Phase 1b Open-Label Trial of Afatinib Plus Xentuzumab (BI 836845) in Patients With EGFR Mutation-Positive NSCLC After Progression on EGFR Tyrosine Kinase Inhibitors

Keunchil Park; Daniel Shao Weng Tan; Wu Chou Su; Byoung Chul Cho; Sang We Kim; Ki Hyeong Lee; Chin Chou Wang; Takashi Seto; Dennis Chin Lun Huang; Helen Hayoun Jung; Ming Chi Hsu; Thomas Bogenrieder; Chia Chi Lin

doi:10.1016/j.jtocrr.2021.100206

Phase 1b Open-Label Trial of Afatinib Plus Xentuzumab (BI 836845) in Patients With EGFR Mutation-Positive NSCLC After Progression on EGFR Tyrosine Kinase Inhibitors

Keunchil Park, Daniel Shao Weng Tan, Wu Chou Su, Byoung Chul Cho, Sang We Kim, Ki Hyeong Lee, Chin Chou Wang, Takashi Seto, Dennis Chin Lun Huang, Helen Hayoun Jung, Ming Chi Hsu, Thomas Bogenrieder, Chia Chi Lin

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

Abstract

Introduction: Insulin-like growth factor signaling has been implicated in acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. This phase 1 trial (NCT02191891) investigated the combination of xentuzumab (an insulin-like growth factor-ligand neutralizing monoclonal antibody) and afatinib (an EGFR TKI) in patients with previously treated EGFR mutation-positive NSCLC. Methods: The trial comprised dose escalation (part A) and expansion (part B). Patients had advanced or metastatic NSCLC that had progressed on EGFR TKI monotherapy or platinum-based chemotherapy (nonadenocarcinoma only, part A) or irreversible EGFR TKI monotherapy (part B). Absence of EGFR T790M mutation was required in part B. Part A used a 3 + 3 design, with a starting dose of xentuzumab 1000 mg/wk (intravenous) and afatinib 30 mg/d (oral). Primary endpoints were the maximum tolerated dose of the combination (part A) and objective response (part B). Results: A total of 16 patients each were treated in parts A and B. Maximum tolerated dose was xentuzumab 1000 mg/wk plus afatinib 40 mg/d. No patients in part B had an objective response, but 10 had stable disease (median [range] duration of disease control: 2.3 [0.8–10.9] mo). The most common drug-related adverse events were diarrhea (75 %), paronychia (69 %), and rash (69 %) in part A and diarrhea (31 %), rash (19 %), paronychia (19 %), and fatigue (19 %) in part B. Conclusions: There were no new safety issues; xentuzumab and afatinib could be safely coadministered. Nevertheless, the combination revealed only modest activity in patients with EGFR mutation-positive, T790M-negative NSCLC after progression on afatinib.

Original language	English
Article number	100206
Journal	JTO Clinical and Research Reports
Volume	2
Issue number	9
DOIs	https://doi.org/10.1016/j.jtocrr.2021.100206
Publication status	Published - 2021 Sept

