Time-to-event estimands and loss to follow-up in oncology in light of the estimands guidance.

Time-to-event estimands are central to many oncology clinical trials. The estimands framework (addendum to the ICH E9 guideline) calls for precisely defining the treatment effect of interest to align with the clinical question of interest and requires predefining the handling of intercurrent events (ICEs) that occur after treatment initiation and "affect either the interpretation or the existence of the measurements associated with the clinical question of interest." We discuss a practical problem in clinical trial design and execution, that is, in some clinical contexts it is not feasible to systematically follow patients to an event of interest. Loss to follow-up in the presence of intercurrent events can affect the meaning and interpretation of the study results. We provide recommendations for trial design, stressing the need for close alignment of the clinical question of interest and study design, impact on data collection, and other practical implications. When patients cannot be systematically followed, compromise may be necessary to select the best available estimand that can be feasibly estimated under the circumstances. We discuss the use of sensitivity and supplementary analyses to examine assumptions of interest.

Chronic pain in female breast cancer survivors - prevalence, characteristics and contributing factors: a cross-sectional pilot study.

BACKGROUND: While the global incidence of breast cancer is increasing, there is also an increase in the numbers of breast cancer survivors and in survival duration, as early detection programs are implemented, and treatments are optimized. Breast cancer survivors in several countries commonly struggle with a range of symptoms (fatigue, insomnia, depression) with 25-80% of survivors suffering from chronic pain. There is a paucity of literature reporting on breast cancer survivors in South Africa. In this pilot study we aimed to determine the prevalence of chronic pain in female breast cancer survivors attending the breast oncology clinic. METHODS: A cross-sectional survey was conducted of all breast cancer survivors attending the Groote Schuur Hospital Breast Unit during one month in 2019. 44 female breast cancer survivors (median age 60.5y) completed a sociodemographic questionnaire, the Brief Pain Inventory, Pain Catastrophizing Scale and measures for neuropathic pain (DN4), health related quality of life (HRQoL; EQ-5d-3 L), physical activity (IPAQ), depression and anxiety (PHQ4), and screening questions to evaluate sleep, happiness and perceived discrimination in the language of their choice. RESULTS: The prevalence of chronic pain (pain on most days for more than three months) was 59% (95%CI 44-72), a significantly higher number than the 18,3% prevalence of chronic pain reported by South African adults. 39% of the women were classified as having neuropathic pain. The median pain severity score was 3.75 (IQR = 2.75-5) and the median pain interference with function score was 4 (IQR = 2.9-5.4). The women were experiencing pain in a median of 2 different body sites (IQR = 1-3). The women with pain were more likely to be unemployed or receiving a disability grant, had significantly worse HRQoL, and significantly worse scores for risk of depression and anxiety. CONCLUSION: The results of this pilot study suggest that chronic pain may be a significant burden for South African breast cancer survivors. Routine screening for chronic pain in breast cancer survivors is recommended with a larger study indicated to explore this issue further.

Effect of elexacaftor/tezacaftor/ivacaftor on airway and systemic inflammation in cystic fibrosis.

Treatment with elexacaftor/tezacaftor/ivacaftor (ETI) has been shown to improve lung function in people with cystic fibrosis (PWCF). However, its biological effects remain incompletely understood. Here we describe alterations in pulmonary and systemic inflammation in PWCF following initiation of ETI. To address this, we collected spontaneously expectorated sputum and matching plasma from PWCF (n=30) immediately prior to ETI therapy, then again at 3 and 12 months. Within 3 months, PWCF demonstrated reduced activity of neutrophil elastase, proteinase three and cathepsin G, and decreased concentrations of interleukin (IL)-1ß and IL-8 in sputum, accompanied by decreased Pseudomonas burden and restoration of secretory leukoprotease inhibitor levels. Once treated with ETI, all airway inflammatory markers studied in PWCF had reduced to levels found in matched non-CF bronchiectasis controls. In PWCF with advanced disease, ETI resulted in decreased plasma concentrations of IL-6, C-reactive protein and soluble TNF receptor one as well as normalisation of levels of the acute phase protein, alpha-1 antitrypsin. These data clarify the immunomodulatory effects of ETI and underscore its role as a disease modifier.

