Evaluation of safety and efficacy of minocycline combined with tyrosine kinase inhibitors in patients of EGFR mutated metastatic lung cancer

Abstract

Background: Tyrosine Kinase Inhibitors (TKI) are used in the first line management of metastatic Non‐Small cell lung cancer in the presence of EGFR activating drivermutations. Skin rash is one of the most common side effects associated with the use of TKIs andMinocycline is recommended for prophylaxis and treatment of TKI induced skin rash. An exploratory analysis of a Phase III study evaluating the role of Minocycline with regard to skin rash showed a trend toward improved survival in such patients. This finding can be backed by appropriate biologic rationale as Minocycline has been shown to inhibit PARP‐1 in in‐vitro studies and EGFRmutated lung cancers are deficient in BRCA1 leading to a synthetic lethality in tumor cells exposed to both these drugs. This study is intended to assess the safety and efficacy of minocycline in patients ofmetastatic Non‐Small Cell Lung cancer treated with a combination of TKIs and Minocycline. Trial design: Objectives Primary To assess and compare Response rates in patients receiving TKIs and minocycline versus those receiving TKI alone To assess the toxicity with addition of minocycline to TKIs Secondary To assess and compare PFS and OS in patients receiving TKIs and minocycline versus those receiving TKIs alone Materials and Methods Type of Study ‐ A phase 2 randomized study Patients ‐ Metastatic NSCLC with EGFR mutations sensitive to Gefitinib Arms ‐ Gefitinib 250mg/day alone Gefitinib 250mg/day+ Minocycline 100mg/day Study site and duration Kidwai Cancer Institute; July 2018 to June 2020 Inclusion Criteria Patients of Metastatic Biopsy Proven NSCLC with an EGFR sensitising mutation to Gefitinib Age 18 ‐ 80 Exclusion Criteria Any other Synchronous / Metachronous cancer or any uncontrolled co‐morbidities Sample size N=50 in each arm Randomization ‐ Simple Random Method, Lottery Method Statistical Analysis ‐ The Mann‐Whitney U test and the χ2 test will be used to determine statistically significant differences between the two groups, Kaplan‐Meier method to assess survival curves, Log‐rank test to evaluate the statistical significance of differences and Cox proportional hazards model for multivariate analysis of the effect of clinicopathological factors on survival.