Bibliographical note

Funding Information:
Disclosure: Dr. Park reports providing consultancy for Boehringer Ingelheim during the conduct of the study; providing consultancy for Amgen, AbbVie, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Hanmi, Johnson & Johnson, Merck Sharp & Dohme, and Merck KGaA; having research grants from AstraZeneca and Merck Sharp & Dohme; and serving as data monitoring committee member for Incyte and BeiGene. Dr. Tan reports having advisory role/serving as consultant/having research grants from Novartis, Bayer, and AstraZeneca; having advisory role/honoraria from Boehringer Ingelheim and Pfizer; having advisory role/serving as consultant from Celgene, Eli Lilly, Loxo Oncology, Takeda Pharmaceutical, and Merrimack; having honoraria from Merck and Roche; and having research grants from GlaxoSmithKline outside of the submitted work. Dr. Cho reports receiving research funding from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono Pharmaceutical, Dizal Pharma, and Merck Sharp & Dohme; having consulting role with Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol Myers Squibb, Ono Pharmaceutical, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda Pharmaceutical, and Merck Sharp & Dohme; having stock ownership from TheraCanVac Inc., Gencurix Inc., and BridgeBio Therapeutics; and having royalty from Champions Oncology. Dr. Lee reports having advisory board role/receiving fees from Bristol Myers Squibb, AstraZeneca, and Merck Sharp & Dohme outside of the submitted work. Dr. Seto reports receiving grants from Nippon Boehringer Ingelheim, during the conduct of the study; grants and personal fees from AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Merck Sharp & Dohme, Nippon Boehringer Ingelheim, Novartis Pharma, Pfizer Japan, and Takeda Pharmaceutical; personal fees from Astellas Pharma, Bristol Myers Squibb, Kyowa Hakko Kirin, Ono Pharmaceutical, Taiho Pharmaceutical, and Thermo Fisher Scientific; grants from AbbVie, Bayer Yakuhin, Kissei Pharmaceutical, Loxo Oncology, and Merck Biopharma; and personal fees from Precision Medicine Asia Co. Ltd. outside of the submitted work. Drs. Huang, Hsu, Jung, and Bogenrieder report having employment with Boehringer Ingelheim. Dr. Lin reports receiving personal fees from BeiGene, Boehringer Ingelheim, Blueprint Medicines, Daiichi Sankyo, Eli Lilly, Novartis, and Roche. The remaining authors declare no conflict of interest.Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Fiona Scott, PhD, CMPP, of Ashfield MedComms, an Ashfield Health company, and funded by Boehringer Ingelheim. This work was supported by Boehringer Ingelheim International GmbH. The study sponsor participated in the design of the study; the collection, analysis, and interpretation of the data; writing this article; and the decision to submit the article for publication.

Funding Information:
Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Fiona Scott, PhD, CMPP, of Ashfield MedComms, an Ashfield Health company, and funded by Boehringer Ingelheim. This work was supported by Boehringer Ingelheim International GmbH. The study sponsor participated in the design of the study; the collection, analysis, and interpretation of the data; writing this article; and the decision to submit the article for publication.

Publisher Copyright:
© 2021 The Authors

All Science Journal Classification (ASJC) codes

Oncology
Pulmonary and Respiratory Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jtocrr.2021.100206

Cite this

Park, K., Tan, D. S. W., Su, W. C., Cho, B. C., Kim, S. W., Lee, K. H., Wang, C. C., Seto, T., Huang, D. C. L., Jung, H. H., Hsu, M. C., Bogenrieder, T., & Lin, C. C. (2021). Phase 1b Open-Label Trial of Afatinib Plus Xentuzumab (BI 836845) in Patients With EGFR Mutation-Positive NSCLC After Progression on EGFR Tyrosine Kinase Inhibitors. JTO Clinical and Research Reports, 2(9), [100206]. https://doi.org/10.1016/j.jtocrr.2021.100206

@article{114f0dc810374066aa793c40f1f7a749,

title = "Phase 1b Open-Label Trial of Afatinib Plus Xentuzumab (BI 836845) in Patients With EGFR Mutation-Positive NSCLC After Progression on EGFR Tyrosine Kinase Inhibitors",

abstract = "Introduction: Insulin-like growth factor signaling has been implicated in acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. This phase 1 trial (NCT02191891) investigated the combination of xentuzumab (an insulin-like growth factor-ligand neutralizing monoclonal antibody) and afatinib (an EGFR TKI) in patients with previously treated EGFR mutation-positive NSCLC. Methods: The trial comprised dose escalation (part A) and expansion (part B). Patients had advanced or metastatic NSCLC that had progressed on EGFR TKI monotherapy or platinum-based chemotherapy (nonadenocarcinoma only, part A) or irreversible EGFR TKI monotherapy (part B). Absence of EGFR T790M mutation was required in part B. Part A used a 3 + 3 design, with a starting dose of xentuzumab 1000 mg/wk (intravenous) and afatinib 30 mg/d (oral). Primary endpoints were the maximum tolerated dose of the combination (part A) and objective response (part B). Results: A total of 16 patients each were treated in parts A and B. Maximum tolerated dose was xentuzumab 1000 mg/wk plus afatinib 40 mg/d. No patients in part B had an objective response, but 10 had stable disease (median [range] duration of disease control: 2.3 [0.8–10.9] mo). The most common drug-related adverse events were diarrhea (75 %), paronychia (69 %), and rash (69 %) in part A and diarrhea (31 %), rash (19 %), paronychia (19 %), and fatigue (19 %) in part B. Conclusions: There were no new safety issues; xentuzumab and afatinib could be safely coadministered. Nevertheless, the combination revealed only modest activity in patients with EGFR mutation-positive, T790M-negative NSCLC after progression on afatinib.",