Estimating the Effect of Tafamidis on Cardiovascular-Related Hospitalization in NYHA Class III Patients with Transthyretin Amyloid Cardiomyopathy in the Presence of Death.

BACKGROUND: The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) demonstrated the effectiveness of tafamidis for the treatment of patients with transthyretin amyloid cardiomyopathy (ATTR-CM). Tafamidis reduced mortality in all subgroups of patients studied. Tafamidis also reduced observed frequency of cardiovascular (CV)-related hospitalizations in all subgroups except those who were New York Heart Association (NYHA) class III at baseline who, paradoxically, had a higher frequency of CV-related hospitalizations than placebo. Given the greater mortality rate with placebo, this analysis assessed the impact of the confounding effect of death on the frequency of CV-related hospitalization in ATTR-ACT. METHODS: In ATTR-ACT, patients with ATTR-CM were randomized to tafamidis (n = 264) or placebo (n = 177) for 30 months. Post hoc analyses first defined and compared the effect of tafamidis treatment in the subset of NYHA class III patients from each treatment arm alive at month 30. The impact of a potential survivor bias was then adjusted for using principal stratification, estimating the frequency of CV-related hospitalization in NYHA class III patients who would have survived regardless of assigned treatment group (defined as the survivor average causal effect [SACE]). RESULTS: In the subset of NYHA class III patients alive at month 30, tafamidis reduced the relative risk of CV-related hospitalization versus placebo (relative risk: 0.95 [95% CI: 0.55-1.65]). In the principal stratification analyses of those patients who would survive to 30 months regardless of treatment, tafamidis treatment was associated with a 24% lower risk of CV-related hospitalization (relative risk: 0.76 [95% CI: 0.45-1.24]). Similarly, there was a larger reduction in CV-related hospitalization frequency with tafamidis in NYHA class I or II patients in the SACE than was initially observed in ATTR-ACT. CONCLUSIONS: Initial data from ATTR-ACT likely underestimated the effect of tafamidis on CV-related hospitalizations due to the confounding effect of death. When SACE was used to adjust for survivor bias, there was a 24% reduction in the frequency of CV-related hospitalization in NYHA class III patients treated with tafamidis.

Targeting of Glycosaminoglycans in Genetic and Inflammatory Airway Disease.

In the lung, glycosaminoglycans (GAGs) are dispersed in the extracellular matrix (ECM) occupying the interstitial space between the capillary endothelium and the alveolar epithelium, in the sub-epithelial tissue and in airway secretions. In addition to playing key structural roles, GAGs contribute to a number of physiologic processes ranging from cell differentiation, cell adhesion and wound healing. Cytokine and chemokine-GAG interactions are also involved in presentation of inflammatory molecules to respective receptors leading to immune cell migration and airway infiltration. More recently, pathophysiological roles of GAGs have been described. This review aims to discuss the biological roles and molecular interactions of GAGs, and their impact in the pathology of chronic airway diseases, such as cystic fibrosis and chronic obstructive pulmonary disease. Moreover, the role of GAGs in respiratory disease has been heightened by the current COVID-19 pandemic. This review underlines the essential need for continued research aimed at exploring the contribution of GAGs in the development of inflammation, to provide a better understanding of their biological impact, as well as leads in the development of new therapeutic agents.

Trikafta Rescues CFTR and Lowers Monocyte P2X7R-induced Inflammasome Activation in Cystic Fibrosis.

