As reported in JAMA Oncology by Osama E. Rahma, MD, and colleagues, initial results of the phase II NRG-GI002 trial showed no improvement in mean neoadjuvant rectal score with the addition of pembrolizumab to chemoradiotherapy in total neoadjuvant therapy for patients with locally advanced rectal cancer.
Osama E. Rahma, MD
Study Details
The U.S. multicenter open-label trial included 185 patients. They were randomly assigned between August 2018 and May 2019 to receive neoadjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) in six cycles over 4 months followed by chemoradiotherapy consisting of capecitabine plus a total radiation dose of 50.4 Gy, with (pembrolizumab group, n = 90) or without (control group, n = 95) pembrolizumab at 200 mg every 3 weeks during and after chemoradiotherapy for up to six doses before surgery. Patients had stage II or III disease with distal location (cT3–4 ≤ 5 cm from anal verge, any N), had bulky disease (any cT4 or tumor within 3 mm of mesorectal fascia), and were at high risk for metastatic disease (cN2) or were not candidates for sphincter-sparing surgery.
The primary endpoint was the neoadjuvant rectal score (0–100, with lower score indicating better prognosis) in the intent-to-treat population. Secondary endpoints included pathologic complete response rate, sphincter-sparing surgery rate, disease-free survival, and overall survival. The current analysis is based on data through August 2020.
Key Findings
No differences in radiotherapy fractions or FOLFOX or capecitabine doses were observed between groups. Totals of 70 and 71 patients in the pembrolizumab and control groups proceeded to surgery, respectively, with 69 and 68 undergoing resection and having a valid neoadjuvant rectal score. The mean score (and standard deviation) was 11.53 ± 12.43 (95% confidence interval [CI] = 8.54–14.51) in the pembrolizumab group vs 14.08 ± 13.82 (95% CI = 10.74–17.43) in the control group (P = .26).
Pathologic complete response was achieved in 22 patients (31.9%, 95% CI = 21.2%–44.2%) in the pembrolizumab group vs 20 (29.4%, 95% CI = 19.0%–41.7%) in the control group (P = .75). Clinical complete response rates were 13.9% vs 13.6% (P = .95). The R0 resection rate was 94.0% vs 89.4% (P = .36). Among patients undergoing resection, the sphincter-sparing surgery rate was 59.4% vs 71.0% (P = .15).
Grade 3 or 4 adverse events occurred in 48.2% of patients in the pembrolizumab group vs 37.3% of the control group. Two deaths occurred during FOLFOX administration, with causes consisting of pneumonia in one patient in the pembrolizumab group and sepsis in one patient in the control group. Immune-related adverse events occurred in 43.2% of the pembrolizumab group and were grade 3 in 3.7% (no grade 4 or 5 events).
The investigators concluded, “Pembrolizumab added to chemoradiotherapy as part of total neoadjuvant therapy was suggested to be safe; however, the [neoadjuvant rectal] score difference does not support further study.”
Dr. Rahma, of NRG Oncology and Dana-Farber Cancer Institute, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was supported by grants from the National Cancer Institute and by Merck. For full disclosures of the study authors, visit jamanetwork.com.
