Later-line therapies after failure of standard treatments for metastatic colorectal cancer
patients are limited; regorafenib and TAS-102 have shown clinical activity for these
patients, however, efficacy outcomes seemed not to be sufficient although there have been
rather higher frequencies of adverse events.
Mismatch repair (MMR) deficiency or microsatellite instability-high (MSI-H) played a role of
negative predictive factor for adjuvant fluorouracil-based chemotherapy in patients with
resected colorectal cancer. In the metastatic setting, deficient MMR or MSI-H represented
poor prognosis; however, their predictive role has been documented after the pembrolizumab
trial was reported. The results of the pembrolizumab trial demonstrated that the PD-1
blockade with pembrolizumab monotherapy showed 40% of confirmed immune-related objective
response rates in patients with MMR deficient metastatic colorectal cancers; hence there was
no objective response in those with MMR proficient tumors. The progression-free rates at 20
weeks were 78% versus 11%, respectively, also favouring those with MMR deficient tumors.
However, the MMR deficiency of MSI-H is found in only about 5% in patients with metastatic
colorectal cancer, which is too small to expand potential candidate of immunotherapy.
One of the proposed mechanism of promising efficacy from pembrolizumab for MMR deficient
colorectal cancer is that MMR deficient or MSI-H colorectal cancers harbour higher somatic
mutation loads than MMR proficient colorectal cancer (a mean of 1782 somatic mutations per
tumor in the MMR deficient tumors versus 73 in the MMR proficient tumors in the results of
pembrolizumab trial); somatic mutations have the potential to encode non-self immunogenic
antigens; therefore, immunotherapy enhancing immune surveillance produced promising treatment
efficacy in the MMR deficient tumors.
The POLE gene encodes the catalytic subunit of DNA polymerase epsilon, and it involves DNA
repair and chromosomal replication. The POLE mutations are located in the exonuclease domain,
and their presence has already been reported in the various cancers including colorectal and
1. Histologically or cytologically confirmed adenocarcinoma of the colon or the rectum.
2. Mismatch repair deficient or microsatellite instable (defined below), or POLE mutated
tumors A. Mismatch repair deficient: loss of expression by immunohistochemical stains
≥ 1 out of 4 markers (MLH1, MSH2, MSH6, PMS2) B. Microsatellite instable: loss of
stability ≥2 out of 5 gene panels (BAT-25, BAT-26, D2S123, D5S346, D17S250)
3. Refractory to at least one agent of prior treatments(fluoropyrimidines, irinotecan or
oxaliplatin) Progressed after at least first-line systemic chemotherapy for metastatic
setting (progressed within 6 months after completion of adjuvant chemotherapy is also
considered as first-line failure)
4. ≥ 1 measurable lesion(s) by RECIST 1.1.
5. Unresectable advanced or metastatic disease.
6. Age over 20 years old.
7. ECOG performance status of 0-1 or lower.
8. Adequate organ functions. A. Bone marrow function: Hemoglobin 9.0≥ g/dL, ANC≥
1,500/mm3, platelet≥ 100,000/mm3 B. Hepatic functions: bilirubin ≤ 1.5 X ULN, AST/ALT
≤ 2.5 X ULN (≤ 5 X ULN in cases of liver metastasis) C. Renal functions: serum Cr ≤
1.5 X ULN or calculated CCr (Cockcroft) > 40 ml/min
9. Be willing and able to comply with the protocol for the duration of the study.
10. Give written informed consent prior to study-specific screening procedures, with the
understanding that the patient has the right to withdraw the study at any time,
11. Female subjects must either be of non-reproductive potential (≥ 60 years old and no
menses for ≥ 1 year without an alternative medical cause, or history of hysterectomy,
or history of bilateral tubal ligation, or history of bilateral oophorectomy) or must
have a negative serum pregnancy test upon study entry.
12. Women of childbearing potential and men must agree to use adequate contraception since
signing of the IC form until at least 90days after the last study drug administration.
1. Any prior treatment with PD-1 or PD-L1 inhibitor, including durvalumab.
2. Involvement in the planning and/or conduct of the study.
3. Receipt of the last dose of chemotherapy ≤ 28 days prior to the first dose of study
4. Mean QT interval corrected for heart rate (QTc) ≥ 470 msec calculated from 3
electrocardiograms (ECGs) using Frediricia's Correction.
5. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
6. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after
consultation with the Study Physician.
7. Patients with irreversible toxicity not reasonably expected to be exacerbated by
treatment with durvalumab may be included only after consultation with the Study
8. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone
replacement therapy) is acceptable.
9. Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or
systemic corticosteroids at physiologic doses, which are not to exceed 10 mg/day of
prednisolone, or an equivalent corticosteroid.
10. Concurrent or previous history of another primary cancer within 3 years prior to
randomisation except for curatively treated cervical cancer in situ, non-melanomatous
skin cancer, superficial bladder cancer (pTis and pT1) and curatively treated thyroid
cancer of any stage. Concurrent, histologically confirmed, unresected thyroid cancer
without distant metastasis could be allowed with the agreement of the chief principal
11. Uncontrolled CNS metastases; permitted if asymptomatic or neurologically stable.
12. Prior radiation therapy would be permitted, but non-radiated evaluable lesions should
be present at study entry.
13. Radiation therapy during study treatment is not permitted, but if the local
investigator decides that radiation therapy should be given during study treatments,
he should be convinced that there is no evidence of disease progression with agreement
of the chief principal investigator.
14. Congestive heart failure ≥ New York Heart Association (NYHA) class 2.
15. Unstable angina, new-onset angina within 3 months, or history of myocardial infarction
within 6 months before the study entry.
16. Active or prior documented autoimmune disease within the past 2 years; subjects with
vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the
past 2 years) are not excluded.
17. Active or prior documented inflammatory bowel disease.
18. History of prior immunodeficiency.
19. History of allogeneic organ transplantation.
20. History of hypersensitivity to durvalumab or any excipient.
21. History of previous clinical diagnosis of active tuberculosis.
22. Receipt of live attenuated vaccination within 30 days prior to study entry.
23. Known history of testing positive for HIV
24. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive
HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive) Except,
resolved HBV infection (as evidenced by detectable HBV surface antibody, detectable
HBV core antibody, undetectable HBV DNA, and undetectable HBV surface antigen) or
Chronic HBV infection (as evidenced by detectable HBV surface antigen or HBV DNA).
Subjects with chronic HBV infection must have HBV DNA < 100 IU/mL and must be on
25. Major surgery or significant traumatic injury within 28 days prior to study treatment.
26. Non-healing wound, ulcer, or bone fracture.
27. Current evidence of significant gastrointestinal bleeding or (impending) obstruction.
28. Concomitant participation in another clinical trial.
29. Pregnant of breast-feeding subjects. Women of child-bearing potential must have
pregnancy test within 7 days and a negative result must be documented before start of
30. Substance abuse, medical, psychological or social conditions that may interfere with
the subject's participation in the study or evaluation of the study results.