Bradford A Perez1, Sungjune Kim2, Minhsuan Wang3, Ahmad M Karimi4, Chase Powell3, Jiannong Li5, Thomas J Dilling6, Alberto Chiappori7, Kujtim Latifi4, Trevor Rose8, Austin Lannon9, Gretchen MacMillan9, James Saller10, G Daniel Grass4, Stephen Rosenberg6, Jhanelle Gray7, Eric Haura7, Ben Creelan7, Tawee Tanvetyanon7, Andreas Saltos7, Michael Shafique7, Theresa A Boyle11, Michael J Schell5, Jose R Conejo-Garcia3, Scott J Antonia12. 1. Department of Radiation Oncology, H Lee Moffitt Cancer Center and Research Institute; Department of Immunology, H Lee Moffitt Cancer Center and Research Institute; Department of Thoracic Oncology, H Lee Moffitt Cancer Center and Research Institute. Electronic address: bradford.perez@moffitt.org. 2. Department of Radiation Oncology, H Lee Moffitt Cancer Center and Research Institute; Department of Immunology, H Lee Moffitt Cancer Center and Research Institute. 3. Department of Immunology, H Lee Moffitt Cancer Center and Research Institute. 4. Department of Radiation Oncology, H Lee Moffitt Cancer Center and Research Institute. 5. Department of Biostatistics, H Lee Moffitt Cancer Center and Research Institute. 6. Department of Radiation Oncology, H Lee Moffitt Cancer Center and Research Institute; Department of Thoracic Oncology, H Lee Moffitt Cancer Center and Research Institute. 7. Department of Thoracic Oncology, H Lee Moffitt Cancer Center and Research Institute. 8. Department of Radiology, H Lee Moffitt Cancer Center and Research Institute. 9. Clinical Trials Office, H Lee Moffitt Cancer Center and Research Institute. 10. Department of Pathology, H Lee Moffitt Cancer Center and Research Institute. 11. Department of Thoracic Oncology, H Lee Moffitt Cancer Center and Research Institute; Department of Pathology, H Lee Moffitt Cancer Center and Research Institute. 12. Department of Medical Oncology, Duke Cancer Institute, Duke University Medical Center.
Abstract
PURPOSE: Consolidative thoracic radiation therapy (TRT) has been shown to improve outcomes for patients with extensive stage small cell lung cancer. We hypothesized that the addition of ipilimumab (IPI) and nivolumab (NIVO) after TRT would improve outcomes for patients with extensive stage small cell lung cancer. METHODS AND MATERIALS: Eligibility required stable disease or better after platinum doublet chemotherapy. Study therapy included consolidative TRT to 30 Gy in 10 fractions, targeting residual primary tumor and initially involved regional lymph nodes. Two weeks after TRT, patients received concurrent IPI (3 mg/kg) and NIVO (1 mg/kg) every 3 weeks for 4 doses followed by NIVO monotherapy (480 mg) every 4 weeks until progression or up to 1 year. RESULTS: The study enrolled 21 patients, with 6-month progression-free survival (PFS) of 24% (90% confidence interval [CI], 11%-40%) and a median PFS of 4.5 months (95% CI, 2.7%-4.6%). The 12-month overall survival (OS) was 48% (95% CI, 29%-64%) with a median OS of 11.7 months (95% CI, 4.7%-16.0%). Fifty-two percent of patients had ≥1 possibly related grade 3 to 4 immune-related adverse event. Grade 3 pulmonary and gastrointestinal immune-related adverse events were recorded in 19% and 24% of patients, respectively. Exploratory analysis showed increased cytotoxic T cell (CD3+CD8+) tumor infiltration was associated with favorable PFS (P = .01) and OS (P = .02). Reduction in peripheral blood CD3+CD8+ from baseline to after first dose of IPI/NIVO was associated with improved PFS (P = .02) and OS (P = .02). CONCLUSIONS: Consolidative IPI and NIVO after platinum-based chemotherapy and TRT demonstrated a toxicity profile consistent with the known adverse events attributable to IPI and NIVO. Although the study regimen did not significantly improve PFS, the OS was higher than historic expectations. CD3+CD8+ tumor infiltration and migration may identify patients most likely to have improved outcomes in small cell lung cancer.