Rationale: Cystic fibrosis (CF) is caused by mutations in the CFTR (CF transmembrane conductance regulator) gene and is characterized by sustained inflammation. ATP triggers IL-1ß secretion via P2X7R (P2X7 receptor) and activation of the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome. Objectives: To explore the effect of the CFTR modulator elexacaftor/tezacaftor/ivacaftor (Trikafta) on CFTR expression and the ATP/P2X7R signaling axis in monocytes and on circulating proinflammatory markers. Methods: Inflammatory mediators were detected in blood from 42 patients with CF before and after 3 months of Trikafta therapy. Markers of inflammasome activation and IL-1ß secretion were measured in monocytes before and after stimulation with ATP and LPS, in the presence or absence of the P2X7R inhibitor A438079. Measurements and Main Results: P2X7R is overexpressed in CF monocytes, and receptor inhibition decreased NLRP3 expression, caspase-1 activation, and IL-1ß secretion. In vitro and in vivo, P2X7R expression is regulated by CFTR function and intracellular chloride (Cl-) levels. Trikafta therapy restored CFTR expression yet decreased P2X7R in CF monocytes, resulting in normalized Cl- and potassium efflux, and reduced intracellular calcium levels. CFTR modulator therapy decreased circulating levels of ATP and LPS and reduced inflammasome activation and IL-1ß secretion. Conclusions: P2X7R expression is regulated by intracellular Cl- levels and in CF monocytes promotes inflammasome activation. Trikafta therapy significantly increased CFTR protein expression and reduced ATP/P2X7R-induced inflammasome activation. P2X7R may therefore be a promising target for reducing inflammation in patients with CF who are noneligible for Trikafta or other CFTR modulator therapy.

Current evidence on the effect of highly effective CFTR modulation on interleukin-8 in cystic fibrosis.

INTRODUCTION: Cystic fibrosis (CF) is a genetically inherited disease, with mortality and morbidity associated with respiratory disease. The inflammatory response in CF is characterized by excessive neutrophil influx to the airways, mainly due to the increased local production and retention of interleukin-8 (IL-8), a potent neutrophil chemoattractant. AREAS COVERED: We discuss how the chemokine IL-8 dominates the inflammatory profile of the airways in CF lung disease. Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies are designed to correct the malfunctioning protein resulting from specific CFTR mutations. This review covers current evidence on the impact of CFTR impairment on levels of IL-8 and outlines the influence of effective CFTR modulation on inflammation in CF with a focus on cytokine production. Review of the literature was carried out using the PUBMED database, Google Scholar, and The Cochrane Library databases, using several appropriate generic terms. EXPERT OPINION: Therapeutic interventions specifically targeting the defective CFTR protein have improved the outlook for CF. Accumulating studies on the effect of highly effective CFTR modulation on inflammation indicate an impact on IL-8 levels. Further studies are required to increase our knowledge of early onset innate inflammatory dysregulation and on anti-inflammatory mechanisms of CFTR modulators.

Effects of non-invasive respiratory support on gas exchange and outcomes in COVID-19 outside the ICU.

Non-invasive respiratory support (NRS) outside of the ICU has played an important role in the management of COVID-19 pneumonia. There is little data to guide selection of NRS modality. We present outcomes of NRS outside the ICU and discuss the effects of NRS on gas exchange with implications for management.

Estimand framework: Are we asking the right questions? A case study in the solid tumor setting.

The estimand framework requires a precise definition of the clinical question of interest (the estimand) as different ways of accounting for "intercurrent" events post randomization may result in different scientific questions. The initiation of subsequent therapy is common in oncology clinical trials and is considered an intercurrent event if the start of such therapy occurs prior to a recurrence or progression event. Three possible ways to account for this intercurrent event in the analysis are to censor at initiation, consider recurrence or progression events (including death) that occur before and after the initiation of subsequent therapy, or consider the start of subsequent therapy as an event in and of itself. The new estimand framework clarifies that these analyses address different questions ("does the drug delay recurrence if no patient had received subsequent therapy?" vs "does the drug delay recurrence with or without subsequent therapy?" vs "does the drug delay recurrence or start of subsequent therapy?"). The framework facilitates discussions during clinical trial planning and design to ensure alignment between the key question of interest, the analysis, and interpretation. This article is a result of a cross-industry collaboration to connect the International Council for Harmonisation E9 addendum concepts to applications. Data from previously reported randomized phase 3 studies in the renal cell carcinoma setting are used to consider common intercurrent events in solid tumor studies, and to illustrate different scientific questions and the consequences of the estimand choice for study design, data collection, analysis, and interpretation.

