PMID- 33166722 OWN - NLM STAT- MEDLINE DCOM- 20210421 LR - 20220531 IS - 1556-1380 (Electronic) IS - 1556-0864 (Linking) VI - 16 IP - 2 DP - 2021 Feb TI - Randomized Phase 2 Studies of Checkpoint Inhibitors Alone or in Combination With Pegilodecakin in Patients With Metastatic NSCLC (CYPRESS 1 and CYPRESS 2). PG - 327-333 LID - S1556-0864(20)30805-4 [pii] LID - 10.1016/j.jtho.2020.10.001 [doi] AB - INTRODUCTION: Checkpoint inhibitors (CPIs) have been approved to treat metastatic NSCLC. Pegilodecakin + CPI suggested promising efficacy in phase 1 IVY, providing rationale for randomized phase 2 trials CYPRESS 1 and CYPRESS 2. METHODS: CYPRESS 1 (N = 101) and CYPRESS 2 (N = 52) included Eastern Cooperative Oncology Group performance status of 0 to 1 and first-line/second-line metastatic NSCLC, respectively, without known EGFR/ALK mutations. Patients were randomized 1:1; control arms received pembrolizumab (CYPRESS 1) or nivolumab (CYPRESS 2); experimental arms received pegilodecakin + CPI. Patients had programmed death-ligand 1 tumor proportion score of greater than or equal to 50% (CYPRESS 1) or 0% to 49% (CYPRESS 2). Primary end point was objective response rate (ORR) per investigator. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. Exploratory end points included immune activation biomarkers. RESULTS: Median follow-up for CYPRESS 1 and CYPRESS 2 was 10.0 and 11.6 months, respectively. Results for pegilodecakin + pembrolizumab versus pembrolizumab were as follows: ORR per investigator 47% versus 44% (OR = 1.1, 95% confidence interval [CI]: 0.5-2.5); median PFS 6.3 versus 6.1 months (hazard ratio [HR] = 0.937, 95% CI: 0.54-1.625); and median OS 16.3 months versus not reached (HR = 1.507, 95% CI: 0.708-3.209). Results per blinded independent central review were consistent. Treatment discontinuation rate owing to adverse events (AEs) doubled in the experimental arm (32% versus 15%). AEs with grade greater than or equal to 3 treatment-related AEs (62% versus 19%) included anemia (20% versus 0%) and thrombocytopenia (12% versus 2%). Results for pegilodecakin + nivolumab versus nivolumab were as follows: ORR per investigator 15% versus 12% (OR = 1.2, 95% CI: 0.3-5.9); median PFS 1.9 versus 1.9 months (HR = 1.006, 95% CI: 0.519-1.951); and median OS 6.7 versus 10.7 months (HR = 1.871, 95% CI: 0.772-4.532). AEs with grade greater than or equal to 3 treatment-related AEs (70.4% versus 16.7%) included anemia (40.7% versus 0%), fatigue (18% versus 0%), and thrombocytopenia (14.8% versus 0%). Biomarker data suggested activation of immunostimulatory signals of interleukin-10R pathway in pegilodecakin-containing arms. CONCLUSIONS: Despite evidence of biological effect in peripheral blood, adding pegilodecakin to CPI did not improve ORR, PFS, or OS, in first-line/second-line NSCLC. Pegilodecakin + CPI has been found to have overall higher toxicity compared with CPI alone, leading to doubling of treatment discontinuation rate owing to AEs. CI - Copyright (c) 2020. Published by Elsevier Inc. FAU - Spigel, David AU - Spigel D AD - Sarah Cannon Research Institute and Tennessee Oncology, Nashville, Tennessee. Electronic address: