The addition of pembrolizumab to chemoradiotherapy as part of total neoadjuvant therapy was considered safe but failed to show improvement in the mean neoadjuvant rectal (NAR) score in patients with locally advanced rectal cancer (LARC), according to research published in JAMA Oncology.

The mainstay of treatment for LARC involves chemotherapy, chemoradiotherapy, and surgery. Although total neoadjuvant therapy is frequently used to decrease locoregional relapse, more than one-third of patients develop recurrent metastatic disease, the study authors stated.

In the prospective, open-label, phase 2 randomized NRG-GI002 trial ( Identifier: NCT02921256), researchers sought to determine whether adding pembrolizumab during and after neoadjuvant chemoradiotherapy would improve the NAR score compared with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) treatment and chemoradiotherapy alone among patients with LARC.

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The study enrolled a total of 185 patients in academic and private practice settings and included those with stage II/III LARC with distal location, those with bulky disease, those at high risk for metastatic disease, and/or those who were not candidates for sphincter-sparing surgery (SSS).

The participants were randomly assigned 1:1 to receive neoadjuvant FOLFOX for 4 months followed by chemoradiotherapy consisting of capecitabine plus a total radiation dose of 50.4 Gy with pembrolizumab (90 patients; pembrolizumab group) or without pembrolizumab (95 patients; control group). Of the 185 patients, 137 were evaluable for the NAR score, with 68 patients in the control group and 69 patients in the pembrolizumab group.

The mean NAR score was 11.53 (standard deviation [SD], 12.43) in the pembrolizumab group (95% CI, 8.54-14.51) and 14.08 (SD, 13.82) in the control group (95% CI, 10.74-17.43); the difference in the NAR scores between the 2 groups was statistically insignificant (P =.26).

Patients (31.9%) in the pembrolizumab group had a slightly higher pathologic complete response rate than the control group (29.4%), but it did not reach statistical significance (P =.75). The clinical complete response rates in the pembrolizumab and control groups were 13.9% and 13.6%, respectively (P =.95). Among patients who underwent tumor resection, the rate of SSS was lower in the pembrolizumab group (59.4%) than in the control group (71.0%; P =.15).

Grade 3 to 4 adverse events (AEs) occurred at a slightly higher frequency in the pembrolizumab group (48.2%) than in the control group (37.3%) during and after chemoradiotherapy. Immune-related AEs occurred in 43.2% of the patients in the pembrolizumab group, which was consistent with the pembrolizumab safety profile. There were 2 deaths reported during FOLFOX treatment: 1 from pneumonia in the pembrolizumab group and 1 from sepsis in the control group.

Overall, “The results do not support combining neoadjuvant pembrolizumab with chemoradiotherapy after FOLFOX treatment of [LARC],” the authors reported.

Disclosure: This research was supported by Merck. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Rahma OE, Yothers G, Hong TS, et al. Use of total neoadjuvant therapy for locally advanced rectal cancer: Initial results from the pembrolizumab arm of a Phase 2 randomized clinical trial. JAMA Oncol. Published online July 1, 2021. doi:10.1001/jamaoncol.2021.1683