Neoadjuvant Concurrent Chemo-Immuno-Radiation Therapy Followed by Surgery and Adjuvant Immunotherapy for Resectable Stage III N2 NSCLC: Primary Results From the SQUAT Trial (WJOG 12119L)

Akira Hamada¹, Junichi Soh², Akito Hata³, Kiyoshi Nakamatsu⁴, Mototsugu Shimokawa⁵, Yasushi Yatabe⁶, Jun Suzuki⁷, Masahiro Tsuboi⁸, Hidehito Horinouchi⁹, Yuichi Sakairi¹⁰, Masayuki Tanahashi¹¹, Shinichi Toyooka¹², Morihito Okada¹³, Natusmi Matsuura¹⁴, Hisayuki Shigematsu¹⁵, Yasumasa Nishimura⁴, Nobuyuki Yamamoto¹⁶, Kazuhiko Nakagawa¹⁷, Tetsuya Mitsudomi¹⁸

Affiliations

¹ Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan; Department of Surgery II, Faculty of Medicine, Yamagata University, Yamagata, Japan.
² Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan; Department of Thoracic Surgery, Osaka Metropolitan University, Graduate School of Medicine, Osaka. Japan.
³ Division of Thoracic Oncology, Kobe Minimally Invasive Cancer Center, Kobe, Japan.
⁴ Department of Radiation Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
⁵ Department of Biostatistics, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
⁶ Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.
⁷ Department of Surgery II, Faculty of Medicine, Yamagata University, Yamagata, Japan.
⁸ Division of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan.
⁹ Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
¹⁰ Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
¹¹ Division of Thoracic Surgery, Respiratory Disease Center, Seirei Mikatahara General Hospital, Hamamatsu, Japan.
¹² Department of General Thoracic Surgery, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
¹³ Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
¹⁴ Department of General Thoracic, Breast and Endocrinological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan.
¹⁵ Department of Thoracic Surgery, Shikoku Cancer Center, Matsuyama, Japan.
¹⁶ Department of Internal Medicine III, Wakayama Medical University, Wakayama, Japan.
¹⁷ Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
¹⁸ Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan; Izumi City General Hospital, Izumi, Japan; Department of Innovative Medicine, Kindai University Faculty of Medicine, Osaka-Sayama, Japan. Electronic address: mitsudom@med.kindai.ac.jp.

PMID: 40216327
DOI: 10.1016/j.jtho.2025.03.051

Clinical Trial

Neoadjuvant Concurrent Chemo-Immuno-Radiation Therapy Followed by Surgery and Adjuvant Immunotherapy for Resectable Stage III N2 NSCLC: Primary Results From the SQUAT Trial (WJOG 12119L)

Akira Hamada et al. J Thorac Oncol. 2025 Aug.

. 2025 Aug;20(8):1098-1107.

doi: 10.1016/j.jtho.2025.03.051. Epub 2025 Apr 9.

Authors

Affiliations

¹ Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan; Department of Surgery II, Faculty of Medicine, Yamagata University, Yamagata, Japan.
² Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan; Department of Thoracic Surgery, Osaka Metropolitan University, Graduate School of Medicine, Osaka. Japan.
³ Division of Thoracic Oncology, Kobe Minimally Invasive Cancer Center, Kobe, Japan.
⁴ Department of Radiation Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
⁵ Department of Biostatistics, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
⁶ Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.
⁷ Department of Surgery II, Faculty of Medicine, Yamagata University, Yamagata, Japan.
⁸ Division of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan.
⁹ Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
¹⁰ Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
¹¹ Division of Thoracic Surgery, Respiratory Disease Center, Seirei Mikatahara General Hospital, Hamamatsu, Japan.
¹² Department of General Thoracic Surgery, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
¹³ Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
¹⁴ Department of General Thoracic, Breast and Endocrinological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan.
¹⁵ Department of Thoracic Surgery, Shikoku Cancer Center, Matsuyama, Japan.
¹⁶ Department of Internal Medicine III, Wakayama Medical University, Wakayama, Japan.
¹⁷ Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
¹⁸ Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan; Izumi City General Hospital, Izumi, Japan; Department of Innovative Medicine, Kindai University Faculty of Medicine, Osaka-Sayama, Japan. Electronic address: mitsudom@med.kindai.ac.jp.

PMID: 40216327
DOI: 10.1016/j.jtho.2025.03.051

Abstract

Introduction: Neoadjuvant chemo-immunotherapy is one of the standard treatment options for resectable stage II to III NSCLC. Nevertheless, this treatment yielded insufficient local control in the CheckMate 816 trial. We hypothesized that adding radiotherapy could improve local control, thereby improving survival outcomes.

