We investigated in the first-line setting our previous finding that patients with chemorefractory KRAS G13D-mutated metastatic colorectal cancer (mCRC) benefit from cetuximab treatment.
Associations ...between tumor KRAS mutation status (wild-type, G13D, G12V, or other mutations) and progression-free survival (PFS), survival, and response were investigated in pooled data from 1,378 evaluable patients from the CRYSTAL and OPUS studies. Multivariate analysis correcting for differences in baseline prognostic factors was performed.
Of 533 patients (39%) with KRAS-mutant tumors, 83 (16%) had G13D, 125 (23%) had G12V, and 325 (61%) had other mutations. Significant variations in treatment effects were found for tumor response (P = .005) and PFS (P = .046) in patients with G13D-mutant tumors versus all other mutations (including G12V). Within KRAS mutation subgroups, cetuximab plus chemotherapy versus chemotherapy alone significantly improved PFS (median, 7.4 v 6.0 months; hazard ratio HR, 0.47; P = .039) and tumor response (40.5% v 22.0%; odds ratio, 3.38; P = .042) but not survival (median, 15.4 v 14.7 months; HR, 0.89; P = .68) in patients with G13D-mutant tumors. Patients with G12V and other mutations did not benefit from this treatment combination. Patients with KRAS G13D-mutated tumors receiving chemotherapy alone experienced worse outcomes (response, 22.0% v 43.2%; odds ratio, 0.40; P = .032) than those with other mutations. Effects were similar in the separate CRYSTAL and OPUS studies.
The addition of cetuximab to first-line chemotherapy seems to benefit patients with KRAS G13D-mutant tumors. Relative treatment effects were similar to those in patients with KRAS wild-type tumors but with lower absolute values.
The addition of cetuximab to irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer (mCRC) was shown to reduce the risk of disease progression and ...increase the chance of response in patients with KRAS wild-type disease. An updated survival analysis, including additional patients analyzed for tumor mutation status, was undertaken.
Patients were randomly assigned to receive FOLFIRI with or without cetuximab. DNA was extracted from additional slide-mounted tumor samples previously used to assess epidermal growth factor receptor expression. Clinical outcome according to the tumor mutation status of KRAS and BRAF was assessed in the expanded patient series.
The ascertainment rate of patients analyzed for tumor KRAS status was increased from 45% to 89%, with mutations detected in 37% of tumors. The addition of cetuximab to FOLFIRI in patients with KRAS wild-type disease resulted in significant improvements in overall survival (median, 23.5 v 20.0 months; hazard ratio HR, 0.796; P = .0093), progression-free survival (median, 9.9 v 8.4 months; HR, 0.696; P = .0012), and response (rate 57.3% v 39.7%; odds ratio, 2.069; P < .001) compared with FOLFIRI alone. Significant interactions between KRAS status and treatment effect were noted for all key efficacy end points. KRAS mutation status was confirmed as a powerful predictive biomarker for the efficacy of cetuximab plus FOLFIRI. BRAF tumor mutation was a strong indicator of poor prognosis.
The addition of cetuximab to FOLFIRI as first-line therapy improves survival in patients with KRAS wild-type mCRC. BRAF tumor mutation is an indicator of poor prognosis.
Early tumor shrinkage (ETS) is associated with long-term outcome in patients with chemorefractory metastatic colorectal cancer (mCRC) receiving cetuximab. This association was investigated in the ...first-line setting in the randomized CRYSTAL and OPUS mCRC trials, after controlling for KRAS tumor mutation status.
Radiologic assessments at week 8 were used to calculate the relative change in the sum of the longest diameters of the target lesions. Time-dependent receiver operating characteristics provided Cτ-indices (time-dependent c-index). Cox regression models and subpopulation treatment effect pattern plot analysis investigated associations between ETS (radiologic tumor size decrease at week 8) and survival and progression-free survival (PFS).
In both trials, in patients with KRAS wild-type mCRC, Cτ values for PFS and survival were higher (P < .001) in those receiving chemotherapy plus cetuximab versus chemotherapy alone, indicating a stronger predictive value of ETS for long-term outcome in these patients. In the CRYSTAL and OPUS trials, respectively, the cutoff value of ETS ≥ 20% (v < 20%) identified patients with KRAS wild-type mCRC receiving chemotherapy plus cetuximab with longer PFS (medians 14.1 v 7.3 months, hazard ratio HR = 0.32; P < .001, and medians 11.9 v 5.7 months, HR = 0.22; P < .001) and survival (medians 30.0 v 18.6 months, HR = 0.53; P < .001 and medians 26.0 v 15.7 months, HR = 0.43; P = .006).
ETS was significantly associated with long-term outcome in patients with KRAS wild-type mCRC treated first-line with chemotherapy plus cetuximab. Validation in prospective trials is required to assess the value of this on-treatment marker in the clinical decision-making process.
Single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq) creates new opportunities to dissect cell type-specific mechanisms of complex diseases. Since pancreatic islets ...are central to type 2 diabetes (T2D), we profiled 15,298 islet cells by using combinatorial barcoding snATAC-seq and identified 12 clusters, including multiple alpha, beta and delta cell states. We cataloged 228,873 accessible chromatin sites and identified transcription factors underlying lineage- and state-specific regulation. We observed state-specific enrichment of fasting glucose and T2D genome-wide association studies for beta cells and enrichment for other endocrine cell types. At T2D signals localized to islet-accessible chromatin, we prioritized variants with predicted regulatory function and co-accessibility with target genes. A causal T2D variant rs231361 at the KCNQ1 locus had predicted effects on a beta cell enhancer co-accessible with INS and genome editing in embryonic stem cell-derived beta cells affected INS levels. Together our findings demonstrate the power of single-cell epigenomics for interpreting complex disease genetics.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Previous trials have shown that the combination of fluorouracil-based chemotherapy and cetuximab is active when used as salvage treatment in patients with metastatic colorectal cancer; the present ...trial shows activity of this combination as first-line treatment as well. The trial also found that for cetuximab to be active, an unmutated
KRAS
gene in the tumor was required.
This trial shows activity of the combination of fluorouracil-based chemotherapy and cetuximab as first-line treatment. The trial also found that for cetuximab to be active, an unmutated KRAS gene in the tumor was required.
Colorectal cancer is the third most common cancer worldwide.
1
Approximately 25% of patients with colorectal cancer present with overt metastatic disease, and metastatic disease develops in 40 to 50% of newly diagnosed patients. Standard first-line treatments include fluorouracil with leucovorin and irinotecan
2
,
3
or oxaliplatin,
4
alone or combined with bevacizumab.
5
The immunoglobulin G1 monoclonal antibody against the epidermal growth factor receptor (EGFR), cetuximab (Erbitux), is effective in combination with irinotecan in patients with metastatic colorectal cancer or as a single agent in patients with metastatic colorectal cancer that progresses even when irinotecan is used.
6
,
7
Phase 1 and 2 studies . . .
Due to limited duration of follow up in clinical trials of cancer treatments, estimates of lifetime survival benefits are typically derived using statistical extrapolation methods. To justify the ...method used, a range of approaches have been proposed including statistical goodness-of-fit tests and comparing estimates against a previous data cut (i.e. interim data collected). In this study, we extend these approaches by presenting a range of extrapolations fitted to four pre-planned data cuts from the JAVELIN Merkel 200 (JM200) trial. By comparing different estimates of survival and goodness-of-fit as JM200 data mature, we undertook an iterative process of fitting and re-fitting survival models to retrospectively identify early indications of likely long-term survival.
Standard and spline-based parametric models were fitted to overall survival data from each JM200 data cut. Goodness-of-fit was determined using an assessment of the estimated hazard function, information theory-based methods and objective comparisons of estimation accuracy. Best-fitting extrapolations were compared to establish which one provided the most accurate estimation, and how statistical goodness-of-fit differed.
Spline-based models provided the closest fit to the final JM200 data cut, though all extrapolation methods based on the earliest data cut underestimated the 'true' long-term survival (difference in restricted mean survival time RMST at 36 months: - 1.1 to - 0.5 months). Goodness-of-fit scores illustrated that an increasingly flexible model was favored as data matured. Given an early data cut, a more flexible model better aligned with clinical expectations could be reasonably justified using a range of metrics, including RMST and goodness-of-fit scores (which were typically within a 2-point range of the statistically 'best-fitting' model).
Survival estimates from the spline-based models are more aligned with clinical expectation and provided a better fit to the JM200 data, despite not exhibiting the definitively 'best' statistical goodness-of-fit. Longer-term data are required to further validate extrapolations, though this study illustrates the importance of clinical plausibility when selecting the most appropriate model. In addition, hazard-based plots and goodness-of-fit tests from multiple data cuts present useful approaches to identify when a more flexible model may be advantageous.
JAVELIN Merkel 200 was registered with ClinicalTrials.gov as NCT02155647 on June 4, 2014.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction
When determining if changes on patient-reported outcome (PRO) scores in clinical trials convey a meaningful treatment benefit, statistical significance tests alone may not communicate ...the patient perspective. Appraising within-patient changes on PRO scores against established thresholds can determine if improvements or deteriorations experienced by individuals are meaningful. To evaluate the appropriateness of thresholds for interpreting meaningful improvements and deterioration within individuals on the European Organisation for Research and Treatment of Cancer (EORTC) 30-item core instrument (QLQ-C30) and 13-item lung cancer module (QLQ-LC13), a series of psychometric methods were applied to data from a phase III randomized controlled clinical trial in non-small cell lung cancer.
Methods
Anchor-based methods of empirical cumulative distribution functions and classification statistics were employed using change scores from Baseline to Week 7 using changes on the QLQ-C30 Global Health Status item as an anchor. Distribution-based methods of one-half standard deviation and standard error of measurement identified the minimum amount of change each domain score can reliably measure.
Results
While the correlations between the domain scores and the anchor item were modest in size (i.e.,
r
≥ 0.30 for only 5 of 24 domains), consideration of multiple methods along with the magnitude of possible step changes on the score allowed for patterns to emerge. The triangulation process planned
a priori
resulted in different methods being the source for different domain scores. Absolute values of the proposed thresholds ranged from 11.11 to 33.33, and all resulted in the same classifications for all EORTC domains, except QLQ-C30 Fatigue, as would the 10-point threshold that is traditionally used.
Conclusion
This study confirms the appropriateness of the 10-point EORTC score threshold generally used by the field for interpreting within-patient changes, but the thresholds proposed from this study enhance interpretability by corresponding to only observable locations along the domain score scale.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
For valid and reliable assessment of patients' Health-Related Quality of Life (HRQoL), it is crucial to use psychometrically robust instruments. In the context of rare diseases such as Merkel cell ...carcinoma (MCC), validated disease-specific instruments are often not available. The Functional Assessment of Cancer Therapy - Melanoma (FACT-M) was originally developed for use in melanoma. Its psychometric performance for use in MCC and minimal important difference (MID) thresholds have been previously reported based on a cohort of metastatic MCC patients who had disease progression following one or more prior line of chemotherapy (NCT02155647 Part A; n = 70). Since then, new data from the phase II JAVELIN Merkel 200 trial among treatment-naïve patients are available (NCT02155647 Part B; n = 102). This study aims to increase accuracy and precision of previously established psychometric properties and MID thresholds of FACT-M in metastatic MCC patients.
Published qualitative research suggests that patients with metastatic MCC had similar experiences and described similar concepts associated with their disease independent of whether they were treatment naïve or had prior treatment. Therefore, it was deemed appropriate to pool FACT-M data from Part A (previously treated) and Part B (treatment-naïve) cohorts for this study. Construct validity was assessed by evaluating item-factor correlations (convergent validity) and known-groups validity using ECOG performance status 0 versus 1. Concurrent validity was assessed using EQ-5D items. Internal consistency reliability was assessed using Cronbach's α. Anchor- and distribution-based approaches were used to derive MID thresholds.
Overall, psychometric tests based on various validity (convergent, known-groups, concurrent) and reliability (Cronbach α) analyses confirmed previous findings in that FACT-M performs well in MCC patients. MID thresholds derived from this study are largely in line with previously established thresholds with some minor adjustments.
In the context of rare diseases, which often have limited data available for psychometric testing, a reasonably large MCC patient sample was available for this study, enhancing accuracy and precision of previously established FACT-M psychometric properties and MID thresholds with only small deviations for use in metastatic MCC patients. Results suggest that the FACT-M is suitable for Merkel cell carcinoma regardless of patients' treatment status.
This study is a pre-planned post-hoc analysis conducted on data collected in Part A and Part B of the JAVELIN Merkel 200 trial. This trial was registered on 2 June 2014 with ClinicalTrials.gov as NCT02155647.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Skin toxicity in patients receiving cetuximab has been associated positively with clinical outcome in several tumor types. This study investigated the effect of cetuximab dose escalation in patients ...with irinotecan-refractory metastatic colorectal cancer who had developed no or mild skin reactions after 21 days of treatment at the standard dose. This article reports clinical and pharmacokinetic (PK) data.
After 21 days of standard-dose cetuximab (400 mg/m(2) initial dose, then 250 mg/m(2) per week) plus irinotecan, patients with ≤ grade 1 skin reactions were randomly assigned to standard-dose (group A) or dose-escalated (to 500 mg/m(2) per week; group B) cetuximab. Patients with ≥ grade 2 skin reactions continued on standard-dose cetuximab plus irinotecan (group C).
The intent-to-treat population comprised 157 patients. PK profiles reflected the dose increase and were predictable across the dose range investigated. Weekly cetuximab doses of up to 500 mg/m(2) were well tolerated, and grade 3 and 4 adverse events were generally comparable between treatment groups. Dose escalation (n = 44) was associated with an increase in skin reactions ≥ grade 2 compared with standard (n = 45) dosing (59% v 38%, respectively). Dose escalation, compared with standard dosing, showed some evidence for improved response rate (30% v 16%, respectively) and disease control rate (70% v 58%, respectively) but no indication of benefit in relation to overall survival. In an exploratory analysis, dose escalation seemed to increase response rate compared with standard dosing in patients with KRAS wild-type but not KRAS mutant tumors.
Cetuximab serum concentrations increased predictably with dose. Higher dose levels were well tolerated. The possible indication for improved efficacy in the dose-escalation group warrants further investigation.
BackgroundUncertainty around key elements of an appropriate patient-reported outcome (PRO) baseline assessment introduces trial-specific variation in oncology clinical trials with a poorly understood ...consequence on drug evaluation decisions. This research investigated the impact of multiple pre-treatment PRO assessments and timing of assessments in a clinical trial. MethodsA post-hoc analysis of a completed phase 3, open-label, randomized, parallel arm clinical trial in non-small cell lung cancer with two pre-treatment PRO assessments (screening and Week 1 Day 1 W1D1). Descriptive analyses, mixed models for repeated measures and time until definitive deterioration analyses were performed to estimate differences between treatment arms. Through model adjustments, different baseline specifications and assessment timing (pre/post-randomization) on W1D1 PROs were evaluated. ResultsPatients with both pre-treatment PRO assessments were included in the analysis (N = 535). Numerically small average change scores were observed between screening and W1D1 (mean change, 0-100 scale ranges): Chest pain (-0.94), Cough (-0.94), Dyspnea (1.27), Physical functioning (-1.19). Both pre-treatment assessments were moderately-highly correlated (r: 0.55-0.78) and no trend was found for deterioration or improvement during this period. Varying baseline definitions in the models produced slight differences in model fit but no impact on the between treatment group effect estimate. W1D1 PRO scores were not statistically influenced by assessment timing pre/post-randomization (p-values: 0.142-0.628). ConclusionFindings from this study question the need for multiple pre-treatment PRO assessments in oncology drug development trials and the degree of bias thought to be introduced through patient knowledge of treatment assignment. Implications for researchers are presented.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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