ABSTRACT
Background: Neoadjuvant chemo-immunotherapy (CheckMate 816 regimen) has become a standard of care in treatment of resectable non-small cell lung cancer (NSCLC) patients in some countries. Addition of radiation therapy (RT) may further improve local control in locally advanced NSCLC patients. Here, we report the primary endpoint, major pathologic response (MPR), of the SQUAT trial (WJOG 12119L, JapicCTI- 195069)-a multicenter, prospective, single-arm, phase II trial of neoadjuvant concurrent chemo-immuno-radiation therapy followed by surgical resection and adjuvant immunotherapy for resectable stage IIIA-B N2 NSCLC. Method(s): Patients with resectable stage IIIA-B N2 NSCLC received concurrent chemoradiotherapy [weekly paclitaxel (40 mg/m2)/carboplatin (AUC 2) for 5 weeks plus involved-field RT 50 Gy] and immunotherapy [durvalumab (1500 mg) Q4W for 2 cycles] followed by surgical resection and adjuvant immunotherapy (durvalumab for up to 1 year). The primary endpoint was MPR rate according to an independent central review (ICR). We assumed the threshold of the MPR rate to be 40% and the expected rate to be 65% with a significance level alpha=0.05 (one-sided) and power 0.8. The sample size was 31 patients, including the 10% ineligible patients. Result(s): Between Jan 2020 and Feb 2022, 31 patients were enrolled from 10 institutions in Japan. Thirty-one patients were evaluated for safety, and 30 patients for efficacy. Of 30 patients (median age, 64 years), 70% and 63% had clinical stage IIIA and non-squamous histology, respectively. The MPR and pathological complete response (pCR) rates by ICR were 63% (90% CI, 47-78, 95% CI, 44-80) and 20% (95% CI, 8-39), respectively. Complete resection was not performed due to adverse events (2 pts) and disease progression (3 pts). Among 25 patients who received complete resection, the MPR and pCR rates were 76% (95% CI, 55-91) and 24% (95% CI, 9-45), respectively. No 30-day postoperative mortality was reported. Conclusion(s): The primary endpoint of MPR rate was met in SQUAT trial. This result suggests that this treatment strategy is promising for resectable stage IIIA-B N2 NSCLC. Clinical trial identification: JapicCTI-195069. Legal entity responsible for the study: WJOG (West Japan Oncology Group). Funding(s): AstraZeneca. Disclosure: T. Miyoshi: Financial Interests, Institutional, Research Grant: AstraZeneca. A. Hamada: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai, Ono Pharmaceuticals;Financial Interests, Personal, Advisory Board: AstraZeneca;Financial Interests, Institutional, Research Grant: AstraZeneca. J. Soh: Financial Interests, Personal, Invited Speaker: Ethicon, Covidien, Intutive;Financial Interests, Institutional, Research Grant: AstraZeneca. A. Hata: Financial Interests, Institutional, Research Grant: MSD, Eli Lilly, Boehringer Ingelheim, AstraZeneca;Financial Interests, Personal, Invited Speaker: Eli Lilly, Chugai, Pfizer, AstraZeneca, Boehringer Ingelheim. Y. Yatabe: Financial Interests, Personal, Invited Speaker: MSD, Chugai-pharma, AstraZeneca, Pfizer, Thermo Fisher Science, ArcherDx, Novartis, Elli-Lily, Daiichi Sankyo, Jansen-Pharma, Amgen;Financial Interests, Institutional, Research Grant: Thermo Fisher Science, ArcherDx, AstraZeneca. J. Suzuki: Financial Interests, Institutional, Research Grant: AstraZeneca. M. Tsuboi: Financial Interests, Personal, Invited Speaker, Lecture: Johnson & Johnson Japan;Financial Interests, Personal, Advisory Board, Lectures, Advisory boards: AstraZeneca KK, Chugai Pharmaceutical Co.,Ltd, MSD;Financial Interests, Personal, Invited Speaker, Lectures: Eli Lilly Japan, Bristol Myers Squibb KK, Teijin Pharma, Taiho Pharma, Medtronic Japan, ONO Pharmaceutical Co.,Ltd;Financial Interests, Personal, Advisory Board, Advisory boards: Novartis;Financial