Enigmatic and Unusual Cases of Upper Extremity Pain: Mislabeling As Malingerers.

With the intricate anatomy of the hand and upper extremity, there are many possible etiologies of pain. In addition, one must be alert to conditions typically affecting other areas of the body presenting in the hand and upper extremity. To add to the complexity of diagnosis, one must also be aware of potential secondary gains. With this in mind, a thorough history, physical examination, and broad differential can help avoid mislabeling patients with uncommon ailments. In this article, we present 4 cases of unusual causes of hand and upper extremity pain.

Assessing the Impact of COVID-19 on the Clinical Trial Objective and Analysis of Oncology Clinical Trials-Application of the Estimand Framework.

Abstract-Coronavirus disease 2019 (COVID-19) outbreak has rapidly evolved into a global pandemic. The impact of COVID-19 on patient journeys in oncology represents a new risk to interpretation of trial results and its broad applicability for future clinical practice. We identify key intercurrent events (ICEs) that may occur due to COVID-19 in oncology clinical trials with a focus on time-to-event endpoints and discuss considerations pertaining to the other estimand attributes introduced in the ICH E9 addendum. We propose strategies to handle COVID-19 related ICEs, depending on their relationship with malignancy and treatment and the interpretability of data after them. We argue that the clinical trial objective from a world without COVID-19 pandemic remains valid. The estimand framework provides a common language to discuss the impact of COVID-19 in a structured and transparent manner. This demonstrates that the applicability of the framework may even go beyond what it was initially intended for.

Phase III Trial of Adjuvant Sunitinib in Patients with High-Risk Renal Cell Carcinoma: Exploratory Pharmacogenomic Analysis.

PURPOSE: In the S-TRAC trial, adjuvant sunitinib prolonged disease-free survival (DFS) versus placebo in patients with loco-regional renal cell carcinoma at high risk of recurrence after nephrectomy. An exploratory analysis evaluated associations between SNPs in several angiogenesis- or hypoxia-related genes and clinical outcomes in S-TRAC. PATIENTS AND METHODS: Blood samples were genotyped for 10 SNPs and one insertion/deletion mutation using TaqMan assays. DFS was compared using log-rank tests for each genotype in sunitinib versus placebo groups and between genotypes within each of three (sunitinib, placebo, and combined sunitinib plus placebo) treatment groups. P values were unadjusted. RESULTS: In all, 286 patients (sunitinib, n = 142; placebo, n = 144) were genotyped. Longer DFS [HR; 95% confidence interval (CI)] was observed with sunitinib versus placebo for VEGFR1 rs9554320 C/C (HR 0.44; 95% CI, 0.21-0.91; P = 0.023), VEGFR2 rs2071559 T/T (HR 0.46; 95% CI, 0.23-0.90; P = 0.020), and eNOS rs2070744 T/T (HR 0.53; 95% CI, 0.30-0.94; P = 0.028). Shorter DFS was observed for VEGFR1 rs9582036 C/A versus C/C with sunitinib, placebo, and combined therapies (P ≤ 0.05), and A/A versus C/C with sunitinib (P = 0.022). VEGFR1 rs9554320 A/C versus A/A was associated with shorter DFS in the placebo (P = 0.038) and combined (P = 0.006) groups. CONCLUSIONS: Correlations between VEGFR1 and VEGFR2 SNPs and longer DFS with sunitinib suggest germline SNPs are predictive of improved outcomes with adjuvant sunitinib in patients with renal cell carcinoma. Independent validation studies are needed to confirm these findings.

Rural-Urban Differences in Medicare Quality Scores Persist After Adjusting for Sociodemographic and Environmental Characteristics.

PURPOSE: Quality scores are strongly influenced by sociodemographic characteristics and health behaviors, many of which lie outside of the clinician's control. As a result, there is vigorous debate about whether, and how, to risk-adjust quality measures. Yet, rurality has been largely missing from this debate, even though population and environmental characteristics are demonstrably different by rurality. We addressed this gap by examining the influence of county-level population sociodemographic, environmental, and health characteristics on 3 Medicare quality measures. METHODS: We used a cross-sectional analysis of 2016 County Health Rankings data to estimate differences in 3 Medicare quality scores (preventable hospitalizations, HbA1c monitoring, and mammography screening) by rurality. We then adjusted for county-level sociodemographic and environmental characteristics in multivariable regression models in order to see whether the association between rurality and quality was impacted. FINDINGS: Both micropolitan and noncore counties exhibited lower quality scores than metropolitan counties for all 3 measures. After adjustment, noncore counties still had poorer quality on all 3 measures, while micropolitan counties improved on 2 measures. Several county-level sociodemographic and environmental characteristics were associated with quality, although the direction of association depended on the quality measure. CONCLUSIONS: Differences in Medicare quality scores by rurality cannot be entirely explained by differences in population or environmental characteristics. Still, to the extent that clinicians are evaluated-and paid-based on measures that are influenced by both population sociodemographic characteristics and geographic location without adequate risk adjustment, the challenges of delivering care in rural areas will only be exacerbated.

Immune Biomarkers Predictive for Disease-Free Survival with Adjuvant Sunitinib in High-Risk Locoregional Renal Cell Carcinoma: From Randomized Phase III S-TRAC Study.

Purpose: Adjuvant sunitinib therapy compared with placebo prolonged disease-free survival (DFS) in patients with locoregional high-risk renal cell carcinoma (RCC) in the S-TRAC trial (ClinicalTrials.gov number NCT00375674). A prospectively designed exploratory analysis of tissue biomarkers was conducted to identify predictors of treatment benefit.Experimental Design: Tissue blocks were used for immunohistochemistry (IHC) staining of programmed cell death ligand 1 (PD-L1), CD4, CD8, and CD68. DFS was compared between < versus ≥ median IHC parameter using the Kaplan-Meier method. For biomarkers with predictive potential, receiver operating characteristics curves were generated.Results: Baseline characteristics were similar in patients with (n = 191) and without (n = 419) IHC analysis. Among patients with IHC, longer DFS was observed in patients with tumor CD8+ T-cell density ≥ versus < median [median (95% CI), not reached (6.83-not reached) versus 3.47 years (1.73-not reached); hazard ratio (HR) 0.40 (95% CI, 0.20-0.81); P = 0.009] treated with sunitinib (n = 101), but not with placebo (n = 90). The sensitivity and specificity for CD8+ T-cell density in predicting DFS were 0.604 and 0.658, respectively. Shorter DFS was observed in placebo-treated patients with PD-L1+ versus PD-L1- tumors (HR 1.75; P = 0.103). Among all patients with PD-L1+ tumors, DFS was numerically longer with sunitinib versus placebo (HR 0.58; P = 0.175).Conclusions: Greater CD8+ T-cell density in tumor tissue was associated with longer DFS with sunitinib but not placebo, suggesting predictive treatment effect utility. Further independent cohort validation studies are warranted. The prognostic value of PD-L1 expression in primary tumors from patients with high-risk nonmetastatic RCC should also be further explored. Clin Cancer Res; 24(7); 1554-61. ©2018 AACR.

Comparison of two doses of intravenous temsirolimus in patients with relapsed/refractory mantle cell lymphoma.

Temsirolimus 175 mg once-weekly for 3 weeks, followed by 75 mg once-weekly intravenously dosed (175/75 mg) is approved in the European Union for treatment of relapsed/refractory mantle cell lymphoma (MCL). A phase IV study explored whether similar efficacy, but improved safety could be achieved with 75 mg without 175 mg loading doses (ClinicaTrials.gov: NCT01180049). Patients with relapsed/refractory MCL were randomized to once-weekly temsirolimus 175/75 mg (n = 47) or 75 mg (n = 42). Treatment continued until objective disease progression. Primary endpoint: progression-free survival (PFS). Secondary endpoints included overall survival (OS) and adverse events (AEs). Median PFS was 4.3 versus 4.5 months (hazard ratio [HR] 0.731; 80% confidence interval [CI], 0.520-1.027), and median OS 18.7 versus 11.0 months (HR 0.681; 80% CI, 0.472-0.982) with 175/75 mg versus 75 mg. There were fewer patients with serious AEs, dose reduction, or death with 175/75 mg (57.4%, 48.9%, and 48.9%) versus 75 mg (73.8%, 64.3%, and 65.1%). Temsirolimus 175/75 mg remains the preferred dosing regimen for relapsed/refractory MCL.

