Phase 1 study of DS‐1205c combined with gefitinib for EGFR mutation‐positive non‐small cell lung cancer
Abstract Background Tyrosine kinase inhibitors (TKIs) are effective for the treatment of non‐small cell lung cancer (NSCLC) patients with activating mutations of the epidermal growth factor receptor (EGFR), but responses are not durable as tumors develop resistance. DS‐1205c is a novel, specific, or...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-03-01
|
| Series: | Cancer Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cam4.5508 |
| _version_ | 1827974975618809856 |
|---|---|
| author | Koichi Goto Yoshimasa Shiraishi Haruyasu Murakami Hidehito Horinouchi Ryo Toyozawa Masayuki Takeda Makiko Uno Nigel Crawford Joseph McGill Takeshi Jimbo Masato Ishigami Gensuke Takayama Shintaro Nakayama Shoichi Ohwada Makoto Nishio |
| author_facet | Koichi Goto Yoshimasa Shiraishi Haruyasu Murakami Hidehito Horinouchi Ryo Toyozawa Masayuki Takeda Makiko Uno Nigel Crawford Joseph McGill Takeshi Jimbo Masato Ishigami Gensuke Takayama Shintaro Nakayama Shoichi Ohwada Makoto Nishio |
| author_sort | Koichi Goto |
| collection | DOAJ |
| description | Abstract Background Tyrosine kinase inhibitors (TKIs) are effective for the treatment of non‐small cell lung cancer (NSCLC) patients with activating mutations of the epidermal growth factor receptor (EGFR), but responses are not durable as tumors develop resistance. DS‐1205c is a novel, specific, orally bioavailable, small‐molecule AXL receptor TKI. In preclinical studies, DS‐1205c restored TKI antitumor activity in a TKI acquired‐resistance EGFR‐mutant NSCLC tumor xenograft model. Methods This first‐in‐human, multicenter, open‐label Phase 1 study (registered at ClinicalTrials.gov: NCT03599518) primarily evaluated the safety and tolerability of combination therapy with DS‐1205c and gefitinib in Japanese patients with metastatic or unresectable EGFR‐mutant NSCLC and tumor progression during treatment with EGFR‐TKIs. Patients (n = 20) received DS‐1205c monotherapy (200–1200 mg twice daily [BID]) in a 7‐day safety monitoring period before combination DS‐1205c/gefitinib (250 mg once daily) in 21‐day cycles. Results The observed common treatment‐emergent adverse events (TEAEs) were increased aspartate aminotransferase (35%), increased alanine aminotransferase (30%), rash maculo‐papular (30%), and diarrhea (25%). No serious TEAEs were reported. Plasma concentrations and pharmacokinetic parameters of DS‐1205a (free form of DS‐1205c) were unaffected by concomitant administration of gefitinib. No patient achieved a complete or partial response and 5 patients (25%) had stable disease. Conclusion DS‐1205c was generally safe and well tolerated at all dose levels, but the safety profile of ≤800 mg BID was more favorable than 1200 mg BID. The recommended dose for dose‐expansion cohorts of DS‐1205c in combination therapy with gefitinib was 800 mg BID. |
| first_indexed | 2024-04-09T20:02:49Z |
| format | Article |
| id | doaj.art-4ccb84ac3b1f40d88e709e0bae4a3f6b |
| institution | Directory Open Access Journal |
| issn | 2045-7634 |
| language | English |
| last_indexed | 2024-04-09T20:02:49Z |
| publishDate | 2023-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj.art-4ccb84ac3b1f40d88e709e0bae4a3f6b2023-04-02T20:55:00ZengWileyCancer Medicine2045-76342023-03-011267090710410.1002/cam4.5508Phase 1 study of DS‐1205c combined with gefitinib for EGFR mutation‐positive non‐small cell lung cancerKoichi Goto0Yoshimasa Shiraishi1Haruyasu Murakami2Hidehito Horinouchi3Ryo Toyozawa4Masayuki Takeda5Makiko Uno6Nigel Crawford7Joseph McGill8Takeshi Jimbo9Masato Ishigami10Gensuke Takayama11Shintaro Nakayama12Shoichi Ohwada13Makoto Nishio14National Cancer Center Hospital East Kashiwa JapanKyushu University Hospital Fukuoka JapanShizuoka Cancer Center Shizuoka JapanNational Cancer Center Hospital Tokyo JapanNational Hospital Organization Kyushu Cancer Center Fukuoka JapanKindai University Hospital Osaka JapanDaiichi Sankyo Co. Ltd. Tokyo JapanDaiichi Sankyo Inc. Basking Ridge New Jersey USADaiichi Sankyo Inc. Basking Ridge New Jersey USADaiichi Sankyo Co. Ltd. Tokyo JapanDaiichi Sankyo Co. Ltd. Tokyo JapanDaiichi Sankyo Co. Ltd. Tokyo JapanDaiichi Sankyo Co. Ltd. Tokyo JapanDaiichi Sankyo Co. Ltd. Tokyo JapanDepartment of Thoracic Medical Oncology The Cancer Institute Hospital of Japanese Foundation for Cancer Research Tokyo JapanAbstract Background Tyrosine kinase inhibitors (TKIs) are effective for the treatment of non‐small cell lung cancer (NSCLC) patients with activating mutations of the epidermal growth factor