Inclusion Criteria:

        Entry criteria for SCREENING Phase

          1. Histologically confirmed diagnosis of metastatic colorectal cancer.

          2. Documented RAS extended mutations in the archival sample (cohort P only).

          3. ECOG performance status 0-1.

          4. SCREENING phase informed consent signed.

          5. Understanding and accepting the need for undergoing two tumor biopsies if eligible for
             PRIMING Phase.

          6. Age ≥ 18 years.

          7. Availability of all diagnostic FFPE blocks (primary tumor and or metastases), or at
             least 20 slides (primary tumor and/or metastases). Formalin-fixed, paraffin embedded
             (FFPE) tissue blocks are preferred to slides.

          8. Normal organ functions.

        Entry Criteria for PRIMING Phase

          1. Fulfilment of all the SCREENING inclusion criteria;

          2. PRIMING informed consent signed;

          3. Confirming the willingness to undergo two tumor biopsies,

          4. Acceptance that, if the mutational load determination is unfeasible for technical
             reasons (not enough tissue, substandard test performance, etc.), access to TRIAL phase
             will not be possible.

          5. Imaging documented failure of previous standard CRC therapies including
             fluoropyrimidine, oxaliplatin, irinotecan plus or minus antiangiogenics agents
             (Bevacizumab, Aflibercept, Regorafenib, others).

          6. At least one measurable tumor lesion as per RECIST v1.1. Lesions in previously
             irradiated areas or those that have received other loco-regional therapies (i.e.

             percutaneous ablation) should not be considered measurable unless there is clear
             documented evidence of progression of the lesion since therapy. Imaging must be
             performed maximum within 28 days prior to enrolment.

          7. ECOG performance status 0 or 1;

          8. Following results in the SCREENING Phase tests:

               -  Proficient MMR status assessed by IHC or MSI-Low status defined by PCR (Bethesda
                  panel);

               -  Negative score for the MGMT protein expression IHC test;

               -  Positive score for the MGMT promoter methylation performed on Tissue.

          9. Women with childbearing potential should complete a pregnancy test and be willing to
             use highly effective contraceptive methods.

         10. Normal organ functions.

        Entry Criteria for TRIAL Phase

          1. 1. Fulfilment of all the SCREENING inclusion criteria and Deficient MMR status (IHC)
             or MSI-High status (PCR) (cohort D only).

          2. Fulfilment of all the SCREENING and PRIMING inclusion criteria (cohort P only).

          3. TRIAL Phase informed consent signed (both cohorts).

          4. Imaging documented PD to TMZ (cohort P only).

          5. A mutational load value > 20 mutations/MB at TMZ-ML assay (cohort P only).

          6. Imaging documented failure of previous standard CRC therapies including
             fluoropyrimidine, oxaliplatin, irinotecan plus or minus targeted agents (Bevacizumab,
             Aflibercept, Regorafenib, Cetuximab, Panitumumab, others) (cohort D only).

          7. At least one measurable tumor lesion as per RECIST v1.1. Lesions in previously
             irradiated areas or those that have received other loco-regional therapies (i.e.
             percutaneous ablation) should not be considered measurable unless there is clear
             documented evidence of progression of the lesion since therapy. Imaging must be
             performed maximum within 28 days prior to enrolment (both cohorts).

          8. Woman with childbearing potential should complete a pregnancy test and be willing to
             use highly effective contraceptive methods (both cohorts).

          9. Normal organ functions. Blood specimens must be collected within 10 days prior to the
             start of study treatment (both cohorts).

        Exclusion Criteria:

          1. A woman of child bearing potential who has a positive urine pregnancy test within 72
             hours prior to allocation (see Appendix 3). If the urine test is positive or cannot be
             confirmed as negative, a serum pregnancy test will be required.

          2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with
             an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4,
             OX-40, CD137).

          3. Has received prior systemic anti-cancer therapy including investigational agents
             within 4 weeks [could consider shorter interval for kinase inhibitors or other short
             half-life drugs] prior to allocation.

               1. Note: Participants must have recovered from all AEs due to previous therapies to
                  ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.

               2. Note: If participant received major surgery, they must have recovered adequately
                  from the toxicity and/or complications from the intervention prior to starting
                  study treatment.

          4. Has received prior radiotherapy within 2 weeks of start of study treatment (with
             pembrolizumab). Participants must have recovered from all radiation-related
             toxicities, not require corticosteroids, and not have had radiation pneumonitis. A
             1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to
             non-CNS disease.

          5. Has received a live vaccine within 30 days prior to the first dose of study drug.
             Examples of live vaccines include, but are not limited to, the following: measles,
             mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, and typhoid
             vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines
             and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live
             attenuated vaccines and are not allowed.

          6. Is currently participating in or has participated in a study of an investigational
             agent or has used an investigational device within 4 weeks prior to the first dose of
             study treatment.

             a. Note: Participants who have entered the follow-up phase of an investigational study
             may participate as long as it has been 4 weeks after the last dose of the previous
             investigational agent.

          7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
             (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 7 days prior to the first dose of study drug.

          8. Has a known additional malignancy that is progressing or has required active treatment
             within the past 3 years. Note: Participants with basal cell carcinoma of the skin,
             squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma,
             cervical cancer in situ) that have undergone potentially curative therapy are not
             excluded.

          9. Has known active CNS metastases and/or carcinomatous meningitis. Participants with
             previously treated brain metastases may participate provided they are radiological
             stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging
             (note that the repeat imaging should be performed during study screening), clinically
             stable and without requirement of steroid treatment for at least 14 days prior to
             first dose of study treatment.

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

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

         12. Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.

         13. Has a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis.

         14. Has an active infection requiring systemic therapy.

         15. Has a known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is
             required.

         16. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
             reactive) or known active Hepatitis C virus infection. Note: no testing for Hepatitis
             B and Hepatitis C is required unless mandated by local health authority.

         17. Has a known history of active TB (Bacillus Tuberculosis).

         18. Has a 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.

         19. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial

         20. Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the study, starting with the screening visit through 120 days
             after the last dose of trial treatment..