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BACKGROUND Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI-sensitizing and EGFR T790M resistance mutations. Evidence suggests that the addition of chemotherapy may extend the benefits of EGFR-TKI therapy. METHODS In this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with EGFR-mutated (exon 19 deletion or L858R mutation) advanced non-small-cell lung cancer (NSCLC) who had not previously received treatment for advanced disease to receive osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg per square meter of body-surface area] plus either cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or to receive osimertinib monotherapy (80 mg once daily). The primary end point was investigator-assessed progression-free survival. Response and safety were also assessed. RESULTS A total of 557 patients underwent randomization. Investigator-assessed progression-free survival was significantly longer in the osimertinib-chemotherapy group than in the osimertinib group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; PcO.OOl). At 24 months, 57% (95% CI, 50 to 63) of the patients in the osimertinib-chemotherapy group and 41% (95% CI, 35 to 47) of those in the osimertinib group were alive and progression-free. Progression-free survival as assessed according to blinded independent central review was consistent with the primary analysis (hazard ratio, 0.62; 95% CI, 0.48 to 0.80). An objective (complete or partial) response was observed in 83% of the patients in the osimertinib-chemotherapy group and in 76% of those in the osimertinib group; the median response duration was 24.0 months (95% CI, 20.9 to 27.8) and 15.3 months (95% CI, 12.7 to 19.4), respectively. The incidence of grade 3 or higher adverse events from any cause was higher with the combination than with monotherapy -- a finding driven by known chemotherapy-related adverse events. The safety profile of osimertinib plus pemetrexed and a platinum-based agent was consistent with the established profiles of the individual agents. CONCLUSIONS First-line treatment with osimertinib-chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy among patients with EGFR-mutated advanced NSCLC. [ABSTRACT FROM AUTHOR]

Background: The COmparisoN of Faslodex In Recurrent or Metastatic breast cancer (CONFIRM) trial (NCT00099437 ) compared fulvestrant 500 mg with fulvestrant 250 mg in postmenopausal women with locally advanced or metastatic estrogen receptor (ER)-positive breast cancer who had recurred or progressed following prior endocrine therapy. Fulvestrant 500 mg was associated with a statistically significant increase in progression-free survival compared with fulvestrant 250 mg (Di Leo A et al. J Clin Oncol 2010; 28: 4594-4600). At the time of the primary analysis approximately 50% of patients had died. Median overall survival was 25.1 months and 22.8 months for fulvestrant 500 mg and 250 mg, respectively (hazard ratio [HR] 0.84; 95% confidence interval [CI] 0.69, 1.03; p = 0.091). A follow-up analysis of overall survival was subsequently planned for when 75% of patients had died and the results are presented here. Methods: CONFIRM was a randomized, double-blind, parallel-group, multicenter, Phase III study. Patients were randomized 1:1 to either fulvestrant 500 mg (500 mg i.m. on Days 0, 14 and 28 and every 28 days thereafter) or fulvestrant 250 mg (250 mg i.m. every 28 days). After the primary analysis, patients on fulvestrant 250 mg were permitted to switch to 500 mg and all patients were followed up for overall survival, regardless of treatment discontinuation, unless consent was withdrawn. Overall survival was analyzed using an unadjusted log-rank test. No adjustments were made for multiplicity. Serious adverse events (SAEs) were also reported. Results: In total, 736 women (median age 61.0 years) were randomized between February 2005 and August 2007 from 128 centers in 17 countries (fulvestrant 500 mg: n=362; fulvestrant 250 mg: n=374). At time of follow-up analysis, 63 (9.0%) patients were lost to follow-up, 16 (2.2%) patients had withdrawn consent, 103 (14.0%) patients were still ongoing (21 [2.9%] on treatment and 82 [11.1%] not on treatment), and 554 (75.3%) patients had died. Eight (2.1%) patients crossed over from fulvestrant 250 mg to 500 mg. Median overall survival was 26.4 months for fulvestrant 500 mg and 22.3 months for fulvestrant 250 mg (HR 0.81; 95% CI, 0.69, 0.96; nominal p = 0.016). During the treatment period, a total of 32 (8.9%) patients had at least one SAE in the fulvestrant 500 mg and 25 (6.7%) patients