author = "Keunchil Park and Tan, {Daniel Shao Weng} and Su, {Wu Chou} and Cho, {Byoung Chul} and Kim, {Sang We} and Lee, {Ki Hyeong} and Wang, {Chin Chou} and Takashi Seto and Huang, {Dennis Chin Lun} and Jung, {Helen Hayoun} and Hsu, {Ming Chi} and Thomas Bogenrieder and Lin, {Chia Chi}",

note = "Funding Information: Disclosure: Dr. Park reports providing consultancy for Boehringer Ingelheim during the conduct of the study; providing consultancy for Amgen, AbbVie, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Hanmi, Johnson & Johnson, Merck Sharp & Dohme, and Merck KGaA; having research grants from AstraZeneca and Merck Sharp & Dohme; and serving as data monitoring committee member for Incyte and BeiGene. Dr. Tan reports having advisory role/serving as consultant/having research grants from Novartis, Bayer, and AstraZeneca; having advisory role/honoraria from Boehringer Ingelheim and Pfizer; having advisory role/serving as consultant from Celgene, Eli Lilly, Loxo Oncology, Takeda Pharmaceutical, and Merrimack; having honoraria from Merck and Roche; and having research grants from GlaxoSmithKline outside of the submitted work. Dr. Cho reports receiving research funding from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono Pharmaceutical, Dizal Pharma, and Merck Sharp & Dohme; having consulting role with Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol Myers Squibb, Ono Pharmaceutical, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda Pharmaceutical, and Merck Sharp & Dohme; having stock ownership from TheraCanVac Inc., Gencurix Inc., and BridgeBio Therapeutics; and having royalty from Champions Oncology. Dr. Lee reports having advisory board role/receiving fees from Bristol Myers Squibb, AstraZeneca, and Merck Sharp & Dohme outside of the submitted work. Dr. Seto reports receiving grants from Nippon Boehringer Ingelheim, during the conduct of the study; grants and personal fees from AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Merck Sharp & Dohme, Nippon Boehringer Ingelheim, Novartis Pharma, Pfizer Japan, and Takeda Pharmaceutical; personal fees from Astellas Pharma, Bristol Myers Squibb, Kyowa Hakko Kirin, Ono Pharmaceutical, Taiho Pharmaceutical, and Thermo Fisher Scientific; grants from AbbVie, Bayer Yakuhin, Kissei Pharmaceutical, Loxo Oncology, and Merck Biopharma; and personal fees from Precision Medicine Asia Co. Ltd. outside of the submitted work. Drs. Huang, Hsu, Jung, and Bogenrieder report having employment with Boehringer Ingelheim. Dr. Lin reports receiving personal fees from BeiGene, Boehringer Ingelheim, Blueprint Medicines, Daiichi Sankyo, Eli Lilly, Novartis, and Roche. The remaining authors declare no conflict of interest.Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Fiona Scott, PhD, CMPP, of Ashfield MedComms, an Ashfield Health company, and funded by Boehringer Ingelheim. This work was supported by Boehringer Ingelheim International GmbH. The study sponsor participated in the design of the study; the collection, analysis, and interpretation of the data; writing this article; and the decision to submit the article for publication. Funding Information: Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Fiona Scott, PhD, CMPP, of Ashfield MedComms, an Ashfield Health company, and funded by Boehringer Ingelheim. This work was supported by Boehringer Ingelheim International GmbH. The study sponsor participated in the design of the study; the collection, analysis, and interpretation of the data; writing this article; and the decision to submit the article for publication. Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = sep,