PURPOSE: Consolidative thoracic radiation therapy (TRT) has been shown to improve outcomes for patients with extensive stage small cell lung cancer. We hypothesized that the addition of ipilimumab (IPI) and nivolumab (NIVO) after TRT would improve outcomes for patients with extensive stage small cell lung cancer. METHODS AND MATERIALS: Eligibility required stable disease or better after platinum doublet chemotherapy. Study therapy included consolidative TRT to 30 Gy in 10 fractions, targeting residual primary tumor and initially involved regional lymph nodes. Two weeks after TRT, patients received concurrent IPI (3 mg/kg) and NIVO (1 mg/kg) every 3 weeks for 4 doses followed by NIVO monotherapy (480 mg) every 4 weeks until progression or up to 1 year. RESULTS: The study enrolled 21 patients, with 6-month progression-free survival (PFS) of 24% (90% confidence interval [CI], 11%-40%) and a median PFS of 4.5 months (95% CI, 2.7%-4.6%). The 12-month overall survival (OS) was 48% (95% CI, 29%-64%) with a median OS of 11.7 months (95% CI, 4.7%-16.0%). Fifty-two percent of patients had ≥1 possibly related grade 3 to 4 immune-related adverse event. Grade 3 pulmonary and gastrointestinal immune-related adverse events were recorded in 19% and 24% of patients, respectively. Exploratory analysis showed increased cytotoxic T cell (CD3+CD8+) tumor infiltration was associated with favorable PFS (P = .01) and OS (P = .02). Reduction in peripheral blood CD3+CD8+ from baseline to after first dose of IPI/NIVO was associated with improved PFS (P = .02) and OS (P = .02). CONCLUSIONS: Consolidative IPI and NIVO after platinum-based chemotherapy and TRT demonstrated a toxicity profile consistent with the known adverse events attributable to IPI and NIVO. Although the study regimen did not significantly improve PFS, the OS was higher than historic expectations. CD3+CD8+ tumor infiltration and migration may identify patients most likely to have improved outcomes in small cell lung cancer.
Authors: B Jeremic; Y Shibamoto; N Nikolic; B Milicic; S Milisavljevic; A Dagovic; J Aleksandrovic; G Radosavljevic-Asic Journal: J Clin Oncol Date: 1999-07 Impact factor: 44.544
Authors: Rodabe N Amaria; Sangeetha M Reddy; Hussein A Tawbi; Michael A Davies; Merrick I Ross; Isabella C Glitza; Janice N Cormier; Carol Lewis; Wen-Jen Hwu; Ehab Hanna; Adi Diab; Michael K Wong; Richard Royal; Neil Gross; Randal Weber; Stephen Y Lai; Richard Ehlers; Jorge Blando; Denái R Milton; Scott Woodman; Robin Kageyama; Daniel K Wells; Patrick Hwu; Sapna P Patel; Anthony Lucci; Amy Hessel; Jeffrey E Lee; Jeffrey Gershenwald; Lauren Simpson; Elizabeth M Burton; Liberty Posada; Lauren Haydu; Linghua Wang; Shaojun Zhang; Alexander J Lazar; Courtney W Hudgens; Vancheswaran Gopalakrishnan; Alexandre Reuben; Miles C Andrews; Christine N Spencer; Victor Prieto; Padmanee Sharma; James Allison; Michael T Tetzlaff; Jennifer A Wargo Journal: Nat Med Date: 2018-10-08 Impact factor: 53.440
Authors: Daphne W Dumoulin; Anne-Marie C Dingemans; Joachim G J V Aerts; Jordi Remon; Dirk K M De Ruysscher; Lizza E L Hendriks Journal: Transl Lung Cancer Res Date: 2021-06