Pembrolizumab Plus CRT Combo Found Unbeneficial in LARC

Results from the recent phase II NRG-GI002 trial found the combination of neoadjuvant pembrolizumab with chemoradiotherapy (CRT) after FOLFOX treatment is unbeneficial for patients with locally advanced rectal cancer (LARC). (JAMA Oncol. 2021 Jul 1;7(8):1225-1230).

“We sought to assess whether the addition of pembrolizumab during and after neoadjuvant chemotherapy can lead to an improvement in the neoadjuvant rectal (NAR) score compared to treatment with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) and chemoradiotherapy alone,” wrote Osama Rahma, MD, NRG Oncology, Philadelphia, Pennsylvania, and co-investigators.

The open-label, randomized trial enrolled patients based on clinical tumor and nodal stages. Further, eligibility requirements included stage II or III LARC with distal location (cT3-4≤5 cm from anal verge), bulky disease (any cT4 or tumor within 3 mm of mesorectal fascia), high risk status for metastatic disease, or ineligibility for sphincter-sparing surgery (SSS).

Out of 185 patients, 95 were randomized to the control arm and 95 to the pembrolizumab arm. Further, randomization to neoadjuvant FOLFOX for 4 months was set on a 1:1 basis and CRT (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 prior to surgery.

The primary endpoint was the NAR score. Secondary endpoints were available after definitive surgery and included pathologic complete response (pCR) rate, SSS, disease-free survival (DFS), and overall survival (OS).

Out of all patients, 137 were evaluable for NAR scores, with 68 from the control arm and 69 from the pembrolizumab arm. The mean NAR score was 11.53 (12.43) for pembrolizumab patients (95% CI, 8.54-14.51) versus 14.08 (13.82) for the control arm patients (95% CI, 10.74-17.43) (P=.26). Additionally, the pCRrate was 31.9% in the pembrolizumab arm vs 29.4% in the control arm (P=.75).

Further data show that the clinical complete response rate (CRR) was 13.9% in the pembrolizumab arm vs 13.6% in the control arm (P=.95). Patients who underwent SSS were 59.4% vs 71%, respectively (P=.15).

Notably, grade 3 to 4 adverse events were slightly higher in the pembrolizumab arm (48.2%) vs the control arm (37.3%) during CRT, with 2 deaths occurring during FOLFOX.

“Pembrolizumab added to CRT as part of total neoadjuvant therapy was suggested to be safe; however, the NAR score difference does not support further study,” concluded Dr Rahma et al. – Alexa Stoia