doi = "10.1016/j.jtocrr.2021.100206",

language = "English",

volume = "2",

journal = "JTO Clinical and Research Reports",

issn = "2666-3643",

publisher = "Elsevier Inc.",

number = "9",

}

Park, K, Tan, DSW, Su, WC, Cho, BC, Kim, SW, Lee, KH, Wang, CC, Seto, T, Huang, DCL, Jung, HH, Hsu, MC, Bogenrieder, T & Lin, CC 2021, 'Phase 1b Open-Label Trial of Afatinib Plus Xentuzumab (BI 836845) in Patients With EGFR Mutation-Positive NSCLC After Progression on EGFR Tyrosine Kinase Inhibitors', JTO Clinical and Research Reports, vol. 2, no. 9, 100206. https://doi.org/10.1016/j.jtocrr.2021.100206

TY - JOUR

T1 - Phase 1b Open-Label Trial of Afatinib Plus Xentuzumab (BI 836845) in Patients With EGFR Mutation-Positive NSCLC After Progression on EGFR Tyrosine Kinase Inhibitors

AU - Park, Keunchil

AU - Tan, Daniel Shao Weng

AU - Su, Wu Chou

AU - Cho, Byoung Chul

AU - Kim, Sang We

AU - Lee, Ki Hyeong

AU - Wang, Chin Chou

AU - Seto, Takashi

AU - Huang, Dennis Chin Lun

AU - Jung, Helen Hayoun

AU - Hsu, Ming Chi

AU - Bogenrieder, Thomas

AU - Lin, Chia Chi

N1 - Funding Information: Disclosure: Dr. Park reports providing consultancy for Boehringer Ingelheim during the conduct of the study; providing consultancy for Amgen, AbbVie, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Hanmi, Johnson & Johnson, Merck Sharp & Dohme, and Merck KGaA; having research grants from AstraZeneca and Merck Sharp & Dohme; and serving as data monitoring committee member for Incyte and BeiGene. Dr. Tan reports having advisory role/serving as consultant/having research grants from Novartis, Bayer, and AstraZeneca; having advisory role/honoraria from Boehringer Ingelheim and Pfizer; having advisory role/serving as consultant from Celgene, Eli Lilly, Loxo Oncology, Takeda Pharmaceutical, and Merrimack; having honoraria from Merck and Roche; and having research grants from GlaxoSmithKline outside of the submitted work. Dr. Cho reports receiving research funding from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono Pharmaceutical, Dizal Pharma, and Merck Sharp & Dohme; having consulting role with Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol Myers Squibb, Ono Pharmaceutical, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda Pharmaceutical, and Merck Sharp & Dohme; having stock ownership from TheraCanVac Inc., Gencurix Inc., and BridgeBio Therapeutics; and having royalty from Champions Oncology. Dr. Lee reports having advisory board role/receiving fees from Bristol Myers Squibb, AstraZeneca, and Merck Sharp & Dohme outside of the submitted work. Dr. Seto reports receiving grants from Nippon Boehringer Ingelheim, during the conduct of the study; grants and personal fees from AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Merck Sharp & Dohme, Nippon Boehringer Ingelheim, Novartis Pharma, Pfizer Japan, and Takeda Pharmaceutical; personal fees from Astellas Pharma, Bristol Myers Squibb, Kyowa Hakko Kirin, Ono Pharmaceutical, Taiho Pharmaceutical, and Thermo Fisher Scientific; grants from AbbVie, Bayer Yakuhin, Kissei Pharmaceutical, Loxo Oncology, and Merck Biopharma; and personal fees from Precision Medicine Asia Co. Ltd. outside of the submitted work. Drs. Huang, Hsu, Jung, and Bogenrieder report having employment with Boehringer Ingelheim. Dr. Lin reports receiving personal fees from BeiGene, Boehringer Ingelheim, Blueprint Medicines, Daiichi Sankyo, Eli Lilly, Novartis, and Roche. The remaining authors declare no conflict of interest.Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Fiona Scott, PhD, CMPP, of Ashfield MedComms, an Ashfield Health company, and funded by Boehringer Ingelheim. This work was supported by Boehringer Ingelheim International GmbH. The study sponsor participated in the design of the study; the collection, analysis, and interpretation of the data; writing this article; and the decision to submit the article for publication. Funding Information: Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Fiona Scott, PhD, CMPP, of Ashfield MedComms, an Ashfield Health company, and funded by Boehringer Ingelheim. This work was supported by Boehringer Ingelheim International GmbH. The study sponsor participated in the design of the study; the collection, analysis, and interpretation of the data; writing this article; and the decision to submit the article for publication. Publisher Copyright: © 2021 The Authors

