Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions.

BACKGROUND: Amivantamab has been approved for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertions who have had disease progression during or after platinum-based chemotherapy. Phase 1 data showed the safety and antitumor activity of amivantamab plus carboplatin-pemetrexed (chemotherapy). Additional data on this combination therapy are needed. METHODS: In this phase 3, international, randomized trial, we assigned in a 1:1 ratio patients with advanced NSCLC with EGFR exon 20 insertions who had not received previous systemic therapy to receive intravenous amivantamab plus chemotherapy (amivantamab-chemotherapy) or chemotherapy alone. The primary outcome was progression-free survival according to blinded independent central review. Patients in the chemotherapy group who had disease progression were allowed to cross over to receive amivantamab monotherapy. RESULTS: A total of 308 patients underwent randomization (153 to receive amivantamab-chemotherapy and 155 to receive chemotherapy alone). Progression-free survival was significantly longer in the amivantamab-chemotherapy group than in the chemotherapy group (median, 11.4 months and 6.7 months, respectively; hazard ratio for disease progression or death, 0.40; 95% confidence interval [CI], 0.30 to 0.53; P<0.001). At 18 months, progression-free survival was reported in 31% of the patients in the amivantamab-chemotherapy group and in 3% in the chemotherapy group; a complete or partial response at data cutoff was reported in 73% and 47%, respectively (rate ratio, 1.50; 95% CI, 1.32 to 1.68; P<0.001). In the interim overall survival analysis (33% maturity), the hazard ratio for death for amivantamab-chemotherapy as compared with chemotherapy was 0.67 (95% CI, 0.42 to 1.09; P = 0.11). The predominant adverse events associated with amivantamab-chemotherapy were reversible hematologic and EGFR-related toxic effects; 7% of patients discontinued amivantamab owing to adverse reactions. CONCLUSIONS: The use of amivantamab-chemotherapy resulted in superior efficacy as compared with chemotherapy alone as first-line treatment of patients with advanced NSCLC with EGFR exon 20 insertions. (Funded by Janssen Research and Development; PAPILLON ClinicalTrials.gov number, NCT04538664.).

Amivantamab compared with real-world therapies in patients with advanced non-small cell lung cancer harboring EGFR exon 20 insertion mutations who progressed after platinum-based chemotherapy.

BACKGROUND: In the single-arm CHRYSALIS study, amivantamab showed durable responses and manageable safety in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion mutations (ex20ins) who progressed on prior platinum-based chemotherapy. External controls can provide context for interpreting amivantamab efficacy. METHODS: External controls were selected from three US-based databases (ConcertAI, COTA, and Flatiron). Key inclusion criteria were diagnosis of EGFR ex20ins advanced NSCLC, prior platinum-based chemotherapy, and performance status score ≤ 1. Duplicate external controls were identified using a tokenization procedure and removed, and adjustment for differences in baseline characteristics between amivantamab-treated and external control cohorts was achieved using propensity score weighting. RESULTS: Amivantamab-treated and pooled external control cohorts included 81 and 125 patients, respectively. Baseline characteristics were generally similar across cohorts, except more amivantamab-treated patients were Asian (56% vs 13%). Most common therapies received by external controls were non-platinum-based chemotherapy (25.1%), immuno-oncology therapies (24.2%), EGFR tyrosine kinase inhibitors (16.3%), and platinum-based chemotherapy (16.3%). Overall response rate was 40% among amivantamab-treated patients and 16% among external controls. Amivantamab-treated patients had longer progression-free survival (median 8.3 vs 2.9 months; hazard ratio [HR; 95% CI]: 0.47 [0.34-0.65]), time to next therapy (median 14.8 vs 4.8 months; HR [95% CI]: 0.40 [0.28-0.57]), and overall survival (median 22.8 vs 12.8 months; HR [95% CI]: 0.49 [0.31-0.77]) than external controls. Results were consistent in sensitivity analyses comparing each external control dataset against the amivantamab-treated group separately. CONCLUSION: Among post-platinum patients with EGFR ex20ins advanced NSCLC, those treated with amivantamab had improved outcomes, including 10-month longer overall survival, versus external controls.

Association between ultrasound-detected synovitis and knee pain: a population-based case-control study with both cross-sectional and follow-up data.

