The NEOPRISM-CRC study is a phase II clinical trial. The purpose of the trial is to evaluate the efficacy and safety of pembrolizumab (Study IMP) in patients with high risk Stage 2 or Stage 3 MMR-deficient colorectal cancer stratified with tumour mutation burden status.

Pembrolizumab is a type of immunotherapy that has demonstrated excellent results in clinical trials for patients with advanced colorectal cancer who have certain genetic characteristics (mismatch repair deficiency (MMR-d) / high microsatellite instability (MSI-H)). There are previous studies providing evidence that checkpoint inhibitors when given before surgery have shown better local and systemic anti-tumour responses in melanoma and glioblastoma than surgery alone. The main question the researcher wants to investigate is whether pembrolizumab given prior to having surgery improves pathological complete response rate in advanced colorectal cancer patients with MSI-H or MMR-d. The trial will investigate whether the treatment is safe, and whether it improves the chances of the tumour being removed completely, and whether this delays or prevents the cancer from coming back. The trial will also investigate whether pembrolizumab causes any delay to surgery due to side effects. The trial will also measure post-surgery complications and impact of the treatment on patient's quality of life.

Target recruitment is 32 patients and recruitment is expected to take place over a 24 month period.

Once patients have consented to the NEOPRISM-CRC trial, a trial colonoscopy will be performed and tissue samples taken during the procedure will be shipped to the FoundationOne Medicine testing Laboratory and analysed to determine the TMB (tumour mutation burden) status assessed by the FOUNDATIONONE®CDx (FM1) test. In addition, a PCR (Polymerase Chain reaction) test or Microsatellite testing will be done to confirm the Microsatellite Instability (MSI) status.

Patients will receive one of two pre-operative regimens depending upon their TMB status/MSI status

All patients will have one cycle of pembrolizumab 200 mg IV (a cycle is 21 days). Prior to cycle 2 the FM1 result should be available and patients will continue their treatment as follows:

• If results is TMB-high or medium (or MSI-h if FM1 test is not evaluable): A further two cycles of pembrolizumab 200 mg IV every 21 days and then will proceed to surgery 4 - 6 weeks after last dose of pembrolizumab
• If result is TMB-low (or if FM1 test and MSI result are not evaluable): No further cycles of pembrolizumab; will proceed to surgery 4 - 6 weeks after last dose of pembrolizumab

Following surgery, patients will receive standard of care adjuvant treatment which may include post-operative chemotherapy in accordance with investigators clinical decision. Patients will continue to be followed up according to routine standard of care for a maximum of 5 years after surgery.

Inclusion criteria:

1.     Histologically proven adenocarcinoma of the colon which is MMR-d by IHC or MSI-H by PCR (or microsatellite testing).

2.      ECOG performance status 0-1 and patient eligible for planned curative surgery

a.      Radiological node positive T1-4CRC

 OR

b.    high risk T3defined as EITHER ≥5mm of extramural depth of invasion OR unequivocal EMVI on imaging (regardless of depth)

OR

T4 disease

3.      Patients with rectal cancer are eligible if neoadjuvant chemo-radiotherapy is not required to achieve a R0resection.

4.     Patients with acute colonic obstruction may enter the trial only after obstruction is relieved by a successful defunctioning stoma/stent

5.      Adequate bone marrow function

6.      Adequate renal function

7.      Adequate liver function

8.     Adequate coagulation

9.      Aged ≥18 years

10.  Able and willing to provide written informed consent

11.  Willing to use highly effective contraception for the duration of trial treatment and for 120 days after the last dose of pembrolizumab

Exclusion criteria:

1.     Any patient for whom radiotherapy is advised by the MDT

2.     Strong evidence of distant metastases or peritoneal nodules (M1)

3.     Prior therapy with ananti-PD-1, anti-PD-L1 or anti-PD-L2 agent

4.      Any systemic anti-cancer therapy/investigational agents within 4 weeks prior to registration

5.     Received a live vaccine or live-attenuated vaccine within 30 days prior to registration. Administration of killed vaccines is allowed

6.     Any investigational agents or investigational devices within 4 weeks prior to registration

7.     Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of pembrolizumab

8.     Concurrent/previous malignancy that could compromise assessment of primary or secondary endpoints of the trial

9.     Active CNS metastases and/or carcinomatous meningitis

10.  Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.

11. Previous severe/life-threatening skin adverse reaction with other immune-stimulatory anticancer agents

12. Active autoimmune disease that has required systemic treatment in past 2 years

13.  History of(non-infectious) pneumonitis/interstitial lung disease that required steroids ,or current pneumonitis/interstitial lung disease

14.  Active infection requiring systemic therapy

15.  Known history of HIV

16.  Known hepatitis B or C infection

17.  Known history of active TB (Mycobacterium tuberculosis)

18.  Allogenic tissue/solid organ transplant.

19.  Peritonitis (secondary to perforated tumour)

20.  Has colonic obstruction that has not been defunctioned or stented

21.  History  or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

22. Known psychiatric or substance abuse disorder that would interfere with the patients ability to cooperate with the requirements of the study.

23.  Women who are pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial