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Purpose To validate a plasma vemurafenib steady-state trough concentration (C ss , min ) threshold that predicts survival outcomes of patients with BrafV 600 mutated melanoma., Methods: A pooled analysis of individual patient data from two advanced melanoma trials involving vemurafenib ± cobimetinib therapy was performed. Day 23 was chosen as the landmark time when steady-state concentration reached. Optimal C ss , min threshold was determined via assessment of discriminative performance and model fitting. Association between vemurafenib C ss , min and survival was modelled using Cox proportional hazards regression., Results: Vemurafenib plasma concentration data were available for 402 patients who were on stable dose for the first 3 weeks. When compared to a previously described plasma vemurafenib C ss , min threshold of 42 mg/L, we identified that a cutoff concentration of 50 mg/L by day 23 was strongly associated with progression-free survival and overall survival. The association remained statistically significant after adjusting for important clinical confounding variables. Sub-group analysis showed that while the addition of cobimetinib resulted in a lower day 23 plasma vemurafenib C ss , min , the threshold was still associated with overall survival and not in the monotherapy cohort., Conclusion: A plasma vemurafenib C ss , min threshold of 50 mg/L is strongly associated with survival outcomes in patients with advanced melanoma. This new threshold needs to be validated prospectively in future studies.

Background: Rash is one of the most common severe adverse events associated with use of vemurafenib for the treatment of melanoma, either as monotherapy or in combination with cobimetinib. The study aimed to identify pre-treatment patient characteristics predictive of developing severe rash with vemurafenib therapy., Methods: This was a secondary pooled analysis of individual patient data from the BRIM-2, BRIM-3 and coBRIM clinical trials, including all patients treated with vemurafenib alone and vemurafenib plus cobimetinib. Patient age, sex, performance status, body weight, body mass index, liver function markers and estimated glomerular filtration rate were assessed for association with development of severe (grade 3 or 4) rash using logistic regression., Results: Of 962 patients treated with vemurafenib, 150 (16%) patients experienced severe rash. Female sex was identified as a significant risk factor for severe rash development (P < 0.001), having a two-fold increased risk compared to males (22% vs 11%, odds ratio [OR] 2.17; 95% CI 1.52 to 3.09). Low body weight was also associated with increased risk of severe rash (P = 0.002), but this association was not significant after adjustment for sex. The association between sex and risk of severe rash was consistent across clinical trials and treatments (vemurafenib monotherapy, vemurafenib plus cobimetinib)., Conclusion: Females had approximately two-fold increased risk of developing severe rash compared to males in clinical trials of vemurafenib alone or in combination with cobimetinib.

Background: Studies of patients treated with bevacizumab and other vascular epithelial growth factor (VEGF) inhibitors have reported that hypertension adverse events (AEs) are associated with improved overall survival (OS) or progression-free survival (PFS)., Objective: Our objective was to evaluate the association between early AEs and survival outcomes for patients treated with ramucirumab, an antibody targeting the VEGF receptor-2 (VEGFR-2), plus FOLFIRI for metastatic colorectal cancer (mCRC)., Methods: Data from 529 patients treated with ramucirumab plus FOLFIRI for mCRC in the RAISE clinical trial (NCT01183780) were evaluated to see whether early (first 6 weeks of therapy) AEs predicted subsequent OS and PFS. A Cox proportional hazard approach was used to evaluate associations between early AEs and survival outcomes. A secondary analysis between FOLFIRI and placebo was conducted as a sensitivity analysis., Results: Of 529 patients treated with ramucirumab plus FOLFIRI, 479 were alive and progression free at 6 weeks after commencing therapy. No significant association was identified between hypertension occurring within the first 42 days of ramucirumab plus FOLFIRI therapy and OS (grade 1-2, hazard ratio [HR] 0.90 [95% confidence interval (CI) 0.66-1.24]; grade 3+, HR 1.02 [95% CI 0.67-1.55]; P = 0.803) or PFS (grade 1-2, HR 0.98 [95% CI 0.74-1.28]; grade 3+, HR 0.93 [95% CI 0.64-1.37]; P = 0.93). However, there was a significant association between diarrhea occurring within the first 42 days of ramucirumab plus FOLFIRI therapy and worse OS (grade 1-2, HR 0.96 [95% CI 0.76-1.20]; grade 3+, HR 2.72 [95% CI 1.67-4.44]; P = 0.001) and PFS (grade 1-2, HR 1.01 [95% CI 0.83-1.23]; grade 3+, HR 2.22 [95% CI 1.43-3.45]; P = 0.005). No other AEs were significantly associated with OS or PFS., Conclusions: Ramucirumab-induced hypertension was not associated with improved OS and PFS in patients with mCRC treated with ramucirumab and FOLFIRI, but severe diarrhea was associated with poorer OS and PFS., Clinical Trial Registration: No. NCT01183780.

Purpose: Ado-trastuzumab emtansine (T-DM1) treatment in HER2+ advanced breast cancer patients is generally well tolerated, but when adverse events occur dose adjustments may be required. This study evaluated the impact of early adverse events requiring T-DM1 dose interruptions or reductions on overall survival (OS) and progression-free survival (PFS) in HER2+ advanced metastatic breast cancer patients in the clinical trials EMILIA and TH3RESA., Patients and Methods: The study included 893 participants initiated on T-DM1 treatment. A landmark approach set at 4 months was used to evaluate the association between early adverse events requiring T-DM1 dose interruptions or reductions and OS/PFS. Cox proportional hazard analysis modeled the association between events requiring T-DM1 dose interruptions or reductions and OS/PFS. Associations were reported as hazard ratios with 95% confidence intervals., Results: Adverse events requiring T-DM1 dose interruptions or reductions within the first 4 months of treatment were not significantly associated with OS (hazard ratio (HR) [95% CI]: dose interrupted = 1.15 [0.85-1.55]; dose reduced = 0.75 [0.49-1.14]; P = 0.214) nor PFS (hazard ratio (HR) [95% CI]: dose interrupted = 1.13 [0.87-1.48]; dose reduced = 0.90 [0.62-1.31]; P = 0.534)., Conclusion: The occurrence of early adverse events requiring T-DM1 dose interruptions or reductions do not appear to be associated with altered long-term OS or PFS within a pooled analysis of data from EMILIA and TH3RESA.

Introduction: There is substantial variability in survival and response outcomes for patients using immune checkpoint inhibitors (ICIs), and predictive markers are required to guide treatment decisions. A lung immune prognostic index (LIPI) was recently developed to predict ICI treatment outcomes and we aim to evaluate whether LIPI is predictive of survival and response for patients treated with atezolizumab for advanced NSCLC., Methods: Pooled analysis was performed of patient-level data of four clinical trials of atezolizumab for NSCLC. Based on pre-treatment derived neutrophil-to-lymphocyte ratio greater than 3 and lactate dehydrogenase greater than the upper limit of normal, patients were assigned to one of three groups: good LIPI, 0 risk factors; intermediate LIPI, 1 risk factor; or poor LIPI, 2 risk factors. The primary outcome was overall survival (OS)., Results: In a pooled cohort of 1,489 patients treated with atezolizumab, the LIPI group was significantly associated with OS (p < 0.001), progression-free survival (p < 0.001), and response (p < 0.001). Median OS for good (n = 678), intermediate (n = 631), and poor (n = 180) LIPI groups was 18.4 months, 11.3 months, and 4.5 months, respectively. Association between LIPI and OS was consistently identified across a range of atezolizumab-treated subgroups. For docetaxel-treated patients (n = 687), LIPI was similarly associated with survival (p < 0.001) and response (p = 0.005)., Conclusions: Pre-treatment LIPI is a convenient prognostic marker able to identify atezolizumab-treated patient groups with significantly different survival and response outcomes. However, LIPI is also a prognostic marker of survival and response for patients treated with chemotherapy; thus, it is not specifically predictive for ICI treatment., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objectives: Common therapies for HER2-positive advanced breast cancer (ABC) are associated with heterogeneity in prognosis and treatment benefit. Prognostic models of survival outcomes with ado-trastuzumab-emtansine (T-DM1) have not been evaluated., Material and Methods: A pre-treatment prognostic model for overall survival (OS) and progression-free survival (PFS) based on clinicopathological factors was developed for HER2-positive ABC patients initiating second-line and later T-DM1 using data from the randomised clinical trials EMILIA and TH3RESA (n = 893). Pre-treatment prognostic groups were identified via recursive partitioning analysis., Results: The most significant OS/PFS pre-treatment risk predictors were metastatic sites count (≤2 versus > 2) and ECOG performance-status (0 versus ≥ 1) (P < 0.05). Based on these two factors, patients can be characterised as one of three prognostic groups (good = 0 factors; intermediate = 1 factor; poor = 2 factors). The prognostic groups were identified as significantly associated with OS (P < 0.001) and PFS (P < 0.001). Median OS for the good, intermediate and poor prognostic groups were 40 (95%CI: 36-48), 25 (23-30) and 16 (14-19) months, respectively, and median PFS was 12 (10-15), 8 (7-9) and 6 (4-7) months., Conclusion: Pre-treatment prognostic groups with significant differences in OS and PFS for HER2-positive ABC patients initiating second-line and later T-DM1 were identified. For HER2-positive ABC patients considering initiating second-line and later T-DM1, the prognostic groups enable more personalized expectations of disease control, survival and absolute treatment benefit., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Leflunomide is the most recently introduced conventional disease-modifying anti-rheumatic drugs in Australia. It has several unique methods for initiation, unique monitoring recommendations and a distinctive cessation protocol in the event of serious toxicity. The aim of this study was to evaluate initiation and monitoring practices of Australian rheumatologists using leflunomide. A survey was emailed twice, approximately 3 months apart to 332 rheumatologist members of the Australian Rheumatology Association. Wave analysis was used to assess evidence of non-response bias. The response rate to the survey was 20% and there was no difference between the responses of waves 1 and 2. Fifty percent of the respondents indicated that 20 mg once daily was the initial dose of leflunomide that they most commonly prescribed, 45% indicated 10 mg once daily, whilst only 3% preferred to initiate leflunomide at 100 mg daily for 2-3 days followed by 10 mg once a day as recommended when first marketed. Of the responders, 12% had used doses above 20 mg daily and 70% had used alternate daily dosing with leflunomide. In a patient taking leflunomide with an ALT or AST >3 times the ULN on two or more blood tests, 75% of responders indicated they would stop leflunomide immediately and 20% would follow cessation by administering a cholestyramine washout. The choice of initial leflunomide dose among responding Australian rheumatologists varied considerably, although most preferred not to use the loading dose. Despite the recommendation of clinical guidelines, the use of a cholestyramine washout procedure for hepatic toxicity is not universal.

Leflunomide's active metabolite teriflunomide inhibits dihydro-oroate dehydrogenase, an enzyme essential to proliferation of T lymphocytes. As teriflunomide must reach the target site to have this effect, this study assessed the distribution of teriflunomide into T lymphocytes, as intracellular concentrations may be a superior response biomarker to plasma concentrations. CD3 MicroBeads (Miltenyi Biotec, Bergisch Gladbach, Germany) were used to extract CD3 + T cells from the peripheral blood of patients with rheumatoid arthritis who were taking a stable dose of leflunomide. Unbound plasma and intra-CD3 + T cell teriflunomide concentrations were quantified using liquid chromatography-mass spectrometry. Concentration (log transformed) and partition differences were assessed through paired Student t tests. Sixteen patients provided plasma steady-state teriflunomide samples, and eight provided a sample 6-12 weeks later. At time-point one, the geometric mean teriflunomide concentration (range) in CD3 + T cells was 18.12 μg/L (6.15-42.26 μg/L) compared with 69.75 μg/L (32.89-263.1 μg/L) unbound in plasma (P < 0.001). The mean partition coefficient (range) for unbound plasma teriflunomide into CD3 + T cells was 0.295 (0.092-0.632), which was significantly different from unity (P < 0.001). The median (range) change in teriflunomide concentration between the two time points was 14% (-10% to 40%) in unbound plasma and -29% (-69 to 138%) for CD3 + T cells. Because teriflunomide concentrations in CD3 + T cells were lower and displayed a higher intraindividual variability than the unbound plasma concentrations, its applicability as a therapeutic drug-monitoring marker may be limited., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

Aim: Leflunomide, via its active metabolite teriflunomide, is used in rheumatoid arthritis (RA) treatment, yet approximately 20 to 40% of patients cease due to toxicity. The aim was to develop a time-to-event model describing leflunomide cessation due to toxicity within a clinical cohort and to investigate potential predictors of cessation such as total and free teriflunomide exposure and pharmacogenetic influences., Methods: This study included individuals enrolled in the Early Arthritis inception cohort at the Royal Adelaide Hospital between 2000 and 2013 who received leflunomide. A time-to-event model in nonmem was used to describe the time until leflunomide cessation and the influence of teriflunomide exposure and pharmacogenetic variants. Random censoring of individuals was simultaneously described. The clinical relevance of significant covariates was visualized via simulation., Results: Data from 105 patients were analyzed, with 34 ceasing due to toxicity. The baseline dropout hazard and baseline random censoring hazard were best described by step functions changing over discrete time intervals. No statistically significant associations with teriflunomide exposure metrics were identified. Of the screened covariates, carriers of the C allele of CYP1A2 rs762551 had a 2.29 fold increase in cessation hazard compared with non-carriers (95% CI 2.24, 2.34, P = 0.016)., Conclusions: A time-to-event model described the time between leflunomide initiation and cessation due to side effects. The C allele of CYP1A2 rs762551 was linked to increased leflunomide toxicity, while no association with teriflunomide exposure was identified. Future research should continue to investigate exposure-toxicity relationships, as well as potentially toxic metabolites., (© 2015 The British Pharmacological Society.)