Interests, Personal, Invited Speaker: Daiichi Sankyo company limited, MSD, AstraZeneca, Novartis;Financial Interests, Institutional, Research Grant: Beohringer-Ingelheim Japan, MSD, AstraZeneca KK, Ono Pharmaceutical Co.,Ltd, Bristol Myers Squibb KK, Novartis;Financial Interests, Institutional, Invited Speaker: Eli Lilly Japan. H. Horinouchi: Financial Interests, Personal, Invited Speaker: AstraZeneca, Eli Lilly, BMS/ONO, Merck Sharp & Dohme, Roche/Chugai, Novartis, Pfizer, Boehringer Ingelheim, Kyowa-Kirin, Nihon Kayaku, AbbVie, Roche/Chugai;Financial Interests, Personal, Advisory Board: AstraZeneca, Eli Lilly, BMS/ONO, Merck Sharp & Dohme, Roche/Chugai, Amgen, Nihon Kayaku;Financial Interests, Institutional, Research Grant: Roche/Chugai, Merck Sharp & Dohme, Daiichi Sankyo, ONO pharmaceutical, AstraZeneca;Financial Interests, Institutional, Invited Speaker: AbbVie. I. Yoshino: Financial Interests, Institutional, Research Grant: AstraZeneca. T. Masayuki: Financial Interests, Institutional, Research Grant: AstraZeneca. S. Toyooka: Financial Interests, Personal, Invited Speaker: Chugai, Taiho, Ono Pharmaceuticals, Kyorin, Daiichi Sankyo, Medtronic, Johnson and Johnson;Financial Interests, Personal, Advisory Role: Kyorin;Financial Interests, Institutional, Research Grant: Illumina, Eurofins, Taiho, Chugai, Eli Lilly, AstraZeneca. M. Okada: Financial Interests, Institutional, Research Grant: AstraZeneca. T. Go: Financial Interests, Institutional, Research Grant: AstraZeneca. M. Yamashita: Financial Interests, Institutional, Research Grant: AstraZeneca. N. Yamamoto: Financial Interests, Personal, Invited Speaker: MSD K.K, AstraZeneca, Ono Pharmaceutical Co., Ltd., Thermo Fisher Scientific, Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Boehringer Ingelheim, Novartis, Pfizer Inc., Bristol Myers Squibb, Nippon Kayaku, GlaxoSmithKline K.K., Sanofi K.K., Hisamitsu Pharmaceutical Co.,Inc., Merk biopharma;Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Boehringer Ingelheim, Novartis, Bristol Myers Squibb, Nippon Kayaku, Life Technologies Japan Ltd., Amgen Inc., Guardant Health Japan, Janssen Pharmaceutical K.K.;Financial Interests, Institutional, Research Grant: MSD K.K;Financial Interests, Institutional, Invited Speaker: AstraZeneca, Ono Pharm ceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Pfizer Inc., Amgen Inc., Janssen Pharmaceutical K.K.;Financial Interests, Institutional, Funding: Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Toppan printing, Terumo. K. Nakagawa: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Amgen Inc., Nippon Kayaku Co., Ltd., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., MSD K.K., Pfizer Japan Inc., Nippon Boehringer Ingelheim Co., Ltd., Taiho Pharmaceutical Co.,Ltd., Bayer Yakuhin, Ltd., CMIC ShiftZero K.K., Life Technologies Japan Ltd., Neo Communication, Merck Biopharma Co., Ltd., Kyowa Kirin Co., Ltd., Takeda Pharmaceutical Co., Ltd., 3H Clinical Trial Inc., Care Net, Inc., Medical Review Co., Ltd., Medical Mobile Communications co., Ltd, Yodosha Co., Ltd., Nikkei Business Publications, Inc., Japan Clinical Research Operations, CMIC Co., Ltd., Novartis Pharma K.K., Taiyo Pharma Co., Ltd.;Financial Interests, Personal, Advisory Board: Ono Pharmaceutical Co.,Ltd., Eli Lilly Japan K.K.;Financial Interests, Institutional, Other, patents sales fee: Daiichi Sankyo Co., Ltd.;Financial Interests, Institutional, Research Grant: Parexel International Corp., Pra Healthsciences, Eps Corporation., Kissei Pharmaceutical Co., Ltd., EPS International Co.,Ltd,., Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co.,Ltd., MSD K.K., Ono Pharmaceutical Co.,Ltd., PPD-SNBL K.K, SymBio Pharmaceuticals Limited., IQVIA Services Japan K.K., Syneos Health Clinical K.K., Nippon Kayaku Co.,Ltd., EP-CRSU