TY - JOUR
T1 - Use of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer
T2 - Initial Results from the Pembrolizumab Arm of a Phase 2 Randomized Clinical Trial
AU - Rahma, Osama E.
AU - Yothers, Greg
AU - Hong, Theodore S.
AU - Russell, Marcia M.
AU - You, Y. Nancy
AU - Parker, William
AU - Jacobs, Samuel A.
AU - Colangelo, Linda H.
AU - Lucas, Peter C.
AU - Gollub, Marc J.
AU - Hall, William A.
AU - Kachnic, Lisa A.
AU - Vijayvergia, Namrata
AU - O'Rourke, Mark A.
AU - Faller, Bryan A.
AU - Valicenti, Richard K.
AU - Schefter, Tracey E.
AU - Moxley, Katherine M.
AU - Kainthla, Radhika
AU - Stella, Philip J.
AU - Sigurdson, Elin
AU - Wolmark, Norman
AU - George, Thomas J.
N1 - Publisher Copyright:
© 2021 American Medical Association. All rights reserved.
PY - 2021/7/1
Y1 - 2021/7/1
N2 - 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.
AB - 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.
KW - Anal Canal/pathology
KW - Antibodies, Monoclonal, Humanized
KW - Antineoplastic Combined Chemotherapy Protocols/adverse effects
KW - Chemoradiotherapy/methods
KW - Fluorouracil/adverse effects
KW - Humans
KW - Male
KW - Middle Aged
KW - Neoadjuvant Therapy/methods
KW - Neoplasm Recurrence, Local/pathology
KW - Neoplasm Staging
KW - Organ Sparing Treatments
KW - Rectal Neoplasms/drug therapy
UR - http://www.scopus.com/inward/record.url?scp=85113344164&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000669020200005&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1001/jamaoncol.2021.1683
DO - 10.1001/jamaoncol.2021.1683
M3 - Article
C2 - 34196693
SN - 2374-2437
VL - 7
SP - 1225
EP - 1230
JO - JAMA Oncology
JF - JAMA Oncology
IS - 8
ER -