Cancer

Internal medicine

Surgery

Oncology

Randomized controlled trial

Clinical endpoint

Total mesorectal excision

Capecitabine

FOLFOX

Neoadjuvant therapy

Chemoradiotherapy

Oxaliplatin

Regimen

Radiation therapy

Colorectal cancer

Breast cancer

Medicine

JAMA Oncology

<h3>Importance</h3> 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. <h3>Objective</h3> 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. <h3>Design, Setting, and Participants</h3> 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. <h3>Interventions</h3> 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. <h3>Main Outcomes and Measures</h3> 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). <h3>Results</h3> 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) (<i>P</i> = .26). The pCR rate was 31.9% in the PA vs 29.4% in the CA (<i>P</i> = .75). The clinical complete response rate was 13.9% in the PA vs 13.6% in the CA (<i>P</i> = .95). The percentage of patients who underwent SSS was 59.4% in the PA vs 71.0% in the CA (<i>P</i> = .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. <h3>Conclusions and Relevance</h3> 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. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02921256

Use of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer