A randomized, double-blind, phase III study comparing two doses of erlotinib for second-line treatment of current smokers with advanced non-small-cell lung cancer (CurrentS)

Smit, Egbert F.; Wu, Yi‐Long; Gervais, Radj; Zhou, Caicun; Felip, Enriqueta; Feng, Jifeng; Güçlü, Salih Zeki; Hoiczyk, Mathias; Dorokhova, Elena; Freudensprung, Ulrich; Grange, Susan; Pérez-Moreno, Pablo; Mitchell, Lada; Reck, Martin

doi:10.1016/j.lungcan.2016.06.019

Cited by 11 publications

(6 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Plasma levels of erlotinib and its metabolite OSI-420 quantified by LC-MS/MS were within the range reported by other studies ( 6 , 12 ). While the erlotinib concentrations were found higher in the E300 treated patients in a previous phase III randomized NSCLC study ( 12 ), erlotinib concentrations measured in plasma by LC-MS/MS in this study were impressively similar between the E300 smoker group (average erlotinib concentration of 2500.8 ng/mL) and the E150 non-smoker group (average erlotinib concentration of 2503.8 ng/mL). This finding, in concordance with similar tumor response rates as measured by CT imaging, supports the concept of dosing erlotinib according to smoking status in the management of patients with HNSCC.…”

Section: Discussionsupporting

confidence: 86%

“…A study that administered erlotinib to healthy volunteers found that the geometric mean of the area under the curve (0-infinity) for the 150 mg dose was 2.8-fold lower among smokers than in non-smokers and similar to non-smokers who received the 300 mg dose ( 11 ). A follow-up phase III study of current smokers with NSCLC confirmed that higher dosing of erlotinib (300 mg daily, elected based on prior pharmacokinetic data ( 11 )) achieved higher plasma concentrations than standard dosing (150 mg daily) but did not yield a significant difference in clinical outcomes ( 12 ). In addition to increased drug clearance, there may also be a direct effect of nicotine contributing to erlotinib resistance ( 13 ).…”

Section: Introductionmentioning

confidence: 94%

See 1 more Smart Citation

Early [18]FDG PET/CT scan predicts tumor response in head and neck squamous cell cancer patients treated with erlotinib adjusted per smoking status

et al. 2022

View full text Add to dashboard Cite

Translational RelevanceEvaluation of targeted therapies is urgently needed for the majority of patients with metastatic/recurrent head and neck squamous cell carcinoma (HNSCC) who progress after immunochemotherapy. Erlotinib, a targeted inhibitor of epidermal growth factor receptor pathway, lacks FDA approval in HNSCC due to inadequate tumor response. This study identifies two potential avenues to improve tumor response to erlotinib among patients with HNSCC. For the first time, this study shows that an increased erlotinib dose of 300 mg in smokers is well-tolerated and produces similar plasma drug concentration as the regular dose of 150 mg in non-smokers, with increased study-specific defined tumor response. The study also highlights the opportunity for improved patient selection for erlotinib treatment by demonstrating that early in-treatment [18]FDG PET/CT is a potential predictor of tumor response, with robust statistical correlations between metabolic changes on early in-treatment PET (4-7 days through treatment) and anatomic response measured by end-of-treatment CT.PurposePatients with advanced HNSCC failing immunochemotherapy have no standard treatment options. Accelerating the investigation of targeted drug therapies is imperative. Treatment with erlotinib produced low response rates in HNSCC. This study investigates the possibility of improved treatment response through patient smoking status-based erlotinib dose optimization, and through early in-treatment [18]FDG PET evaluation to differentiate responders from non-responders.Experimental designIn this window-of-opportunity study, patients with operable HNSCC received neoadjuvant erlotinib with dose determined by smoking status: 150 mg (E150) for non-smokers and 300 mg (E300) for active smokers. Plasma erlotinib levels were measured using mass spectrometry. Patients underwent PET/CT before treatment, between days 4-7 of treatment, and before surgery (post-treatment). Response was measured by diagnostic CT and was defined as decrease in maximum tumor diameter by ≥ 20% (responders), 10-19% (minimum-responders), and < 10% (non-responders).ResultsNineteen patients completed treatment, ten of whom were smokers. There were eleven responders, five minimum-responders, and three non-responders. Tumor response and plasma erlotinib levels were similar between the E150 and E300 patient groups. The percentage change on early PET/CT and post-treatment PET/CT compared to pre-treatment PET/CT were significantly correlated with the radiologic response on post-treatment CTs: R=0.63, p=0.0041 and R=0.71, p=0.00094, respectively.ConclusionThis pilot study suggests that early in-treatment PET/CT can predict response to erlotinib, and treatment with erlotinib dose adjusted according to smoking status is well-tolerated and may improve treatment response in HNSCC. These findings could help optimize erlotinib treatment in HNSCC and should be further investigated.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT00601913, identifier NCT00601913.

show abstract

Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 94%

Early [18]FDG PET/CT scan predicts tumor response in head and neck squamous cell cancer patients treated with erlotinib adjusted per smoking status

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Moreover, Roberts and his colleagues also discussed coping strategies in advanced cancer, focusing on either a ‘problem-focused’ or ‘emotion-focused’ therapy 14. In contrast, much has been written about the novel cancer therapeutics themselves 15–17. During the last couple of years, new mutations have been recovered in patients with lung cancer (EGFR), breast cancer (BRCA1, BRCA2 and HER2) and several other cancers, resulting in the development of new genotype-directed therapy throughout the patient’s disease course.…”