david.spigel@sarahcannon.com. FAU - Jotte, Robert AU - Jotte R AD - U.S. Oncology Research, Houston, Texas; Rocky Mountain Cancer Centers, Denver, Colorado. FAU - Nemunaitis, John AU - Nemunaitis J AD - Division of Hematology and Oncology, University of Toledo College of Medicine, Toledo, Ohio. FAU - Shum, Merrill AU - Shum M AD - The Oncology Institute of Hope and Innovation, Whittier, California. FAU - Schneider, Jeffrey AU - Schneider J AD - New York University Winthrop Hospital, Mineola, New York. FAU - Goldschmidt, Jerome AU - Goldschmidt J AD - Oncology and Hematology Association of SW Virginia, Blacksburg, Virginia. FAU - Eisenstein, Jennifer AU - Eisenstein J AD - Colorado Permanente Medical Group/Kaiser Lafayette, Denver, Colorado. FAU - Berz, David AU - Berz D AD - Beverly Hills Cancer Center, Beverly Hills, California. FAU - Seneviratne, Lasika AU - Seneviratne L AD - Los Angeles Hematology Oncology Medical Group, Los Angeles, California. FAU - Socoteanu, Matei AU - Socoteanu M AD - Texas Oncology-Longview Cancer Center, Longview, Texas. FAU - Bhanderi, Viralkumar AU - Bhanderi V AD - Florida Cancer Specialist, Tallahassee, Florida. FAU - Konduri, Kartik AU - Konduri K AD - Baylor Charles A. Sammons Cancer Center, Texas Oncology PA, Dallas, Texas. FAU - Xia, Meng AU - Xia M AD - Eli Lilly and Company, Indianapolis, Indiana. FAU - Wang, Hong AU - Wang H AD - Eli Lilly and Company, Indianapolis, Indiana. FAU - Hozak, Rebecca R AU - Hozak RR AD - Eli Lilly and Company, Indianapolis, Indiana. FAU - Gueorguieva, Ivelina AU - Gueorguieva I AD - Eli Lilly and Company, Indianapolis, Indiana. FAU - Ferry, David AU - Ferry D AD - Eli Lilly and Company, New York, New York. FAU - Gandhi, Leena AU - Gandhi L AD - Eli Lilly and Company, New York, New York. FAU - Chao, Bo H AU - Chao BH AD - Eli Lilly and Company, New York, New York. FAU - Rybkin, Igor AU - Rybkin I AD - Henry Ford Cancer Institute, Detroit, Michigan. LA - eng SI - ClinicalTrials.gov/NCT03382899 SI - ClinicalTrials.gov/NCT03382912 PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20201106 PL - United States TA - J Thorac Oncol JT - Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer JID - 101274235 RN - 0 (Immune Checkpoint Inhibitors) RN - 0 (pegilodecakin) RN - 130068-27-8 (Interleukin-10) RN - 3WJQ0SDW1A (Polyethylene Glycols) SB - IM CIN - J Thorac Oncol. 2021 Feb;16(2):187-190. PMID: 33494924 MH - Antineoplastic Combined Chemotherapy Protocols MH - Humans MH - Immune Checkpoint Inhibitors/*therapeutic use MH - Interleukin-10 MH - *Lung Neoplasms/drug therapy MH - Polyethylene Glycols/therapeutic use OTO - NOTNLM OT - Interleukin (IL)-10 OT - Nivolumab OT - Non-small cell lung cancer OT - Pegilodecakin OT - Pembrolizumab EDAT- 2020/11/10 06:00 MHDA- 2021/04/22 06:00 CRDT- 2020/11/09 20:13 PHST- 2020/07/10 00:00 [received] PHST- 2020/08/10 00:00 [revised] PHST- 2020/10/02 00:00 [accepted] PHST- 2020/11/10 06:00 [pubmed] PHST- 2021/04/22 06:00 [medline] PHST- 2020/11/09 20:13 [entrez] AID - S1556-0864(20)30805-4 [pii] AID - 10.1016/j.jtho.2020.10.001 [doi] PST - ppublish SO - J Thorac Oncol. 2021 Feb;16(2):327-333. doi: 10.1016/j.jtho.2020.10.001. Epub 2020 Nov 6.