Discussion
tumor, DLTs, pneumonia, hematuria, tumors, TRAEs
TUMOR, PNEUMONIA, DISEASE, HEMATURIA, TUMOR GROWTH, TUMORS
This open-label, phase 1 study provided novel findings regarding the safety and tumor response of DS-1205c, a kinase inhibitor that selectively targets AXL, in combination with osimertinib in 13 patients with metastatic or unresectable Overall, a small number of TRAEs were reported and assessment of the relationship between DS-1205c dosage and any TRAE was not possible. Although at least one TEAE or TRAE occurred in 100% and 61.5% of patients, respectively, no TRAEs were serious, and grade ≥ 3 TRAEs were limited to one case of non-serious grade 3 hematuria in a patient receiving 200 mg bid, and one case of a non-serious grade 4 increase in lipase in a patient receiving DS-1205c 800 mg bid (the only clinically significant change from in a laboratory value). No patients had a TRAE that required treatment discontinuation, and only 1 patient had a TRAE requiring study treatment interruption. A patient receiving DS-1205c (200 mg bid) developed a DLTs (grade 3 pneumonia and increased ALT) and no DLTs occurred at higher dosages. No treatment-related safety signals associated with vital signs, physical examination findings, electrocardiogram, or ECOG-PS were observed. Moreover, no clinically significant findings on cardiac function were shown during the initial 7-day DS-1250c monotherapy run-in period. The safety profile of DS-1205c in combination with osimertinib was consistent with that of DS-1205c in combination with gefitinib reported previously [Stable disease was the best overall response with DS-1205c and was achieved by the majority (69.2%) of patients. As no patients achieved a CR or PR, the DCR was also 69.2%. The response did not appear to be related to the dosage of DS-1205c, as stable disease was achieved by ≥ 1 patient in each dosage cohort. Stable disease beyond 100 days was experienced by 3 patients, and beyond 200 days by 2 patients (1 each receiving twice-daily DS-1205c 200 and 400 mg). In the 9 patients that achieved SD, most (n = 6; 66.7%) had received osimertinib as their most recent TKI before the start of the study, 2 patients (both of whom had osimertinib as their most recent TKI) appeared to have tumor shrinkage, and PFS ranged from 6.9 weeks to longer than 36 weeks.The PK analysis demonstrated that exposure to DS-1205a tended to increase in a less than dose-proportional manner, the PK profile of DS-1205c did not appear to be affected by the coadministration of osimertinib, and the pharmacokinetics of osimertinib and its metabolites AZ5104 and AZ7550 were not affected by DS-1205c (see The results of our study are limited by its small sample size, which hindered our ability to determine if there was a correlation between exploratory outcomes and clinical efficacy. The heterogeneity in the mutation status of patients, as well as in the prior use of different EGFR TKIs may have influenced the results obtained with DS-1205c plus osimertinib. During preclinical research with DS-1205b (the sulfate trihydrate of DS-1205a [the free form of DS-1205c]), high expression of AXL was observed in tumors that were resistant to long-term administration of osimertinib, while the combination of DS-1205b and osimertinib strongly suppressed tumor growth [