Co., Ltd., Mebix, Inc., Bristol Myers Squibb K.K., Janssen Pharmaceutical K.K., Eisai Co., Ltd., AstraZeneca K.K., Mochida Pharmaceutical Co., Ltd., Covance Japan Inc., Japan linical Research Operations, Takeda Pharmaceutical Co.,Ltd., GlaxoSmithKline K.K., Sanofi K.K., Chugai Pharmaceutical Co.,Ltd., Nippon Boehringer Ingelheim Co.,Ltd., Sysmex Corporation, Medical Reserch Support, Eli Lilly Japan K.K., Amgen Inc., Novartis Pharma K.K., Novartis Pharma K.K., Srl, Inc. T. Mitsudomi: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai, Novartis, MSD, Bristol Myers Squibb, Ono, Pfizer, Eli Lilly, Merck Biopharma;Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Chugai, Novartis, MSD, Bristol Myers Squibb, Ono, Pfizer, Amgen, Janssen, Takeda, Eli-Lilly;Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim, AstraZeneca, Chugai, MSD, Taiho, Daiichi Sankyo, Ono;Non-Financial Interests, Personal, Leadership Role: Interanational Association for Study of Lung Cancer. All other authors have declared no conflicts of interest. Copyright © 2022 European Society for Medical Oncology
ABSTRACT
Background: CAN is a monoclonal antibody that inhibits proinflammatory IL-1beta-driven pathways that may play a role in tumor growth in early-stage NSCLC. Preclinical data suggest targeting IL-1beta could decrease inflammation and immunosuppression in the tumor microenvironment (TME). Method(s): CANOPY-N (NCT03968419) is a phase II, randomized, open-label study of neoadjuvant CAN, PEM or CAN+PEM in resectable NSCLC. Eligibility: Stage IB-IIIA NSCLC;treatment (tx) naive;ECOG PS 0-1;and eligible for planned resection 4-6 weeks after first dose. Pts were randomized 2:2:1 to the tx arms: CAN, CAN+PEM or PEM. CAN and PEM were both given as two 200 mg doses once every 3 weeks. Primary endpoint: major pathological response (MPR) rate based on central review. Key secondary endpoints: overall response rate (ORR), surgical feasibility rate, and safety. Changes in CD8+ T cell, tumor-associated macrophage (TAM) and regulatory T cell (Treg) levels, among others, were assessed in exploratory biomarker analyses. Result(s): 88 pts enrolled across 3 arms: CAN (n=35), CAN+PEM (n=35) and PEM (n=18). 87 pts completed planned neoadjuvant tx. Four pts did not have surgery: 3 due to disease progression (CAN) and 1 to pt decision (CAN+PEM). MPR rates were 2.9% (CAN), 17.1% (CAN+PEM) and 11.1% (PEM). ORRs were 0% (CAN), 8.6% (CAN+PEM) and 11.1% (PEM). Gr >=3 AEs occurred in 37.1%, 28.6% and 22.2% of pts, of which 0%, 11.4% and 11.1% were tx related, in the CAN, CAN+PEM and PEM arms, respectively. Decreases in TAMs and Tregs were seen in CAN arms whereas increases in CD8+ T cells were seen in PEM arms. Modulations were more pronounced with CAN+PEM (Table). [Formula presented] Conclusion(s): CANOPY-N did not meet the primary endpoint of MPR rate, with minimal clinical efficacy and no increase in CD8+ T cells with CAN alone. No new safety signals were seen. IL-1beta inhibition impacted inflammation and immunosuppression in the TME. Clinical trial identification: CACZ885V2201C / NCT03968419. Editorial acknowledgement: Editorial assistance was provided by Ollie Butlin, MSc of Articulate Science Ltd., and was funded by Novartis Pharmaceuticals Corporation. Legal entity responsible for the study: Novartis Pharmaceuticals Corporation. Funding(s): Novartis Pharmaceuticals Corporation. Disclosure: T.S.K. Mok: Financial Interests, Personal, Invited Speaker: AbbVie, ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Daiichi Sankyo, Fishawack Facilitate, InMed Medical Communication, Lunit USA, Inc., Merck Serono, MSD, Roche, MD Health, Medscape/WebMD, PeerVoice, Touch Medical Media, Permanyer SL, Prime Oncology, Research to Practice, Sanofi-Aventis, Takeda, PER, Daz Group, Lucence Health Inc., Janssen