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

JTO Clin Res Rep. 2021 Jul 10;2(9):100206. doi: 10.1016/j.jtocrr.2021.100206. eCollection 2021 Sep.

Authors

Keunchil Park¹, Daniel Shao Weng Tan², Wu-Chou Su³, Byoung Chul Cho⁴, Sang-We Kim⁵, Ki Hyeong Lee⁶, Chin-Chou Wang⁷, Takashi Seto⁸, Dennis Chin-Lun Huang^{9

10}, Helen Hayoun Jung^{11

12}, Ming-Chi Hsu¹³, Thomas Bogenrieder^{14

15

16}, Chia-Chi Lin¹⁷

Affiliations

¹ Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
² Department of Medical Oncology, National Cancer Center, Singapore, Singapore.
³ Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
⁴ Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.
⁵ Department of Oncology, Asan Medical Center, Seoul, South Korea.
⁶ Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, South Korea.
⁷ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
⁸ Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.
⁹ Boehringer Ingelheim Taiwan Limited, Taipei, Taiwan.
¹⁰ Present Address: Merck Sharp & Dohme Taiwan, Taipei, Taiwan.
¹¹ Boehringer Ingelheim Korea, Seoul, South Korea.
¹² Present Address: Kanaph Therapeutics, Seoul, South Korea.
¹³ Boehringer Ingelheim (People's Republic of China) Investment Co. Ltd., Shanghai, People's Republic of China.
¹⁴ RCV Medicine, Boehringer Ingelheim RCV, Vienna, Austria.
¹⁵ Department of Urology, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
¹⁶ Present Address: Amal Therapeutics, Geneva, Switzerland.
¹⁷ Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.

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.

Keywords: Afatinib; EGFR tyrosine kinase inhibitor; IGF; NSCLC; Xentuzumab.