Adjuvant Sunitinib for High-risk Renal Cell Carcinoma After Nephrectomy: Subgroup Analyses and Updated Overall Survival Results.

BACKGROUND: Adjuvant sunitinib significantly improved disease-free survival (DFS) versus placebo in patients with locoregional renal cell carcinoma (RCC) at high risk of recurrence after nephrectomy (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.59-0.98; p=0.03). OBJECTIVE: To report the relationship between baseline factors and DFS, pattern of recurrence, and updated overall survival (OS). DESIGN, SETTING, AND PARTICIPANTS: Data for 615 patients randomized to sunitinib (n=309) or placebo (n=306) in the S-TRAC trial. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Subgroup DFS analyses by baseline risk factors were conducted using a Cox proportional hazards model. Baseline risk factors included: modified University of California Los Angeles integrated staging system criteria, age, gender, Eastern Cooperative Oncology Group performance status (ECOG PS), weight, neutrophil-to-lymphocyte ratio (NLR), and Fuhrman grade. RESULTS AND LIMITATIONS: Of 615 patients, 97 and 122 in the sunitinib and placebo arms developed metastatic disease, with the most common sites of distant recurrence being lung (40 and 49), lymph node (21 and 26), and liver (11 and 14), respectively. A benefit of adjuvant sunitinib over placebo was observed across subgroups, including: higher risk (T3, no or undetermined nodal involvement, Fuhrman grade ≥2, ECOG PS ≥1, T4 and/or nodal involvement; hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.55-0.99; p=0.04), NLR ≤3 (HR 0.72, 95% CI 0.54-0.95; p=0.02), and Fuhrman grade 3/4 (HR 0.73, 95% CI 0.55-0.98; p=0.04). All subgroup analyses were exploratory, and no adjustments for multiplicity were made. Median OS was not reached in either arm (HR 0.92, 95% CI 0.66-1.28; p=0.6); 67 and 74 patients died in the sunitinib and placebo arms, respectively. CONCLUSIONS: A benefit of adjuvant sunitinib over placebo was observed across subgroups. The results are consistent with the primary analysis, which showed a benefit for adjuvant sunitinib in patients at high risk of recurrent RCC after nephrectomy. PATIENT SUMMARY: Most subgroups of patients at high risk of recurrent renal cell carcinoma after nephrectomy experienced a clinical benefit with adjuvant sunitinib. TRIAL REGISTRATION: ClinicalTrials.gov NCT00375674.

Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy.

BACKGROUND: Sunitinib, a vascular endothelial growth factor pathway inhibitor, is an effective treatment for metastatic renal-cell carcinoma. We sought to determine the efficacy and safety of sunitinib in patients with locoregional renal-cell carcinoma at high risk for tumor recurrence after nephrectomy. METHODS: In this randomized, double-blind, phase 3 trial, we assigned 615 patients with locoregional, high-risk clear-cell renal-cell carcinoma to receive either sunitinib (50 mg per day) or placebo on a 4-weeks-on, 2-weeks-off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. The primary end point was disease-free survival, according to blinded independent central review. Secondary end points included investigator-assessed disease-free survival, overall survival, and safety. RESULTS: The median duration of disease-free survival was 6.8 years (95% confidence interval [CI], 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI, 3.8 to 6.6) in the placebo group (hazard ratio, 0.76; 95% CI, 0.59 to 0.98; P=0.03). Overall survival data were not mature at the time of data cutoff. Dose reductions because of adverse events were more frequent in the sunitinib group than in the placebo group (34.3% vs. 2%), as were dose interruptions (46.4% vs. 13.2%) and discontinuations (28.1% vs. 5.6%). Grade 3 or 4 adverse events were more frequent in the sunitinib group (48.4% for grade 3 events and 12.1% for grade 4 events) than in the placebo group (15.8% and 3.6%, respectively). There was a similar incidence of serious adverse events in the two groups (21.9% for sunitinib vs. 17.1% for placebo); no deaths were attributed to toxic effects. CONCLUSIONS: Among patients with locoregional clear-cell renal-cell carcinoma at high risk for tumor recurrence after nephrectomy, the median duration of disease-free survival was significantly longer in the sunitinib group than in the placebo group, at a cost of a higher rate of toxic events. (Funded by Pfizer; S-TRAC ClinicalTrials.gov number, NCT00375674 .).