Pharmaceutical NV, Jiahui Holdings Co., LiangYiHui Healthcare, Merck Pharmaceuticals HK Ltd, MiRXES, Novartis, OrigiMed Co. Ltd., Pfizer, Shanghai BeBirds Translation & Consulting Co., Ltd., Taiho Pharmaceutical Co., Ltd, AstraZeneca;Financial Interests, Personal, Advisory Board: AbbVie, ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Blueprint Medicines, Berry Oncology, CStone Pharma, Daiichi Sankyo, Fishawack Facilitate, Eisai, Gritstone Oncology, Guardant Health, G1 Therapeutics, Hengrui, Ignyta, IQVIA, Incyte Corporation, Inivata, Janssen, Loxo Oncology, Qiming Dev., Lunit USA, Inc., Merck Serono, MSD, Roche, Mirati Therapeutics, MoreHealth, Novartis, OrigiMed, Puma Tech., Sanofi-Aventis, Takeda, Virtus Medical, Yuhan, Curio Science, Bayer Healthcare Pharmaceuticals Ltd., Covidien LP, C4 Therapeutics, Cirina Ltd., Da Volterrra, F. Hoffmann-La Roche Ltd / Genentech, Gilead Sciences, Lucence Health Inc., Medscape LLC / WebMD, MiRXES, OSE Immunotherapeutics, Pfizer, SFJ Pharmaceutical Ltd., Synergy Research, Tigermed, Vertex Pharmaceuticals, Berry Oncology, D3 Bio Ltd., Lakeshore Biotech;Financial Interests, Personal, Invited Speaker, Former known as Hutchison Chi-Med: HutchMed;F nancial Interests, Personal, Officer, Chairman: ACT Genomics-Sanomics Group;Financial Interests, Personal, Stocks/Shares: Sanomics Ltd., Biolidics Ltd., Aurora Tele-Oncology, AstraZeneca;Financial Interests, Personal, Stocks/Shares, Former known as Hutchison Chi-Med: HutchMed;Financial Interests, Institutional, Funding, For clinical trials performed at CUHK: Merck Serono, AstraZeneca, BMS, MSD, Novartis, Pfizer, Roche, SFJ Pharmaceuticals, XCovery, Takeda, G1 Therapeutics, Clovis Oncology;Non-Financial Interests, Personal, Advisory Role: geneDecode;Non-Financial Interests, Personal, Other, Invited Speaker: AstraZeneca, Aurora Tele-Oncology, Lunit USA, Inc., Sanomics Ltd.;Non-Financial Interests, Personal, Leadership Role, Term ended on 30 June 2022: American Society of Clinical Oncology (ASCO);Non-Financial Interests, Personal, Leadership Role: Asian Thoracic Oncology Research Group (ATORG), Chinese Lung Cancer Research Foundation Limited (CLCRF), Hong Kong Cancer Fund (HKCF), Hong Kong Cancer Therapy Society (HKCTS), St. Stephen's College & Prep. School (Hong Kong);Non-Financial Interests, Personal, Leadership Role, Term ended: Chinese Society of Clinical Oncology (CSCO);Non-Financial Interests, Personal, Leadership Role, Term ended on 30 April 2019: International Association for the Study of Lung Cancer (IASLC). M. Tsuboi: Financial Interests, Personal, Invited Speaker, Lecture: Johnson & Johnson Japan;Financial Interests, Personal, Advisory Board, Lectures, Advisory boards: AstraZeneca KK, Chugai Pharmaceutical CO.,LTD, MSD;Financial Interests, Personal, Invited Speaker, Lectures: Eli Lilly Japan, Bristol Myers Squibb KK, Teijin Pharma, Taiho Pharma, Medtronic Japan, ONO Pharmaceutical CO.,LTD;Financial Interests, Personal, Advisory Board, Advisory boards: Novartis;Financial Interests, Personal, Invited Speaker: Daiichi-Sankyo company limited, MSD, AstraZeneca, Novartis;Financial Interests, Institutional, Research Grant: Beohringer-Ingelheim Japan, MSD, AstraZeneca KK, Ono Pharmaceutical CO.,LTD, Bristol Myers Squibb KK, Novartis;Financial Interests, Institutional, Invited Speaker: Eli Lilly Japan. J.M. Lee: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Astrazeneca, Roche/Genentech, Novartis;Financial nterests, Personal, Invited Speaker, LCMC3, LCMC4, NAUTIKA-1: Roche/Genentech;Financial Interests, Personal, Invited Speaker, CANOPY-N, GEOMETRY-1: Novartis. E.S. Kim: Financial Interests, Personal, Other, Consulting/Research: Regeneron, Takeda, Novartis. J. Zhang: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Biodesix, Bristol Myers Squibb, Cardinal