Section: Introductionmentioning

confidence: 99%

Complex challenges for patients with protracted incurable cancer: an ethnographic study in a comprehensive cancer centre in the Netherlands

et al. 2019

View full text Add to dashboard Cite

ObjectiveAdvances in oncology increasingly result in protracted disease trajectories for patients with incurable cancer. In this disease phase, patients are aware of the incurable nature of cancer although they are not yet approaching the last phase of life. We explored the challenges for patients confronted with protracted incurable cancer.DesignEthnographic study (2015–2017) based on conversations with patients, observations at a day-care unit and a selection of information from the medical records of patients who died during the study period.SettingThe day-care unit of a comprehensive cancer centre in the Netherlands.ParticipantsNineteen patients with stage IV breast cancer (in remission, >1 year after diagnosis) and 11 patients with stage IV lung-cancer (in remission, >6 months after diagnosis).ResultsIn patients who had died during the study period, the treatment response often fluctuated between stable, remission and progression throughout the course of the disease. Patients reported that this fluctuation could be overwhelming. However, as patients grew accustomed to having protracted incurable cancer, the distress associated with fluctuations (perceived in scan results) slowly faded. Patients reported that cancer became part of who they were. At the day-care unit, most patients talked about their disease in an optimistic or neutral way and expressed delight in life. They often expressed gratefulness for the possible prolongation of life, expressed hope and tried to stay optimistic. This was frequently reinforced by optimistic doctors and nurses. Relatives, however, could downplay such optimism. Moreover, some patients acknowledged that hope was qualified by their personal challenges regarding their disease.ConclusionsIn situations where tumours remained in remission or were stable for extended periods, patients grew accustomed to having cancer. At the day-care unit, medical professionals typically encouraged an attitude of being hopeful and optimistic, which could be downplayed by relatives. More research is warranted to explore this protracted disease phase and this optimistic view among healthcare professionals.

show abstract

“…The authors found 2⋅2-fold higher mean plasma concentrations in the 300 mg QD compared to the 150 mg QD group. However, no progression free survival (PFS) improvement was observed in the higher dosed patients [12]. Mita et al investigated dose escalation in patients who initially received 150 mg QD, increasing the dose up to a level of tolerable skin toxicity.…”

Section: Non-small Cell Lung Cancer (Nsclc)mentioning

confidence: 99%

High-dose administration of tyrosine kinase inhibitors to improve clinical benefit: A systematic review

Gerritse¹,

Janssen²,

Labots

et al. 2021

Cancer Treatment Reviews

View full text Add to dashboard Cite

Background: Innovative strategies to fully exploit the antitumor activity of multitargeted tyrosine kinase inhibitors (TKIs) are urgently needed. Higher concentrations of TKIs at their target site, i.e. intratumorally, may lead to broader kinase inhibition, which might be essential for the optimal suppression of tumor growth and induction of apoptosis. To reach these higher intratumoral concentrations, without encountering dose limiting toxicity, alternative TKI dosing strategies employing higher daily and high intermittent doses have been studied. In this systematic review, we evaluated the current clinical evidence to support (intermittent) high TKI dosing regimens. Methods: A systematic review was conducted in the following databases: PubMed®, EMBASE® and Cochrane Library©, to evaluate efficacy of alternatively scheduled high-dosed regimen (a higher dose in a regular daily schedule than registered or a higher dose in an alternative intermittent schedule) of TKIs in (haemato-)oncology. Data were extracted independently by two authors according to predefined criteria. Extracted data were tabulated to summarize key findings. Results: Out of twenty studies that met the inclusion criteria, thirteen investigated higher daily dose schedules of either afatinib, axitinib, erlotinib, gefitinib, imatinib, sorafenib, and sunitinib. Five of these studies included pharmacokinetic analyses, reporting marginal higher maximum drug concentrations (C max ) in plasma (1.3-4fold higher) compared to the standard dose schedules. Seven clinical trials investigated intermittent high-dose schedules requiring treatment breaks, with the following TKIs: afatinib, erlotinib, gefitinib, lapatinib, sorafenib, and sunitinib. Six of these included pharmacokinetic results, all reporting higher (2-21-fold) C max in plasma compared to the standard daily dose schedule, with manageable toxicity. No data on tumor concentrations were presented. Data on the efficacy outcomes were limited due to small sample size, study designs, phase 1 population and heterogeneous tumor types. Conclusions: Early phase clinical studies show that high-dose intermittent TKI-treatment schedules can lead to an increased C max compared to standard (low-dose) daily administration with manageable toxicity. These higher concentrations are assumed to reflect higher intratumoral concentrations. Further investigation of the potential improvement in clinical benefit of a high-dose intermittent strategy with multitargeting TKIs is warranted.

show abstract

A randomized, double-blind, phase III study comparing two doses of erlotinib for second-line treatment of current smokers with advanced non-small-cell lung cancer (CurrentS)

Cited by 11 publications

References 12 publications

Early [18]FDG PET/CT scan predicts tumor response in head and neck squamous cell cancer patients treated with erlotinib adjusted per smoking status

Early [18]FDG PET/CT scan predicts tumor response in head and neck squamous cell cancer patients treated with erlotinib adjusted per smoking status

Complex challenges for patients with protracted incurable cancer: an ethnographic study in a comprehensive cancer centre in the Netherlands

High-dose administration of tyrosine kinase inhibitors to improve clinical benefit: A systematic review

Contact Info

Product

Resources

About