Dostarlimab in rectal cancer

Dostarlimab in rectal cancer

• neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer
  • a subset of rectal cancer is caused by a deficiency in mismatch repair (1)
  • because mismatch repair-deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it has been hypothesized that checkpoint blockade could be effective in patients with mismatch repair-deficient, locally advanced rectal cancer (1)
    
    
  • PD-1 is an inhibitory immune checkpoint receptor expressed on activated T cells
    • through interactions with its ligands, programmed cell death ligands 1 and 2 (PD-L1 and PD-L2), PD-1 suppresses activated effector T-cell functions, including proliferation, cytokine production, and cytotoxic activity
    • upregulation of PD-L1 by tumor cells is one of the mechanisms by which tumor cells can evade the immune system and interfere with cancer-specific immune responses
  • dostarlimab is a humanized, monoclonal antibody (mAb) of the immunoglobulin G (IgG) 4kappa isotype designed to bind to PD-1 and block interaction with its ligands, PD-L1 and PD-L2 (2)
    
    
• a prospective phase 2 study in which single-agent dostarlimab, an anti-PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair-deficient stage II or III rectal adenocarcinoma
  • treatment was to be followed by standard chemoradiotherapy and surgery
  • patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy and surgery
  • primary end points were sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy
  • results:
    • 12 patients completed treatment with dostarlimab and have undergone at least 6 months of follow-up
    • all 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor remaining
  • study authors concluded:
    • mismatch repair-deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade
    • longer follow-up is needed to assess the duration of response

Reference:

• Cerek A et al. PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer. NEJM June 5, 2022 DOI: 10.1056/NEJMoa2201445
• Kumar S, Ghosh S, Sharma G, et al. Preclinical characterization of dostarlimab, a therapeutic anti-PD-1 antibody with potent activity to enhance immune function in in vitro cellular assays and in vivo animal models. MAbs. 2021;13(1):1954136. doi:10.1080/19420862.2021.1954136