Health, Daiichi Sankyo, Hengrui Therapeutics, Eli Lilly, Mirati, Nexus Health, Novartis, Novocure, Sanofi, Takeda Oncology;Financial Interests, Personal, Invited Speaker: AstraZeneca, MJH Life Sciences, Regeneron, Sanofi;Financial Interests, Institutional, Research Grant, PI and Sponsor: AstraZeneca, Biodesix, Nilogen, Genentech;Financial Interests, Institutional, Invited Speaker: Hengrui Therapeutics, Mirati, Novartis, Abbvie, BeiGene, Merck;Financial Interests, Institutional, Research Grant, PI, basic science research: Mirati;Non-Financial Interests, Personal, Member, American Society of Clinical Oncology: ASCO;Non-Financial Interests, Personal, Member, American Association for Cancer Research: AACR;Non-Financial Interests, Personal, Member, International Association for the Study of Lung Cancer: IASLC;Non-Financial Interests, Personal, Member, Chinese American Hematologist and Oncologist Network: CAHON. J. Duan: Financial Interests, Personal, Stocks/Shares: Novartis Pharmaceuticals Corporation. C. Lobetti-Bodoni: Financial Interests, Personal, Full or part-time Employment, Clinical Development Medical Director: Novartis Oncology;Financial Interests, Personal, Stocks/Shares: Novartis Oncology;Other, Personal, Other, My husband is a Roche employer: Roche;Other, Personal, Other, My husband had consultancy in the last two years with these companies: Sanofi and Takeda;Other, Personal, Other, My husband ha honoraria in the last 2 years with these companies: Takeda, Jansenn-Cilag Ltd;Other, Personal, Other, My husband owns stock of this company: Harlock Helatcare Consulting Ltd. J.C. Brase: Financial Interests, Personal, Full or part-time Employment: Novartis;Financial Interests, Personal, Stocks/Shares: Novartis. A. Savchenko: Financial Interests, Personal, Full or part-time Employment: Novartis;Financial Interests, Personal, Stocks/Shares: Novartis. P. Garrido Lopez: Financial Interests, Personal, Advisory Board: Abbvie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, GlaxoSmithKline, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, sanofi;Financial Interests, Personal, Invited Speaker: AstraZeneca, Janssen, MSD, Novartis, Pfizer, Roche, Takeda, Novartis, IO Biotech;Financial Interests, Personal, Advisory Board, Spouse: Boehringer Ingelheim, Gebro, Janssen, Nordic;Financial Interests, Personal, Invited Speaker, Spouse: Boehringer Ingelheim, Janssen;Financial Interests, Personal, Other, Data monitoring committee for a clinical trial in 2020: Novartis;Financial Interests, Personal, Other, Lung Cancer Medical Education TASC Committee 2021: Janssen;Financial Interests, Institutional, Invited Speaker: Novartis, Janssen, AstraZeneca, Pfizer, Blue print, Apollomics, Amgen, Array Biopharma;Financial Interests, Personal, Invited Speaker, study entitled JNJ-372: Janssen;Non-Financial Interests, Personal, Leadership Role, Council member as Women for Oncology Committee ChairFellowship and Award Committee and Press CommitteeFaculty for lung and other thoracic tumours: ESMO;Non-Financial Interests, Personal, Leadership Role, President of the Spanish Federation of Medical Societies (FACME): FACME;Other, Personal, Other, My son is working in the pharma company TEVA as an engineer. I do not have any kind ofrelationship with TEVA: TEVA;Non-Financial Interests, Personal, Leadership Role, Former President of Spanish Medical Oncology SocietyMember of the Spanish National Health Advisory Board: SEOM;Non-Financial Interests, Personal, Leadership Role, Member of the Scientific Committee of the Spanish Against Cancer Research Foundation (aecc) and also Borad member: AECC;Non-Financial Interests, Personal, Leadership Role, IASLC Women in Tho acic Oncology Working Group Member: IASLC. All other authors have declared no conflicts of interest. Copyright © 2022