ctDNA as marker of response and recurrence in patients with MMR-deficient rectal cancer treated with immunotherapy.

A phase II trial in collaboration with Danish colorectal Cancer Group and MOMA

Background
The principal therapy of patients with resectable rectal patients is surgery. In patients with more advanced tumours (locally advanced rectal cancer) patients are treated with preoperative chemoradiotherapy (or radiotherapy) followed by surgery. In Denmark, around 20% of patients receive preoperative therapy. This combination results in high cure rates but are also associated with significantly morbidity from both surgery as well as radiotherapy which includes incontinence, diarrhea, use of pads, sexual dysfunction as well as chronic pain.

Preoperative chemoradiotherapy results in clearance of tumour tissue (clinical complete response) in around 30% of patients. In these patients, there has been a shift towards an organ-sparring approach (watch&wait strategy without surgery). In these patients achieving clinical complete response, around 30% of patients may experience local recurrence (which may be cured by surgery) and around 10% will experience distant recurrence.

Deficient DNA mismatch repair (dMMR), represents a loss of function of the mismatch repair (MMR) pathway, a DNA repair pathway that plays a key role in maintaining genomic stability, and results in the malignant cell is unable to repair mistakes made during the division process. Roughly 10% of early rectal cancer are dMMR. These patients have a better prognosis compared to patients with proficient MMR, and they do not benefit from adjuvant monotherapy with 5-FU. Recent studies have shown great improvements in the prognosis for these patients when they are treated with immunotherapy in the metastatic setting. Only a few small studies have tested immunotherapy in patients with localized disease, but with previously unseen results in case of pathological complete responses. The aim of the present study is to evaluate the efficacy of ctDNA as marker for response and recurrence when patients with dMMR rectal cancer are treated immunotherapy (nivolumab and ipilimumab).

Material and methods
The study design is a national investigator initiated multicenter phase II trial. Thirty-nine patients with histologically verified resectable rectal cancer stage 1-3 as well as histologically verified dMMR or MSI adenocarcinoma, and no signs of metastatic disease will be included. At baseline, patients will be evaluated by clinical (endoscopy), serological (ctDNA) and radiological examination (MR scan). After informed consent, patients will be treated with one cycle combination immunotherapy of Nivolumab 3 mg/kg days 1 and 15 and Ipilimumab 1 mg/kg day 1. Four weeks after completion of immunotherapy (day 15 + 28 days) patients will be evaluated by clinical (endoscopy with biopsies), serological (ctDNA) and radiological examination (MR scan). In case of clinical complete response, a strategy of “watch&wait” will be discussed with the patient. In patients with major but not complete response a reevaluation after 8 weeks will be offered. In case of a non-complete response or by patient request, the patient will be offered standard curatively intended surgery.

ctDNA will be isolated from the longitudinally collected plasma samples using standard methods and scrutinized for measurable methylation.

Results
The primary endpoint is number of patients with complete clinical and serological response. Secondary endpoints include number of patients without resection and without any sign of recurrence after 12 months, response rate according to MR scan, overall survival, adverse events, and quality of life.

Discussion
The results of this study have the potential to change current treatment guidelines, not only in Denmark, but worldwide. Patients with rectal cancer and dMMR could potentially in the future be offered a highly effective treatment often with few side effects resulting in an organ-sparring approach with maintained quality of life. In addition, the ctDNA follow-up offers the potential to optimize follow-up for patients who are treated with a watch&wait strategy - hopefully to discover a cancer recurrence at an early curative stage and reduce number of worrying follow-up examinations