PY - 2021/9

Y1 - 2021/9

N2 - Introduction: Insulin-like growth factor signaling has been implicated in acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. This phase 1 trial (NCT02191891) investigated the combination of xentuzumab (an insulin-like growth factor-ligand neutralizing monoclonal antibody) and afatinib (an EGFR TKI) in patients with previously treated EGFR mutation-positive NSCLC. Methods: The trial comprised dose escalation (part A) and expansion (part B). Patients had advanced or metastatic NSCLC that had progressed on EGFR TKI monotherapy or platinum-based chemotherapy (nonadenocarcinoma only, part A) or irreversible EGFR TKI monotherapy (part B). Absence of EGFR T790M mutation was required in part B. Part A used a 3 + 3 design, with a starting dose of xentuzumab 1000 mg/wk (intravenous) and afatinib 30 mg/d (oral). Primary endpoints were the maximum tolerated dose of the combination (part A) and objective response (part B). Results: A total of 16 patients each were treated in parts A and B. Maximum tolerated dose was xentuzumab 1000 mg/wk plus afatinib 40 mg/d. No patients in part B had an objective response, but 10 had stable disease (median [range] duration of disease control: 2.3 [0.8–10.9] mo). The most common drug-related adverse events were diarrhea (75 %), paronychia (69 %), and rash (69 %) in part A and diarrhea (31 %), rash (19 %), paronychia (19 %), and fatigue (19 %) in part B. Conclusions: There were no new safety issues; xentuzumab and afatinib could be safely coadministered. Nevertheless, the combination revealed only modest activity in patients with EGFR mutation-positive, T790M-negative NSCLC after progression on afatinib.

AB - Introduction: Insulin-like growth factor signaling has been implicated in acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. This phase 1 trial (NCT02191891) investigated the combination of xentuzumab (an insulin-like growth factor-ligand neutralizing monoclonal antibody) and afatinib (an EGFR TKI) in patients with previously treated EGFR mutation-positive NSCLC. Methods: The trial comprised dose escalation (part A) and expansion (part B). Patients had advanced or metastatic NSCLC that had progressed on EGFR TKI monotherapy or platinum-based chemotherapy (nonadenocarcinoma only, part A) or irreversible EGFR TKI monotherapy (part B). Absence of EGFR T790M mutation was required in part B. Part A used a 3 + 3 design, with a starting dose of xentuzumab 1000 mg/wk (intravenous) and afatinib 30 mg/d (oral). Primary endpoints were the maximum tolerated dose of the combination (part A) and objective response (part B). Results: A total of 16 patients each were treated in parts A and B. Maximum tolerated dose was xentuzumab 1000 mg/wk plus afatinib 40 mg/d. No patients in part B had an objective response, but 10 had stable disease (median [range] duration of disease control: 2.3 [0.8–10.9] mo). The most common drug-related adverse events were diarrhea (75 %), paronychia (69 %), and rash (69 %) in part A and diarrhea (31 %), rash (19 %), paronychia (19 %), and fatigue (19 %) in part B. Conclusions: There were no new safety issues; xentuzumab and afatinib could be safely coadministered. Nevertheless, the combination revealed only modest activity in patients with EGFR mutation-positive, T790M-negative NSCLC after progression on afatinib.

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Phase 1b Open-Label Trial of Afatinib Plus Xentuzumab (BI 836845) in Patients With EGFR Mutation-Positive NSCLC After Progression on EGFR Tyrosine Kinase Inhibitors

Abstract

Bibliographical note

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