Osama E Rahma1,2, Greg Yothers1,3, Theodore S Hong1,4, Marcia M Russell1,5,6, Y Nancy You7, William Parker1,8, Samuel A Jacobs1, Linda H Colangelo1,3, Peter C Lucas1,9, Marc J Gollub10, William A Hall1,11, Lisa A Kachnic1,12,13, Namrata Vijayvergia1,14, Mark A O'Rourke1,15, Bryan A Faller16, Richard K Valicenti17, Tracey E Schefter1,18, Sagila George19, Radhika Kainthla20, Philip J Stella1,21, Elin Sigurdson22, Norman Wolmark1,23, Thomas J George1,24. 1. NRG Oncology, Philadelphia, Pennsylvania. 2. Department of Medical Oncology, Dana-Farber Cancer Institute/Alliance, Boston, Massachusetts. 3. Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania. 4. Department of Radiation Oncology, Massachusetts General Hospital, Boston. 5. Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California. 6. David Geffen School of Medicine at UCLA, Los Angeles, California. 7. Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston. 8. Department of Medical Physics, McGill University Health Centre, Montréal, Quebec, Canada. 9. Department of Pathology, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania. 10. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York. 11. Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee. 12. Department of Radiation Oncology, Columbia University Irving Medical Center, Herbert Irving Comprehensive Cancer Center, New York, New York. 13. SWOG Cancer Research Network, San Antonio, Texas. 14. Fox Chase Cancer Center, Philadelphia, Pennsylvania. 15. National Cancer Institute Community Oncology Research Program, Prisma Health Cancer Institute, Greenville, South Carolina. 16. Missouri Baptist Medical Center, Heartland Cancer Research, National Cancer Institute Community Oncology Research Program, St Louis. 17. Department of Radiation Oncology, UC Davis, Davis, California. 18. Department of Radiation Oncology, University of Colorado Cancer Center, Aurora. 19. Section of Hematology/Oncology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City. 20. Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas. 21. Department of Medical Oncology, St Joseph Mercy Hospital, Ann Arbor, Michigan. 22. Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania. 23. Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania. 24. Department of Medicine, University of Florida Health Cancer Center, Gainesville.
Abstract
IMPORTANCE: Total neoadjuvant therapy (TNT) is often used to downstage locally advanced rectal cancer (LARC) and decrease locoregional relapse; however, more than one-third of patients develop recurrent metastatic disease. As such, novel combinations are needed. OBJECTIVE: To assess whether the addition of pembrolizumab during and after neoadjuvant chemoradiotherapy can lead to an improvement in the neoadjuvant rectal (NAR) score compared with treatment with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) and chemoradiotherapy alone. DESIGN, SETTING, AND PARTICIPANTS: In this open-label, phase 2, randomized clinical trial (NRG-GI002), patients in academic and private practice settings were enrolled. Patients with stage II/III LARC with distal location (cT3-4 ≤ 5 cm from anal verge, any N), with bulky disease (any cT4 or tumor within 3 mm of mesorectal fascia), at high risk for metastatic disease (cN2), and/or who were not candidates for sphincter-sparing surgery (SSS) were stratified based on clinical tumor and nodal stages. Trial accrual opened on August 1, 2018, and ended on May 31, 2019. This intent-to-treat analysis is based on data as of August 2020. INTERVENTIONS: Patients were randomized (1:1) to neoadjuvant FOLFOX for 4 months and then underwent chemoradiotherapy (capecitabine with 50.4 Gy) with or without intravenous pembrolizumab administered at a dosage of 200 mg every 3 weeks for up to 6 doses before surgery. MAIN OUTCOMES AND MEASURES: The primary end point was the NAR score. Secondary end points included pathologic complete response (pCR) rate, SSS, disease-free survival, and overall survival. This report focuses on end points available after definitive surgery (NAR score, pCR, SSS, clinical complete response rate, margin involvement, and safety). RESULTS: A total of 185 patients (126 [68.1%] male; mean [SD] age, 55.7 [11.1] years) were randomized to the control arm (CA) (n = 95) or the pembrolizumab arm (PA) (n = 90). Of these patients, 137 were evaluable for NAR score (68 CA patients and 69 PA patients). The mean (SD) NAR score was 11.53 (12.43) for the PA patients (95% CI, 8.54-14.51) vs 14.08 (13.82) for the CA patients (95% CI, 10.74-17.43) (P = .26). The pCR rate was 31.9% in the PA vs 29.4% in the CA (P = .75). The clinical complete response rate was 13.9% in the PA vs 13.6% in the CA (P = .95). The percentage of patients who underwent SSS was 59.4% in the PA vs 71.0% in the CA (P = .15). Grade 3 to 4 adverse events were slightly increased in the PA (48.2%) vs the CA (37.3%) during chemoradiotherapy. Two deaths occurred during FOLFOX: sepsis (CA) and pneumonia (PA). No differences in radiotherapy fractions, FOLFOX, or capecitabine doses were found. CONCLUSIONS AND RELEVANCE: Pembrolizumab added to chemoradiotherapy as part of total neoadjuvant therapy was suggested to be safe; however, the NAR score difference does not support further study. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02921256.
