Dostarlimab may offer an alternative for dMMR rectal cancer

Treatment with dostarlimab resulted in a complete response in all patients with deficient mismatch repair (dMMR) locally advanced rectal cancer who completed therapy. This treatment may avoid chemoradiation and surgery in these patients, which are associated with toxicity and morbidity. Although the durability of response needs to be assessed in long-term follow-up, PD-1 inhibition may become a new paradigm for the treatment of dMMR rectal cancer [1].

“The standard approach for locally advanced rectal cancer is total neoadjuvant therapy, including chemoradiation and total mesorectal excision,” said Dr Melissa Lumish (Memorial Sloan Kettering Cancer Center, NY, USA). “Although patients who display a complete response may be offered non-operative management, targeted strategies for molecular subtypes of rectal cancer may further diminish toxicity and morbidity in these patients.” Dr Lumish added that patients with dMMR rectal cancer have a 25% increased risk of progression on neoadjuvant chemotherapy. “In contrast, these patients are responsive to immune checkpoint inhibitors.” The current, single-arm, phase 2 trial (NCT04165772) aimed to treat 30 patients with dMMR rectal cancer (stage 2 and 3) with the PD-1 inhibitor dostarlimab (500 mg intravenous, every 3 weeks, 9 cycles). If a complete response (CR) did not occur, patients were treated with chemoradiation therapy. Subsequently, they could receive surgery if a CR was still lacking. The primary objective was the overall response rate to dostarlimab.

In total, 16 patients with dMMR rectal cancer had been enrolled at the time of the presentation, 11 of whom had completed anti-PD-1 therapy. Endoscopic CR was observed in 100% of the patients who had completed anti-PD-1 treatment, without chemoradiation and surgery (see Figure). The other 5 patients that had been included had not yet completed treatment. Similarly, radiographic CR was achieved in all 11 patients that had completed therapy. Dr Lumish argued that the observed 100% clinical CR rate demonstrates that PD-1 inhibition may offer a new paradigm for patients with locally advanced dMMR rectal cancer. However, long-term follow-up needs to objectify the durability of response to dostarlimab. These data are in concordance with the NICHE trial in early stage MSI-H colon cancer where neoadjuvant therapy with one course of ipilumumab 1 plus nivolumab 3 before surgery showed 100% major pathologic response [2].

Figure: Endoscopic response from time since dostarlimab treatment initiation [1]

1. Lumish MA, et al. PD-1 Blockade Alone for Mismatch Repair Deficient Locally Advanced Rectal Cancer: Phase 2 Clinical Trial. Abstract 16, ASCO GI 2022, 20–22 January.
2. Chalabi M, et al. Nat Med. 2020 Apr;26(4):566-576.

 

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Posted on 21 March 202217 May 2024