Therapeutic drug monitoring guided dosing versus standard dosing of alectinib in advanced ALK positive non-small cell lung cancer patients: Study protocol for an international, multicenter phase IV randomized controlled trial (ADAPT ALEC)

Abstract

BackgroundAlectinib is first-line therapy in patients with stage IV non-small cell lung carcinoma (NSCLC) and an anaplastic lymphoma kinase (ALK) fusion. A shorter median progression-free survival (mPFS) was observed when alectinib minimum plasma concentrations during steady state (Cmin,SS) were below 435 ng/mL. This may suggest that patients should have an alectinib Cmin,SS ≥ 435 ng/mL for a more favorable outcome. This potential target could be attained by using therapeutic drug monitoring (TDM), i.e. adjusting the dose based on measured plasma trough concentrations. Hypothetically, this will increase mPFS, but this has not yet been evaluated in a randomized controlled trial (RCT). Therefore, the ADAPT ALEC trial is designed, with the primary objective to prolong mPFS in NSCLC patients treated with alectinib by using TDM.MethodsADAPT ALEC is a multicenter, phase IV RCT, in which patients aged ≥ 18 years with advanced ALK positive (+) NSCLC eligible for alectinib in daily care are enrolled. Participants will be randomized (1:1 ratio) into intervention arm A (TDM) or B (control), stratified by brain metastases and prior ALK treatments. Starting dose in both arms is the approved flat fixed dose of alectinib 600 mg taken twice daily with food. In case of alectinib Cmin,SS < 435 ng/mL, arm A will receive increased doses of alectinib till Cmin,SS ≥ 435 ng/mL when considered tolerable. The primary outcome is mPFS, where progressive disease is defined according to RECIST v1.1 or all-cause death and assessed by CT-scans and MRI brain. Secondary endpoints are feasibility and tolerability of TDM, patient and physician adherence, overall response rate, median overall survival, intracranial PFS, quality of life, toxicity, alectinib-M4 concentrations and cost-effectiveness of TDM. Exploratory endpoints are circulating tumor DNA and body composition.DiscussionThe ADAPT ALEC will show whether treatment outcomes of patients with advanced ALK+ NSCLC improve when using TDM-guided dosing of alectinib instead of fixed dosing. The results will provide high quality evidence for deciding whether TDM should be implemented as standard of care and this will have important consequences for the prescribing of alectinib.Clinical trial registrationClinicalTrials.gov, identifier NCT05525338.

Analysis of Serious Weight Gain in Patients Using Alectinib for ALK-Positive Lung Cancer

“…Recently, a large, multicenter, prospective trial (NCT05525338) has started in which weight and laboratory parameters including appetite and satiety hormones are collected. 67 In conclusion, our study supports the observation that alectinib induces weight gain, and the effects seem to be much greater than anticipated. Alectinib-induced weight gain might be underreported in previous trials and underestimated by caregivers.…”

Peristromal niches protect lung cancers from targeted therapies through a combined effect of multiple molecular mediators

“…The mechanistic complexity of EMDR adds to the challenges posed by the diversity of resistance mechanisms, intratumor heterogeneity 44 and the multifactorial nature of cell-intrinsic therapy resistance identified in recent studies 12, 14, 41 . While the development of new therapies relies on reductionistic molecular oncology studies, the ability of tumor cells to resist therapeutic elimination and the acquired therapy resistance represents a complex dynamical phenomenon, integrating the impact of multiple cell-intrinsic mechanisms, tumor heterogeneity and systemic factors (such as inflammation 45 and variability in drug concentrations due to pharmacokinetics modifiers 46 ). Consequently, the current paradigm of identifying and targeting a single mechanism at a time is unlikely to bring major clinical breakthroughs.…”