Methods: Eligible patients had clinical T1 to T3 or T4 (tumor size) N2 stage IIIA to B NSCLC (American Joint Committee on Cancer version 8), pathologically confirmed as N2 without extranodal invasion. Patients received concurrent chemoradiotherapy (carboplatin [area under the curve = 2] and paclitaxel [40 mg/m²] on days 1, 8, 15, 22, and 29, with 50 Gy radiation over 25 d) and durvalumab (1500 mg) on days 1 and 29, followed by surgical resection within two to six weeks. After surgery, durvalumab adjuvant therapy was administered for up to one year. The primary endpoint was major pathologic response (MPR: ≤10% viable tumor), with secondary endpoints being pathologic complete response, progression-free survival (PFS), overall survival (OS), and safety.

Results: From January 2020 through February 2022, 31 patients were enrolled from 10 Japanese institutions. The MPR rate was 63% (90% confidence interval: 47%-78%), which met the primary endpoint, and the pathologic complete response rate was 23%. At a median follow-up of 28 months, the two-year PFS and OS rates were 43% and 76%, respectively. Grade 3 or 4 adverse events occurred in 48% of cases, including one treatment-related death.

Conclusions: Compared with recently published results of peri-operative chemo-immunotherapy trials, this treatment regimen had a higher MPR rate. Nevertheless, this benefit did not necessarily translate into improved PFS or OS.

Keywords: Chemoradiotherapy; Immune checkpoint inhibitors; Major pathologic response; Neoadjuvant therapy; Quadruple-modality therapy.

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Conflict of interest statement

