Abstract 1249P
Background
This dose-finding study of osimertinib aimed to investigate the safety, pharmacokinetics (PK), and recommended dose (RD) for EGFR-mutated non-small cell lung carcinoma (NSCLC) patients with impaired renal function and low body weight.
Methods
NSCLC patients with activated EGFR mutations, regardless of T790M mutation, were allocated into the following four cohorts according to renal function and body weight: cohort A, normal renal function (eGFR ≥ 50 mL/min/1.73 m2) and normal body weight (≥ 45 kg); cohort B, moderate renal dysfunction (eGFR = 30-50 mL/min/1.73 m2); cohort C, low body weight (< 45 kg); and cohort D, severe renal dysfunction (eGFR < 30 mL/min/1.73 m2 or undergoing dialysis). We evaluated the PK and safety in cohort A as the control group. Cohorts B, C, and D consisted of two parts, dose-escalation using a standard 3 + 3 design and expansion. The starting dose of osimertinib in cohorts A, B, and C was 80 mg once daily, while for cohort D, it was 40 mg once daily. For PK analysis, serial blood samples were collected on days 1 and 15, and pre-dose blood samples were collected on days 29 and 56.
Results
Thirty eligible patients with EGFR-mutated NSCLC were enrolled in eight institutions in Japan. In cohort A, one patient discontinued osimertinib therapy on day six due to an exacerbation of chronic obstructive pulmonary disease. Twenty-nine patients were evaluated for PK and safety (N=12 for A, N=8 for B, N=8 for C, and N=1 for D). In the dose-escalation part, no DLT was observed, and the RD was determined to be 80 mg once in cohorts B and C. Due to the poor accrual, only one patient was included in cohort D. Four serious adverse events occurred in this study, and two considered to be related to osimertinib (heart failure grade 3 in cohort B and ILD grade 3 in cohort C). The PK parameters of osimertinib in cohorts A, B, and C were similar. However, the toxicity of any grade occurred more frequently in cohorts B and C than in cohort A.
Conclusions
The RD of osimertinib was determined to be 80 mg once for patients with moderate renal function (cohort B) and low body weight (cohort C). Although the PK parameters of osimertinib were similar across all cohorts, toxicity occurred more frequently in cohorts B and C than in cohort A.
Clinical trial identification
UMIN000033301.
Editorial acknowledgement
Editage for English language editing.
Legal entity responsible for the study
The authors.
Funding
This research was supported by AMED under Grant Number JP20ck0106464h0003.
Disclosure
T. Hase: Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca; Financial Interests, Personal, Other, Honoraria (Lecture fee): Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria (Lecture fee): Chugai Pharmaceutical; Financial Interests, Personal, Other, Honoraria (Lecture fee): Eli Lilly Japan; Financial Interests, Personal, Other, Honoraria (Lecture fee): Kyowa Kirin; Financial Interests, Personal, Other, Honoraria (Lecture fee): Boehringer Ingelheim; Financial Interests, Personal, Other, Honoraria (Lecture fee): Nippon Kayaku; Financial Interests, Personal, Other, Honoraria (Lecture fee): Novartis Pharma; Financial Interests, Personal, Other, Honoraria (Lecture fee): Ono Pharmaceutical; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Principal Investigator: Chugai Pharmaceutical; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Principal Investigator: Novartis Pharma; Financial Interests, Institutional, Research Grant: Taiho Pharmaceutical. Y. Fujiwara: Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Ono Pharmaceutical; Financial Interests, Personal, Advisory Board: Otsuka Pharmaceutical; Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca; Financial Interests, Personal, Other, Honoraria (Lecture fee): Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria (Lecture fee): Novartis. R.A. Makihara: Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca; Financial Interests, Personal, Other, Honoraria (Lecture fee): Novartis; Financial Interests, Personal, Other, Honoraria (Lecture fee): Eli Lilly; Financial Interests, Personal, Other, Honoraria (Lecture fee): Eisai; Financial Interests, Personal, Other, Honoraria (Lecture fee): Taiho Pharmaceutical. N. Hashimoto: Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca; Financial Interests, Personal, Other, Honoraria (Lecture fee): Boehringer Ingelheim; Financial Interests, Personal, Other, Honoraria (Lecture fee): GlaxoSmithKline; Financial Interests, Personal, Other, Honoraria (Lecture fee): Novartis; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim. Y. Tsubata: Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca K.K.; Financial Interests, Personal, Other, Honoraria (Lecture fee): Daiichi Sankyo Co., Ltd.; Financial Interests, Personal, Other, Honoraria (Lecture fee): Chugai Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Funding: Pfizer Health Research Foundation. T. Takahashi: Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca; Financial Interests, Personal, Other, Honoraria (Lecture fee): Chugai Pharmaceutical; Financial Interests, Personal, Other, Honoraria (Lecture fee): Eli Lilly Japan; Financial Interests, Personal, Other, Honoraria (Lecture fee): Ono Pharmaceutical; Financial Interests, Personal, Other, Honoraria (Lecture fee): MSD; Financial Interests, Personal, Other, Honoraria (Lecture fee): Pfizer Japan; Financial Interests, Personal, Other, Honoraria (Lecture fee): Boehringer Ingelheim Japan; Financial Interests, Personal, Other, Honoraria (Lecture fee): Roche Diagnostics; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical; Financial Interests, Institutional, Research Grant: Eli Lilly Japan; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Pfizer Japan; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim Japan; Financial Interests, Institutional, Research Grant: Amgen. H. Kobayashi: Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca; Financial Interests, Personal, Other, Honoraria (Lecture fee): Eli Lilly; Financial Interests, Personal, Other, Honoraria (Lecture fee): Taiho Pharmaceutical. Y. Shinno: Financial Interests, Personal, Other, Honoraria (Lecture fee): Pfizer; Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca. K. Goto: Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca K.K.; Financial Interests, Institutional, Research Grant: AstraZeneca K.K.; Financial Interests, Personal, Advisory Board: AstraZeneca K.K. Y. Hosomi: Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca; Financial Interests, Personal, Other, Honoraria (Lecture fee): Eli Lilly Japan; Financial Interests, Personal, Other, Honoraria (Lecture fee): Taiho Pharmaceutical; Financial Interests, Personal, Other, Honoraria (Lecture fee): Chugai Pharmaceutical; Financial Interests, Personal, Other, Honoraria (Lecture fee): Ono Pharmaceutical; Financial Interests, Personal, Other, Honoraria (Lecture fee): Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria (Lecture fee): Kyowa Kirin. K. Watanabe: Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca; Financial Interests, Personal, Other, Honoraria (Lecture fee): Taiho Pharmaceutical; Financial Interests, Personal, Other, Honoraria (Lecture fee): Chugai Pharmaceutical; Financial Interests, Personal, Other, Honoraria (Lecture fee): Ono Pharmaceutical; Financial Interests, Personal, Other, Honoraria (Lecture fee): MSD; Financial Interests, Personal, Other, Honoraria (Lecture fee): Pfizer; Financial Interests, Personal, Other, Honoraria (Lecture fee): Boehringer Ingelheim. S. Kitazono: Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca; Financial Interests, Personal, Other, Honoraria (Lecture fee): Chugai Pharmaceutical Co., Ltd.; Financial Interests, Personal, Other, Honoraria (Lecture fee): Daiichi Sankyo; Financial Interests, Personal, Other, Honoraria (Lecture fee): Ono Pharmaceutical Co. N. Yamamoto: Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Chugai; Financial Interests, Personal, Other, Honoraria (Lecture fee): Chugai; Financial Interests, Personal, Advisory Board: Cimic; Financial Interests, Personal, Other, Honoraria (Lecture fee): Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Other, Honoraria (Lecture fee): Eli Lilly; Financial Interests, Personal, Other, Honoraria (Lecture fee): Ono; Financial Interests, Personal, Advisory Board: Otsuka; Financial Interests, Personal, Other, Honoraria (Lecture fee): Pfizer; Financial Interests, Personal, Other, Honoraria (Lecture fee): Sysmex; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: AbbVie; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Astellas; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Bayer; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: BMS; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Boehringer Ingelheim; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Chiome Bioscience; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Chugai; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Daiichi Sankyo; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Eisai; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Eli Lilly; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: GSK; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Janssen Pharma; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Kyowa Hakko Kirin; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Merck; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: MSD; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Novartis; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Ono; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Otsuka; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Pfizer; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Sumitomo Dainippon; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Taiho; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Takeda. All other authors have declared no conflicts of interest.