Abstract 997P
Background
Osimertinib is a standard of care for advanced EGFR-mutated non-small cell lung cancer (EGFR+NSCLC), however acquired resistance inevitably develop in 1-2 year. No effective targeted therapy has been established for EGFR+NSCLC after osimertinib. The EGFR C797S (CS) mutation is one of the most common resistant mechanisms to osimertinib. Brigatinib is shown to overcome CS-mediated osimertinib resistance in combination with anti-EGFR antibody in preclinical models.
Methods
We conducted a phase 1 study of brigatinib plus panitumumab in patients with advanced EGFR+NSCLC after osimertinib treatment, with 3+3 dose escalation design. Candidates were screened based on LC-SCRUM-TRY (UMIN000041957). The primary endpoint was the incidence of dose limiting toxicity (DLT) to determine recommended phase 2 dose (PR2D). The planned dose for initial cohort included brigatinib (90 mg, once daily from C1D1) and panitumumab (4.8 mg/kg, on C1D15, then every 2 weeks).
Results
A total of 5 patients were enrolled in this study between Dec 2020 and Jun 2021. Three patients had CS mutation, and two were negative/unknown for CS. Patients had received a median of 4 (range, 1-7) prior lines of treatment; 4 received ≥2 EGFR-TKIs, no patient received prior immune checkpoint inhibitors. Median washout period from last dose of osimertinib was 10 days (range, 1-392). Three patients experienced early onset pneumonitis (grade [Gr] 2, n=1; Gr 3, n=2), all of which occurred during brigatinib monotherapy period (C1D8, C1D1, and C1D3, respectively). Gr 3 pneumonitis was judged as DLT. All cases of pneumonitis improved with brigatinib interruption for Gr 2 case, and systemic corticosteroid treatment for Gr 3 pneumonitis cases. All of patients discontinued study treatment; 3 patients due to disease progression, 2 patients due to DLT (Gr 3 pneumonitis).
Conclusions
In this study, brigatinib treatment was poorly tolerated with high incidence of early onset pneumonitis in patients with EGFR+NSCLC after osimertinib treatment, leading to early study termination. We should further investigate other strategies to overcome osimertinib resistance.
Clinical trial identification
Japan Registry of Clinical Trial: jRCT2031200231.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Japan Agency for Medical Research and Development (AMED).
Disclosure
H. Izumi: Financial Interests, Personal and Institutional, Research Grant, Invited Speaker: AstraZeneca, Ono Pharmaceutical Co.; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Takeda Pharmaceutical Co., Merck Biopharma Co.; Financial Interests, Institutional, Research Grant: Amgen Inc., Eisai. T. Sakamoto: Financial Interests, Personal, Invited Speaker: Eli Lilly. K. Uchibori: Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, Eli Lilly, Bristol-Myers Squibb Japan, Chugai Pharmaceutical, Ono Pharmaceutical, Thermo Fisher, Takeda Pharmaceutical, Daiichi Sankyo. K. Nishino: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai Pharmaceutical Co., Nippon Boehringer Ingelheim, Eli Lilly Japan, Novartis, Pfizer, Takeda Pharmaceutical Company Limited, Merck, Bristol Myers Squibb, Nippon Kayaku; Financial Interests, Personal, Advisory Board: AstraZeneca, Eli Lilly Japan, Pfizer, Janssen Pharmaceutical K.K.; Financial Interests, Institutional, Research Grant: AstraZeneca, Chugai Pharmaceutical Co., Nippon Boehringer Ingelheim, Eli Lilly Japan, Novartis, Pfizer, Takeda Pharmaceutical Company Limited, Merck, Bristol Myers Squibb, Nippon Kayaku, Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., MSD, Abbvie, Daiichi Sankyo Company, Limited, Amgen, Eisai Co., Ltd. S. Nomura: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai, Kyowa Hakko Bio; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca. K. Ryohei: Financial Interests, Personal, Research Grant, Honoraria and invited speaker: Takeda; Financial Interests, Personal, Research Grant: Chugai, Toppan Printing; Financial Interests, Personal, Invited Speaker: Pfizer; Non-Financial Interests, Personal, Royalties: Eiken Chemical. H. Udagawa: Financial Interests, Institutional, Research Grant: Takeda. Y. Shibata: Financial Interests, Personal, Research Grant: MSD; Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co., Pfizer, Chugai, Novartis, Bristol-Myers Squibb, AstraZeneca, Taiho Pharmaceutical Co. S. Niho: Financial Interests, Personal, Invited Speaker: AstraZeneca, Pfizer, Ono, Chugai, Eli Lilly, Takeda. T. Sakai: Financial Interests, Personal, Invited Speaker: Chugai, AstraZeneca. Y. Zenke: Financial Interests, Personal, Invited Speaker: AstraZeneca, Lilly, Chugai, Boehringer Ingelheim, Ono Pharmaceutical, Bristol-Myers Squibb, Takeda Pharmaceutical, Taiho Pharmaceutical, MSD, Novartis, Nippon-Kayaku; Financial Interests, Institutional, Research Grant: AstraZeneca, MSD, Merck, Daiichi Sankyo. K. Nosaki: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai Pharma, Lilly, MSD, Pfizer, Taiho Pharmaceutical, Jansen, Ono, Takeda; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Takeda, AstraZeneca, MSD, AbbVie, Chugai Pharma. S. Matsumoto: Financial Interests, Personal, Invited Speaker: Merck Biopharma, Eli Lilly, AstraZeneca, Chugai, Novartis; Financial Interests, Institutional, Invited Speaker: Merck Biopharma, Janssen Pharmaceutical K.K. K. Yoh: Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Janssen, Lilly, Taiho, Novartis, Kyowa Kirin, Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Lilly, Pfizer, Daiichi Sankyo, AbbVie, Taiho, MSD, Takeda. K. Goto: Financial Interests, Personal, Invited Speaker: Amgen Inc., Amgen K.K., Amoy Diagnosties Co., Ltd., AstraZeneca K.K., Bayer U.S., Boehringer Ingelheim Japan, Inc., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Guardant Health Inc., Merck Biopharma Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Thermo Fisher Scientific K.K.; Financial Interests, Personal, Advisory Board: Janssen Pharmaceutical K.K.; Financial Interests, Personal, Expert Testimony: Medpace Japan K.K.; Financial Interests, Personal and Institutional, Funding: Amgen Inc., Amgen K.K., AstraZeneca K.K., Boehringer Ingelheim Japan, Inc., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Haihe Biopharma Co., Ltd., Ignyta, Inc., Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Loxo Oncology, Inc., Medical ＆ Biological Laboratories Co., Ltd., Merck Biopharma Co., Ltd., Merus N.V., MSD K.K., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sumitomo Dainippon Pharma Co., Ltd., Spectrum Pharmaceuticals, Inc., Sysmex Corporation., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Turning Point Therapeutics, Inc.; Non-Financial Interests, Member: American Society of Clinical Oncology, The Japan Lung Cancer Society, Japanese Society of Medical Oncology, The Japanese Cancer Association. All other authors have declared no conflicts of interest.