Disclosure Dr. Hamada has received research funding from AstraZeneca and Chugai Pharmaceuticals, honoraria from AstraZeneca, Chugai Pharmaceuticals, Ono Pharmaceuticals, Bristol-Myers Squibb, and ETHICON, and advisory fees from AstraZeneca and Chugai Pharmaceuticals. Dr. Soh has received research funding from AstraZeneca and Chugai Pharmaceuticals and honoraria from AstraZeneca, Chugai Pharmaceuticals, ETHICON, Intuitive Surgical, CSL Behring, Olympus, and Covidien. Dr. Hata has received research funding from MSD, Eli Lilly, Chugai Pharmaceuticals, Taiho, Boehringer Ingelheim, AstraZeneca, and AbbVie, and honoraria from Eli Lilly, MSD, Chugai Pharmaceuticals, Pfizer, AstraZeneca, Boehringer Ingelheim, and Taiho. Dr. Yatabe has received research funding from Merk Biopharma, Chugai-pharma, Konica-Minolta REALM, and Optieum Biotechnologies, honoraria from MSD, Chugai-pharma, AstraZeneca, Merk Biopharma, Novartis, Amgen, Daiichi-Sankyo, and Thermo Fisher Science, advisory role from AstraZeneca, MSD, AbbVie, Novartis, Amgen, Daiichi-Sankyo, Janssen Pharma, and Konica-Minolta REALM, and role of board member from the Japanese Lung Cancer Society, and the Japanese Society of Pathology. Dr. Tsuboi has received research funding from AstraZeneca KK, MSD, Bristol-Myers Squibb KK, Ono Pharmaceutical CO., LTD, Eli Lilly Japan, Novartis, MiRXES, and Johnson & Johnson Japan, honoraria from Johnson & Johnson Japan, Medtronic Japan, AstraZeneca KK, Eli Lilly Japan, Chugai Pharmaceutical Co., Ltd, Taiho Pharma, Bristol-Myers Squibb KK, Ono Pharmaceutical Co., Ltd, Novalis, MSD, Daiichi-Sankyo, and Amgen KK, advisory role from Chugai Pharmaceutical Co., Ltd, AstraZeneca KK, MSD, Novartis, and MiRXES, and role of a board member from the Japanese Lung Cancer Society. Dr. Horinouchi has received research funding from MSD, Abbvie, AstraZeneca, BMS, Ono, Daiichi-Sankyo, Janssen, Chugai, and Roche, honoraria from AstraZeneca, MSD, Eli Lilly, Ono, BMS, Chugai, Roche, Amgen, and Abbvie, and advisory role from AstraZeneca, Chugai, Roche, ONO, BMS, and Abbvie. Dr. Toyooka has received research funding from Eli Lilly, Taiho Pharmaceutical, AstraZeneca, and Chugai Pharma, consulting fees from AstraZeneca and Guardant Health, and honoraria from Chugai Pharma, Daiichi Sankyo Company, Astellas Pharma, Boehringer Ingelheim, Taiho Pharmaceutical, Guardant Health, Ono Pharmaceutical, Bayer, AstraZeneca, Merck & Co, and Eli Lilly. Dr. Okada has received honoraria from Johnson & Johnson, Chugai Pharmaceutical Co., Ltd., MSD K.K., Bristol Myers Squibb, and AstraZeneca plc. Dr. Yamamoto has received research funding from AstraZeneca K.K., A2 Healthcare Corporation, Amgen K.K., Eli Lilly Japan K.K., Mebix, Inc., AbbVie GK, Janssen Pharmaceutical K.K., Bristol Myers Squibb., RPM Co., Ltd, Pfizer R&D Japan G.K., Chugai Pharmaceutical Co., Ltd., MSD K.K., Nippon Boehringer Ingelheim Co., Ltd., PRiME-R,Inc., IQVIA Solutions Japan G.K., Novartis Japan., EPS Corporation, Medpace Japan K.K., and Syneos Health Clinical K.K, honoraria from Amgen K.K., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., AbbVie GK, Janssen Pharmaceutical K.K., Accuray Japan K.K., Guardant Health Japan Corp., Taiho Oncology, Inc., Tsumura & Co., Nippon Kayaku Co., Ltd., Merck Biopharma Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Miyarisan Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., ShiftZero K.K., MSD K.K., Nippon Boehringer Ingelheim Co., Ltd., Eli Lilly Japan K.K., Novartis Japan., Bristol Myers Squibb., Ono Pharmaceutical Co., Ltd., Daiichi Sankyo, INC., Takeda Pharmaceutical Co., Ltd., Terumo.co.jp., Pfizer Japan Inc., USACO Corporation, KYORIN Pharmaceutical Co., Ltd., Medical Review Co., Ltd., and Kowa Company Ltd., and advisory role from MSD K.K., Amgen K.K., Daiichi Sankyo, Inc., USACO Corporation, AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., and Novartis Japan. Dr. Nakagawa has received research funding from IQVIA Services Japan K.K., Syneos Health Clinical K.K., EPS Corporation., Nippon Kayaku Co., Ltd., EPS International Co., Ltd,., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., MSD K.K., Ono Pharmaceutical Co., Ltd., Amgen Inc., Taiho Pharmaceutical Co., Ltd., EP-CRSU Co., Ltd., EP-CRSU Co., Ltd., Mebix, Inc., Bristol-Myers Squibb K.K., Janssen Pharmaceutical K.K., Pfizer R&D Japan G.K., Kobayashi Pharmaceutical Co., Ltd., Pfizer Japan Inc, Astellas Pharma Inc., Eisai Co., Ltd., AstraZeneca K.K., Mochida Pharmaceutical Co., Ltd., Labcorp Development Japan K.K. (Covance Japan Inc.), Japan Clinical Research Operations, Otsuka Pharmaceutical Co., Ltd., GlaxoSmithKline K.K., Sanofi K.K., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., SRL, Inc., Medical Reserch Support, Eli Lilly Japan K.K., Novartis Pharma K.K., CMIC CO., Ltd., Bayer Yakuhin, Ltd, Shionogi & Co., Ltd., PRA Health Sciences Inc., and Ascent Development Services, consulting fees from Eli Lilly Japan K.K., and Ono Pharmaceutical Co., Ltd., honoraria from Ono Pharmaceutical Co., Ltd., Amgen Inc., Nippon Kayaku Co., Ltd., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., MSD K.K., Pfizer Japan Inc., Nippon Boehringer Ingelheim Co., Ltd., Taiho Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., Daiichi Sankyo Co., Ltd., Incyte biosciences Japan, M3, Inc., Global Health Consulting Japan Co., Ltd., The Yomiuri Shimbun, Merck Biopharma Co., Ltd., TAIYO Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Life Technologies Japan Ltd., Neo Communication, Novartis Pharma K.K., Medical Mobile Communications Co., Ltd, Yodosha Co., Ltd., CMIC ShiftZero K.K., Japan Clinical Research Operations, CMIC Co., Ltd., Bristol Myers Squibb Company, Janssen Pharmaceutical K.K., Otuka Pharmaceutical Factory, Inc., and Hisamitsu Pharmaceutical Co., Ltd., and patents from Daiichi Sankyo Co., Ltd. Dr. Mitsudomi has received research funding from AstraZeneca and honoraria from AstraZeneca, Bristol Myers Squibb, Ono, and MSD. The remaining authors declare no conflict of interest.

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Neoadjuvant Concurrent Chemo-Immuno-Radiation Therapy Followed by Surgery and Adjuvant Immunotherapy for Resectable Stage III N2 NSCLC: Primary Results From the SQUAT Trial (WJOG 12119L)

Affiliations

Neoadjuvant Concurrent Chemo-Immuno-Radiation Therapy Followed by Surgery and Adjuvant Immunotherapy for Resectable Stage III N2 NSCLC: Primary Results From the SQUAT Trial (WJOG 12119L)

Authors

Affiliations

Abstract

Conflict of interest statement

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Full Text Sources

Medical

Miscellaneous