receptor (EGFR), but responses are not durable as tumors develop resistance. DS‐1205c is a novel, specific, orally bioavailable, small‐molecule AXL receptor TKI. In preclinical studies, DS‐1205c restored TKI antitumor activity in a TKI acquired‐resistance EGFR‐mutant NSCLC tumor xenograft model. Methods This first‐in‐human, multicenter, open‐label Phase 1 study (registered at ClinicalTrials.gov: NCT03599518) primarily evaluated the safety and tolerability of combination therapy with DS‐1205c and gefitinib in Japanese patients with metastatic or unresectable EGFR‐mutant NSCLC and tumor progression during treatment with EGFR‐TKIs. Patients (n = 20) received DS‐1205c monotherapy (200–1200 mg twice daily [BID]) in a 7‐day safety monitoring period before combination DS‐1205c/gefitinib (250 mg once daily) in 21‐day cycles. Results The observed common treatment‐emergent adverse events (TEAEs) were increased aspartate aminotransferase (35%), increased alanine aminotransferase (30%), rash maculo‐papular (30%), and diarrhea (25%). No serious TEAEs were reported. Plasma concentrations and pharmacokinetic parameters of DS‐1205a (free form of DS‐1205c) were unaffected by concomitant administration of gefitinib. No patient achieved a complete or partial response and 5 patients (25%) had stable disease. Conclusion DS‐1205c was generally safe and well tolerated at all dose levels, but the safety profile of ≤800 mg BID was more favorable than 1200 mg BID. The recommended dose for dose‐expansion cohorts of DS‐1205c in combination therapy with gefitinib was 800 mg BID.https://doi.org/10.1002/cam4.5508AXL inhibitorDS‐1205gefitinibnon‐small cell lung cancerphase I clinical trial |
| spellingShingle | Koichi Goto Yoshimasa Shiraishi Haruyasu Murakami Hidehito Horinouchi Ryo Toyozawa Masayuki Takeda Makiko Uno Nigel Crawford Joseph McGill Takeshi Jimbo Masato Ishigami Gensuke Takayama Shintaro Nakayama Shoichi Ohwada Makoto Nishio Phase 1 study of DS‐1205c combined with gefitinib for EGFR mutation‐positive non‐small cell lung cancer Cancer Medicine AXL inhibitor DS‐1205 gefitinib non‐small cell lung cancer phase I clinical trial |
| title | Phase 1 study of DS‐1205c combined with gefitinib for EGFR mutation‐positive non‐small cell lung cancer |
| title_full | Phase 1 study of DS‐1205c combined with gefitinib for EGFR mutation‐positive non‐small cell lung cancer |
| title_fullStr | Phase 1 study of DS‐1205c combined with gefitinib for EGFR mutation‐positive non‐small cell lung cancer |
| title_full_unstemmed | Phase 1 study of DS‐1205c combined with gefitinib for EGFR mutation‐positive non‐small cell lung cancer |
| title_short | Phase 1 study of DS‐1205c combined with gefitinib for EGFR mutation‐positive non‐small cell lung cancer |
| title_sort | phase 1 study of ds 1205c combined with gefitinib for egfr mutation positive non small cell lung cancer |
| topic | AXL inhibitor DS‐1205 gefitinib non‐small cell lung cancer phase I clinical trial |
| url | https://doi.org/10.1002/cam4.5508 |
| work_keys_str_mv | AT koichigoto phase1studyofds1205ccombinedwithgefitinibforegfrmutationpositivenonsmallcelllungcancer AT yoshimasashiraishi phase1studyofds1205ccombinedwithgefitinibforegfrmutationpositivenonsmallcelllungcancer AT haruyasumurakami phase1studyofds1205ccombinedwithgefitinibforegfrmutationpositivenonsmallcelllungcancer AT hidehitohorinouchi phase1studyofds1205ccombinedwithgefitinibforegfrmutationpositivenonsmallcelllungcancer AT ryotoyozawa phase1studyofds1205ccombinedwithgefitinibforegfrmutationpositivenonsmallcelllungcancer AT masayukitakeda phase1studyofds1205ccombinedwithgefitinibforegfrmutationpositivenonsmallcelllungcancer AT makikouno phase1studyofds1205ccombinedwithgefitinibforegfrmutationpositivenonsmallcelllungcancer AT nigelcrawford phase1studyofds1205ccombinedwithgefitinibforegfrmutationpositivenonsmallcelllungcancer AT josephmcgill phase1studyofds1205ccombinedwithgefitinibforegfrmutationpositivenonsmallcelllungcancer AT takeshijimbo phase1studyofds1205ccombinedwithgefitinibforegfrmutationpositivenonsmallcelllungcancer AT masatoishigami phase1studyofds1205ccombinedwithgefitinibforegfrmutationpositivenonsmallcelllungcancer AT gensuketakayama phase1studyofds1205ccombinedwithgefitinibforegfrmutationpositivenonsmallcelllungcancer AT shintaronakayama phase1studyofds1205ccombinedwithgefitinibforegfrmutationpositivenonsmallcelllungcancer AT shoichiohwada phase1studyofds1205ccombinedwithgefitinibforegfrmutationpositivenonsmallcelllungcancer AT makotonishio phase1studyofds1205ccombinedwithgefitinibforegfrmutationpositivenonsmallcelllungcancer |