Neoadjuvant pembrolizumab in locally-advanced rectal cancer: primary results

Presented by

Dr Osama Rahma, Dana-Farber Cancer Institute, USA

Conference

ASCO GI 2021

Trial

Phase 2

Patients with locally-advanced rectal cancer (LARC) received total neoadjuvant treatment of FOLFOX and chemoradiation therapy with or without pembrolizumab prior to surgery. Results of the primary endpoint analysis as well as first results of secondary endpoints indicate that pembrolizumab treatment did not result in statistically significantly improved outcomes.

Dr Osama Rahma (Dana-Farber Cancer Institute, USA) presented the first results of the pembrolizumab experimental arm of a phase 2 clinical trial (NCT02921256) using total neoadjuvant therapy in LARC [1]. Total neoadjuvant therapy is an emerging treatment option of LARC in which systemic chemotherapy is added to chemoradiotherapy in order to improve clinical outcome as currently loco-regional relapse rates are still 5-6%, and long-time survival is only 65%. Radiation therapy can lead to immunogenic cell death and tumour antigen release, associated with upregulation of immunogenic surface markers and cytokines, eventually causing expression of PD-L1 in both tumour cells and immune cells. The researchers hypothesised that this immunotherapy resistance could be overcome by combining chemoradiation and anti-PD-1 therapy, and tested novel agents in combination with neoadjuvant FOLFOX, followed by chemoradiation.

Stage 2 or stage 3 LARC patients with one or more of the following conditions were included: distal location [cT3-4 #5cm from anal verge, any N]; bulky [any cT4 or tumour within 3mm of mesorectal fascia]; high risk for metastatic disease [cN2]; or not a sphincter-sparing surgery candidate. The patients were randomised to neoadjuvant FOLFOX + chemoradiation + capecitabine ± pembrolizumab (200 mg IV every 3 weeks x 6 doses; control arm n=95; pembrolizumab arm n=90), followed by surgery 8–12 weeks after the last dose of radiotherapy. The primary endpoint was improvement in the Neoadjuvant Rectal Cancer score (NAR). Key secondary endpoints included complete response, local recurrence, disease-free and overall survival, and toxicity.

The primary endpoint was not met; mean NAR score was 14.08 in the control arm versus 11.53 for the pembrolizumab arm (P=0.26). None of the secondary endpoints reached significance either. The side effects observed with additional pembrolizumab therapy were consistent with both chemoradiotherapy and pembrolizumab safety profile. Grade 3/4 adverse events were slightly increased on the pembrolizumab arm during and after chemoradiotherapy (48.2 vs 37.3%). There were 2 deaths during FOLFOX, one on the control arm due to sepsis, the other on the treatment arm due to pneumonia.

In summary, the additional treatment with pembrolizumab did not lead to statistically significantly increased efficacy in primary as well as available secondary endpoints. Analysis of disease-free and overall survival will be presented in the future. Ongoing analysis of genomic and immune correlatives will further explore the immune resistance mechanisms.

Rahma OE, et al. NRG-GI002: A phase II clinical trial platform using total neoadjuvant therapy (TNT) in locally advanced rectal cancer (LARC)—Pembrolizumab experimental arm (EA) primary results. ASCO Gastrointestinal Cancers Symposium 2021, 15-17 January. Abstract 8.

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