Adjusting for treatment switching in the METRIC study shows further improved overall survival with trametinib compared with chemotherapy.

Trametinib, a selective inhibitor of mitogen-activated protein kinase kinase 1 (MEK1) and MEK2, significantly improves progression-free survival compared with chemotherapy in patients with BRAF V600E/K mutation-positive advanced or metastatic melanoma (MM). However, the pivotal clinical trial permitted randomized chemotherapy control group patients to switch to trametinib after disease progression, which confounded estimates of the overall survival (OS) advantage of trametinib. Our purpose was to estimate the switching-adjusted treatment effect of trametinib for OS and assess the suitability of each adjustment method in the primary efficacy population. Of the patients randomized to chemotherapy, 67.4% switched to trametinib. We applied the rank-preserving structural failure time model, inverse probability of censoring weights, and a two-stage accelerated failure time model to obtain estimates of the relative treatment effect adjusted for switching. The intent-to-treat (ITT) analysis estimated a 28% reduction in the hazard of death with trametinib treatment (hazard ratio [HR], 0.72; 95% CI, 0.52-0.98) for patients in the primary efficacy population (data cut May 20, 2013). Adjustment analyses deemed plausible provided OS HR point estimates ranging from 0.48 to 0.53. Similar reductions in the HR were estimated for the first-line metastatic subgroup. Treatment with trametinib, compared with chemotherapy, significantly reduced the risk of death and risk of disease progression in patients with BRAF V600E/K mutation-positive advanced melanoma or MM. Adjusting for switching resulted in lower HRs than those obtained from standard ITT analyses. However, CI are wide and results are sensitive to the assumptions associated with each adjustment method.

Correlation of BRAF Mutation Status in Circulating-Free DNA and Tumor and Association with Clinical Outcome across Four BRAFi and MEKi Clinical Trials.

PURPOSE: Tumor-derived circulating cell-free DNA (cfDNA) is a potential alternative source from which to derive tumor mutation status. cfDNA data from four clinical studies of the BRAF inhibitor (BRAFi) dabrafenib or the MEK inhibitor (MEKi) trametinib were analyzed to determine the association between BRAF mutation status in cfDNA and tumor tissue, and the association of BRAF cfDNA mutation status with baseline factors and clinical outcome. EXPERIMENTAL DESIGN: Patients with BRAF V600 mutation-positive melanoma were enrolled in each study after central confirmation of BRAF status in tumor using a PCR-based assay. BRAF mutation status in cfDNA from patient plasma collected at baseline, 732 of 836 (88%) enrolled patients in total, was determined. RESULTS: BRAF mutations were detectable in cfDNA in 76% and 81% of patients with BRAF V600E/V600K-positive tumors, respectively. Patients negative for BRAF mutations in cfDNA had longer progression-free survival (PFS) and overall survival in each of the four studies, compared with patients with detectable cfDNA BRAF mutations. The presence of BRAF-mutant cfDNA was an independent prognostic factor for PFS after multivariate adjustment for baseline factors in three of four studies. Patients negative for BRAF mutation-positive cfDNA in plasma had higher response rates to dabrafenib and trametinib. CONCLUSIONS: BRAF mutations in cfDNA are detectable in >75% of late-stage melanoma patients with BRAF mutation-positive tumors. The lack of circulating, BRAF mutation-positive cfDNA is clinically significant for metastatic melanoma patients, and may be a prognostic marker for better disease outcome.