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Osimertinib is a potent, third-generation, irreversible, central nervous system active epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that selectively inhibits EGFR-TKI sensitizing and EGFR T790M resistance mutations. It is approved for first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, and for patients with T790M-positive advanced NSCLC whose disease has progressed on or after EGFR-TKI therapy. This study investigated the pharmacokinetics (PK) of fexofenadine (P-glycoprotein substrate) following single- and multiple-dose osimertinib in patients with advanced NSCLC who have progressed on prior EGFR-TKI therapy. This open-label, phase 1 study (NCT02908750) comprised the PK phase and continued access phase. The former comprised 2 distinct periods with a 3- to 7-day washout: treatment period 1 (n = 24, fexofenadine 120 mg, day 1) and treatment period 2 (fexofenadine 120 mg + osimertinib 80 mg single dose on days 1 and 39 and osimertinib 80 mg once daily from days 4 to 41). Patients could continue osimertinib 80 mg once daily based on investigator's discretion in the continued access phase. Fexofenadine area under the plasma concentration-time curve and maximum concentration increased by 56% (90% confidence interval [CI], 35.4-78.6) and 76% (90%CI, 49.3-108.3) following coadministration with osimertinib single dose, and by 27% (90%CI, 11.2-45.8) and 25% (90%CI, 5.6-48.1) when given with osimertinib at steady state, respectively. Following osimertinib coadministration, median fexofenadine time to maximum concentration increased by approximately 30 minutes compared with time to maximum concentration following fexofenadine alone. No new osimertinib safety findings were observed. The increase in fexofenadine exposure following osimertinib coadministration shows osimertinib as a weak P-glycoprotein inhibitor., (© 2019, The American College of Clinical Pharmacology.)

Purpose: To determine the recommended dose and antitumor activity of single-agent elisidepsin as a 24-h intravenous (i.v.) infusion fortnightly [biweekly, d1 and 15 every 4 weeks (q4wk); Arm A, dose-intensity strategy] or as a 3-h i.v. infusion weekly (d1, 8, 15 and 22 q4wk; Arm B, dose-density strategy) in adult patients with unresectable, locally advanced or metastatic pretreated esophageal, gastroesophageal junction and gastric cancer., Methods: Patients were randomized to one of two elisidepsin dosing schedules. Phase Ib starting doses were 8.0 mg flat dose (FD) in Arm A and 3.0 mg FD in Arm B. Phase II subsequently explored antitumor activity of both dosing schedules at the respective recommended doses., Results: Forty-four patients received elisidepsin: 12 in stage Ib and 32 in stage II. The recommended doses were defined as 10 mg FD (Arm A) and 3.75 mg FD (Arm B). Both schedules were well tolerated. Most adverse events were mild or moderate, reversible and predictable with no meaningful differences between schedules. The pharmacokinetic profiles of both schedules were similar to those reported previously in patients with solid tumors treated with a comparable dose. An interim analysis found tumor control in one patient receiving elisidepsin fortnightly, and in none given elisidepsin weekly; patient accrual was therefore discontinued due to lack of efficacy., Conclusions: Both schedules at the recommended doses presented an acceptable safety profile, but lack of response means that we do not recommend further evaluation of single-agent elisidepsin as chemotherapy for unresectable, locally advanced or metastatic gastroesophageal cancer.

Background: Epidermal growth factor receptor (EGFR) inhibitors are in clinical development in cancer treatment. Preclinical studies have shown potential antitumor efficacy of these agents in combination with chemotherapy or with radiotherapy. However, controversial results have been obtained in different clinical trials., Materials and Methods: The effects on proliferation, cell cycle distribution and induction of apoptosis of three different anti-EGFR agents (gefitinib, ZD6474, cetuximab) were evaluated in different sequences of combination with either a platinum derivative (cisplatin, carboplatin, oxaliplatin) or a taxane (docetaxel, paclitaxel) in KYSE30 cells, a model of a human cancer cell line with a functional EGFR autocrine pathway., Results: The combination of a cytotoxic drug with an EGFR inhibitor caused different antiproliferative effects on KYSE30 cancer cells depending on the treatment schedule. An antagonistic effect was observed when treatment with each EGFR inhibitor was done before chemotherapy. In contrast, a synergistic antiproliferative activity was obtained when chemotherapy was followed by treatment with EGFR antagonists. This effect was accompanied by potentiation of apoptosis and arrest of the surviving cancer cells in the G(2)/M phases of the cell cycle., Conclusions: This study provides a rationale for the evaluation of a potentially synergistic sequence of cytotoxic drugs and EGFR inhibitors in a clinical setting.