in the fulvestrant 250 mg groups, and SAEs that were causally related to study treatment were reported for 6 (1.7%) and 3 (0.8%) patients, respectively. SAEs with an outcome of death were reported for 5 (1.4%) and 6 (1.6%) patients, respectively, during the treatment period. Overall, there were no clinically important differences in the profiles of SAEs between the treatment groups and no clustering of SAEs could be detected in either treatment group. Conclusions: Overall survival data from CONFIRM demonstrate that, in patients with locally advanced or metastatic ER positive breast cancer, fulvestrant 500 mg is associated with a clinically relevant 4.1 month difference in median overall survival and 19% reduction in risk of death compared with fulvestrant 250 mg. There were no new safety concerns associated with the use of fulvestrant 500 mg. [ABSTRACT FROM AUTHOR]

Aims: Osimertinib is a third-generation, irreversible, central nervous system-active, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with efficacy in EGFR-mutated non-small cell lung cancer (NSCLC). We assessed the relationship between plasma osimertinib levels and its efficacy and safety events., Methods: Comprehensive pharmacokinetics exposure-response (E-R) modelling was performed utilizing steady state area under the curve (AUC ss ) data from first-line, ≥second-line and adjuvant studies from the osimertinib clinical development programme (20-240 mg once-daily dosing; N = 1689 patients). Analyses were conducted for survival using a proportional hazard model; for interstitial lung disease (ILD) and left ventricular ejection fraction (LVEF) events using a penalized logistic regression model and graphical analysis of potential confounding factors; and for rash and diarrhoea events using descriptive analysis., Results: E-R modelling analyses indicated no clear trend of increasing efficacy with increasing osimertinib AUC ss ; efficacy in all exposure quartiles was significantly better than the control arm (comparator EGFR-TKI, chemotherapy or placebo) irrespective of treatment line. Model-based analysis suggested a potential relationship between increased osimertinib exposure and increased probability of ILD events, predominantly in Japanese patients. Additionally, there were increased probabilities of rash or diarrhoea with increasing osimertinib exposure. The probability of LVEF events showed overlapping confidence intervals for osimertinib ≤80 mg and control., Conclusions: E-R modelling in patients with EGFR-mutated NSCLC demonstrated that increased osimertinib exposure was unlikely to increase efficacy but may increase occurrence of certain adverse events. Hence, long-term treatment with doses ≥80 mg was not expected to provide additional benefit., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Introduction: Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-sensitizing and -resistance mutations may be detected in plasma via circulating tumor DNA (ctDNA). ctDNA level changes reflect alterations in tumor burden and could be a dynamic indicator of treatment effect. This analysis aimed to determine whether longitudinal EGFR-mutation ctDNA testing could detect progressive disease (PD) before radiologic detection., Methods: This was a retrospective, exploratory ctDNA analysis in two phase 3 trials (FLAURA, NCT02296125; AURA3, NCT02151981). Patients had treatment-naïve (FLAURA) or EGFR-TKI pre-treated (AURA3) advanced non-small cell lung cancer (NSCLC) with EGFR mutations and on-study PD (RECIST), with a baseline ctDNA result and EGFR-mutation ctDNA monitoring beyond Cycle 3 Day 1. Patients received osimertinib versus comparator EGFR-TKIs (FLAURA) or chemotherapy (AURA3). Outcomes included time from ctDNA PD to RECIST PD, and to first subsequent treatment (FST; FLAURA only)., Results: ctDNA PD preceded/co-occurred with RECIST-defined PD in 93/146 (64%) patients in FLAURA and 82/146 (56%) in AURA3. Median time from ctDNA PD to RECIST-defined PD (months) was 3.4 and 2.6 in the osimertinib and comparator EGFR-TKI arms (FLAURA) and 2.8 and 1.5 in the osimertinib and chemotherapy arms (AURA3). In FLAURA, median time from ctDNA PD to FST (months) was 6.0 and 4.7 in the osimertinib (n = 51) and comparator EGFR-TKI arms (n = 70)., Conclusions: Among patients with EGFR mutation-positive advanced NSCLC receiving EGFR-TKI or chemotherapy with ctDNA data and RECIST-defined PD, ctDNA PD preceded/co-occurred with RECIST-defined PD in approximately 60% of cases. Longitudinal ctDNA monitoring may detect PD before radiologic PD., (Copyright © 2024. Published by Elsevier Inc.)