DISCUSSION
NSCLC, asthenia, death, nausea, tumor, neutropenia, diarrhea, stomatitis, ILD, NSCLC tumor, TEAEs, vomiting, rash, mild/moderate anorexia
ADVERSE REACTIONS, SKIN, TUMOR, NEUTROPENIA, INTERSTITIAL LUNG DISEASE, STOMATITIS, DISEASE, ADVERSE REACTION, NSCLC, EVENTS
The primary objective of this first‐in‐human study was to assess the safety and tolerability of DS‐1205c in combination with gefitinib in metastatic or unresectable EGFR‐mutant NSCLC subjects and to determine the recommended dose of DS‐1205c in combination therapy for expansion study. Of the EGFR TKIs, gefitinib was selected because it is known to be generally well tolerated and safety data in Japanese patients have been collected sufficiently.Of the 20 patients in the Safety Analysis Set, most of them (85%) had at least one TEAE. Increases in transaminases (AST and ALT) were the most commonly reported TEAEs, found in about one‐third of the patients. The frequency of these events tended to increase with increasing doses of DS‐1205c, but no hepatic events (a TEAE of special interest) were observed. No serious TEAEs or TEAEs associated with death were observed in the study.DS‐1205c in combination with gefitinib was well tolerated, although doses of ≤800 mg BID had a more favorable safety profile compared with the dose of 1200 mg BID. Two patients demonstrated DLT: Grade 3 neutropenia in one patient in Cohort 3 (800 mg BID) and Grade 3 nausea in another in Cohort 5 (1200 mg BID). In addition, one patient in Cohort 5 experienced a TEAE associated with dose interruption, and a second patient in Cohort 5 experienced a TEAE (Grade 2 rash) associated with study discontinuation. Skin reactions, commonly a pustular rash, are very common adverse reactions to gefitinib, but are mainly mild/moderate in severity. Other common adverse reactions include mild/moderate anorexia, diarrhea, vomiting, elevated ALT, nausea, stomatitis and asthenia, which are generally mild in severity. Interstitial lung disease (ILD) is the most serious, relatively common (prevalence of approximately 1%) adverse reaction for gefitinib.In PK analysis, plasma No specific pattern was observed in the PK analysis of gefitinib on Day 1 in Cycle 1 or Day 1 in Cycle 2. The PK of gefitinib has been studied in patients with solid tumorsFive out of 20 patients had stable disease and no patient achieved a complete or partial response. The outcome of stable disease is consistent with preclinical studies showing that DS‐1205c restored the antitumor activity of erlotinib in an erlotinib acquired‐resistance EGFR‐mutant NSCLC tumor xenograft mouse model.The study has some limitations which reflect the Phase I study design. The sample size was relatively small (20 patients) and, although the study was conducted at 8 sites in Japan, the findings may not be generalizable to the wider population of patients with NSCLC.In conclusion, DS‐1205c in combination with gefitinib was well tolerated at all dose levels (200–1200 mg BID). However, doses of ≤800 mg BID had a more favorable safety profile compared with 1200 mg BID. Based on the available safety, PK, and exploratory tumor response data, the recommended dose of DS‐1205c in combination with gefitinib was chosen at 800 mg BID. Further studies are needed to confirm the safety profile and evaluate the efficacy of this dose, and potentially to identify predictive biomarkers for responsive patients.