Assessment, Analysis, and Discussion
NSCLC, cancers, toxicity, hypoxia, cancer, toxicities, rash, nonsquamous NSCLC, reductions of binimetinib in 2 patients
CANCERS, HYPOXIA, CANCER, SOLID TUMORS, METASTATIC DISEASE, MUTANT, ADVERSE EVENT, NSCLC
The addition of HCQ to the MEK inhibitor binimetinib did not demonstrate enough activity to justify expansion in a 2-stage phase II trial in patients with Despite being the most mutated gene in nonsquamous NSCLC, Autophagy is a cellular defense mechanism that has evolved to protect cells from adverse environmental conditions, including nutritional deprivation, hypoxia, or therapeutic stress. Activation of autophagy mediates regulated catabolism of cellular organelles, which are encapsulated first in autophagosomes and metabolized when these fuse to lysosomes. Autophagy has been demonstrated to be a resistance mechanism to chemotherapy in several solid tumors. Inhibition of autophagy can be accomplished pharmacologically with HCQ, which inhibits the fusion of the autophagosome to the lysosome. Several clinical trials have demonstrated the safety of this approach in patients with advanced solid tumors. Pharmacokinetic-pharmacodynamic studies have demonstrated that doses of HCQ 400 mg twice daily or higher effectively blocks autophagy when given alone or in combination with other cancer therapies. In addition, in preclinical models, combination of a MEK inhibitor with HCQ has been shown to be synthetically lethal to RAS mutant cancers. The safety and clinical antitumor activity of combining dabrafenib, trametinib (MEK inhibitor), and HCQ has been demonstrated in patients with Nine patients were enrolled onto stage I of this clinical trial. Most patients (77.7%) had received >3 regimens for metastatic disease. Even though all patients had a favorable ECOG PS (0-1) at study entry, most patients had exposure to several lines of previous cytotoxic therapies. Patients on this trial had a variety of molecular alterations, including The combination of HCQ and binimetinib was poorly tolerated. Overall, 5 of 9 patients (55.6%) developed a grade 3 adverse event (AE), with rash being the most common grade 3 toxicity. These toxicities required dose reductions of binimetinib in 2 patients. Most patients (Our study has some limitations. First, it was a single-arm study with no randomized control design, and hence, selection bias could not be ruled out. Second, we enrolled a heterogenous patient population with different Finally, the dose and schedule were predetermined based on other phase I/II trials, but this might not be the best-suited dose as the next step in patients with NSCLC. Novel autophagy inhibitors such as DCC-3116 (NCT04892017) could be potentially more effective than HCQ, in combination with MEK inhibition in 