BACKGROUND: An important role for synovial pathology in the initiation and progression of knee osteoarthritis has been emphasised recently. This study aimed to examine whether ultrasonography-detected synovial changes associate with knee pain (KP) in a community population. METHODS: A case-control study was conducted to compare people with early KP (n = 298), established KP (n = 100) or no KP (n = 94) at baseline. Multinomial logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) between groups adjusted for radiographic osteoarthritis (ROA) severity and other confounding factors. After 1 year, 255 participants with early and established KP completed the follow-up questionnaire for changes in KP. Logistic regression with adjustment was used to determine predictors of KP worsening. RESULTS: At baseline, effusion was associated with early KP (OR 2.64, 95% CI 1.57-4.45) and established KP (OR 5.07, 95% CI 2.74-9.38). Synovial hypertrophy was also associated with early KP (OR 5.43, 95% CI 2.12-13.92) and established KP (OR 13.27, 95% CI 4.97-35.43). The association with effusion diminished when adjusted for ROA. Power Doppler signal was uncommon (early KP 3%, established KP 2%, controls 0%). Baseline effusion predicted worsening of KP at 1 year (OR 1.95, 95% CI 1.05-3.64). However, after adjusting for ROA, the prediction was insignificant (adjusted OR 0.95, 95% CI 0.44-2.02). CONCLUSIONS: Ultrasound effusion and synovial hypertrophy are associated with KP, but only effusion predicts KP worsening. However, the association/prediction is not independent from ROA. Power Doppler signal is uncommon in people with KP. Further study is needed to understand whether synovitis is directly involved in different types of KP.

Identifying placebo responders and predictors of response in osteoarthritis: a protocol for individual patient data meta-analysis.

BACKGROUND: The management of osteoarthritis (OA) is unsatisfactory, as most treatments are not clinically effective over placebo and most drugs have considerable side effects. On average, 75 % of the analgesic effect from OA treatments in clinical trials can be attributed to a placebo response, and this response varies greatly from patient to patient. This individual patient data (IPD) meta-analysis aims to identify placebo responders and the potential determinants of the placebo response in OA. METHODS: This study is undertaken in conjunction with the OA Trial Bank, an ongoing international consortium aiming to collect IPD from randomised controlled trials (RCTs) for all treatments of OA. RCTs for each treatment of OA have been systematically searched for, and authors of the relevant trials have been contacted to request the IPD. We will use the IPD of placebo-controlled RCTs held by the OA Trial Bank for this project. The IPD in placebo groups will be used to investigate the placebo response according to the minimum clinically important difference (MCID) threshold (e.g. 20 % pain reduction). Responders to placebo will be compared with non-responders to identify predictors of response. The quality of the trials will be assessed and potential determinants will be examined using multilevel logistic regression analyses. DISCUSSION: This study explores the varying magnitude of the placebo response and the proportion of participants that experience a clinically important placebo effect in OA RCTs. Potential determinants of the placebo response will also be investigated. These determinants may be useful for future studies as it may allow participants to be stratified into groups based on their likely response to placebo. The results of this study may also be useful for pharmaceutical companies, who could improve the design of their studies in order to separate the specific treatment from the non-specific contextual (i.e. placebo) effects. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016033212.

Relative efficacy of topical non-steroidal anti-inflammatory drugs and topical capsaicin in osteoarthritis: protocol for an individual patient data meta-analysis.

BACKGROUND: Pain is the most troubling issue to patients with osteoarthritis (OA), yet current pharmacological treatments offer only small-to-moderate pain reduction. Current guidelines therefore emphasise the need to identify predictors of treatment response. In line with these recommendations, an individual patient data (IPD) meta-analysis will be conducted. The study aims to investigate the relative treatment effects of topical non-steroidal anti-inflammatory drugs (NSAIDs) and topical capsaicin in OA and to identify patient-level predictors of treatment response. METHODS: IPD will be collected from randomised controlled trials (RCTs) of topical NSAIDs and capsaicin in OA. Multilevel regression modelling will be conducted to determine predictors for the specific and the overall treatment effect. DISCUSSION: Through the identification of treatment responders, this IPD meta-analysis may improve the current understanding of the pain mechanisms in OA and guide clinical decision-making. Identifying and prescribing the treatment most likely to be beneficial for an individual with OA will improve the efficiency of patient management. SYSTEMATIC REVIEW REGISTRATION: CRD42016035254.

Relative efficacy of different types of exercise for treatment of knee and hip osteoarthritis: protocol for network meta-analysis of randomised controlled trials.

BACKGROUND: 'Exercise' is universally recommended as a core treatment for knee and hip osteoarthritis (OA). However, there are very few head-to-head comparative trials to determine the relative efficacy between different types of exercise. The aim of this study is to benchmark different types of exercises against each other through the use of a common comparator in a network meta-analysis of randomised controlled trials (RCTs). METHODS: This study will include only RCTs published in peer-reviewed journals. A systematic search will be conducted in several electronic databases and other relevant online resources. No limitations are imposed on language or publication date. Participants must be explicitly identified by authors as having OA. Interventions that involved exercise or comparators in any form will be included. Pain is the primary outcome of interest; secondary outcomes will include function and quality of life measures. Quality assessment of studies will be based on the modified Cochrane's risk of bias assessment tool. At least two investigators will be involved throughout all stages of screening and data acquisition. Conflicts will be resolved through discussion. Conventional meta-analysis will be performed based on random effects model and network meta-analysis on a Bayesian model. Subgroup analysis will also be conducted based on study, patient and disease characteristics. DISCUSSION: This study will provide for the first time comprehensive research evidence for the relative efficacy of different exercise regimens for treatment of OA. We will use network meta-analysis of existing RCT data to answer this question. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016033865.