IMPORTANCE: Total neoadjuvant therapy (TNT) is often used to downstage locally advanced rectal cancer (LARC) and decrease locoregional relapse; however, more than one-third of patients develop recurrent metastatic disease. As such, novel combinations are needed. OBJECTIVE: To assess whether the addition of pembrolizumab during and after neoadjuvant chemoradiotherapy can lead to an improvement in the neoadjuvant rectal (NAR) score compared with treatment with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) and chemoradiotherapy alone. DESIGN, SETTING, AND PARTICIPANTS: In this open-label, phase 2, randomized clinical trial (NRG-GI002), patients in academic and private practice settings were enrolled. Patients with stage II/III LARC with distal location (cT3-4 ≤ 5 cm from anal verge, any N), with bulky disease (any cT4 or tumor within 3 mm of mesorectal fascia), at high risk for metastatic disease (cN2), and/or who were not candidates for sphincter-sparing surgery (SSS) were stratified based on clinical tumor and nodal stages. Trial accrual opened on August 1, 2018, and ended on May 31, 2019. This intent-to-treat analysis is based on data as of August 2020. INTERVENTIONS: Patients were randomized (1:1) to neoadjuvant FOLFOX for 4 months and then underwent chemoradiotherapy (capecitabine with 50.4 Gy) with or without intravenous pembrolizumab administered at a dosage of 200 mg every 3 weeks for up to 6 doses before surgery. MAIN OUTCOMES AND MEASURES: The primary end point was the NAR score. Secondary end points included pathologic complete response (pCR) rate, SSS, disease-free survival, and overall survival. This report focuses on end points available after definitive surgery (NAR score, pCR, SSS, clinical complete response rate, margin involvement, and safety). RESULTS: A total of 185 patients (126 [68.1%] male; mean [SD] age, 55.7 [11.1] years) were randomized to the control arm (CA) (n = 95) or the pembrolizumab arm (PA) (n = 90). Of these patients, 137 were evaluable for NAR score (68 CA patients and 69 PA patients). The mean (SD) NAR score was 11.53 (12.43) for the PA patients (95% CI, 8.54-14.51) vs 14.08 (13.82) for the CA patients (95% CI, 10.74-17.43) (P = .26). The pCR rate was 31.9% in the PA vs 29.4% in the CA (P = .75). The clinical complete response rate was 13.9% in the PA vs 13.6% in the CA (P = .95). The percentage of patients who underwent SSS was 59.4% in the PA vs 71.0% in the CA (P = .15). Grade 3 to 4 adverse events were slightly increased in the PA (48.2%) vs the CA (37.3%) during chemoradiotherapy. Two deaths occurred during FOLFOX: sepsis (CA) and pneumonia (PA). No differences in radiotherapy fractions, FOLFOX, or capecitabine doses were found. CONCLUSIONS AND RELEVANCE: Pembrolizumab added to chemoradiotherapy as part of total neoadjuvant therapy was suggested to be safe; however, the NAR score difference does not support further study. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02921256.
Authors: Walid K Chatila; Jin K Kim; Henry Walch; Michael R Marco; Chin-Tung Chen; Fan Wu; Dana M Omer; Danny N Khalil; Karuna Ganesh; Xuan Qu; Anisha Luthra; Seo-Hyun Choi; Yu-Jui Ho; Ritika Kundra; Katharine I Groves; Oliver S Chow; Andrea Cercek; Martin R Weiser; Maria Widmar; Iris H Wei; Emmanouil P Pappou; Garrett M Nash; Philip B Paty; Qian Shi; Efsevia Vakiani; S Duygu Selcuklu; Mark T A Donoghue; David B Solit; Michael F Berger; Jinru Shia; Raphael Pelossof; Paul B Romesser; Rona Yaeger; J Joshua Smith; Nikolaus Schultz; Francisco Sanchez-Vega; Julio Garcia-Aguilar Journal: Nat Med Date: 2022-08-15 Impact factor: 87.241