design of a multiple center cohort study are presented. As it is not considered feasible to randomize patients in this study, potential confounding effects need to be controlled adequately.