This study will be conducted in adult participants diagnosed with any form of an advanced or progressive MSS CRC for which 1st and 2nd line standard therapy (at least one of which contained fluorouracil) is no longer effective or is intolerable. This is a phase 1b, multi-center, open label study designed to assess safety and tolerability of grapiprant in combination with pembrolizumab, to determine the recommended phase 2 dose (RP2D) with pembrolizumab, and to evaluate and characterize the PK of grapiprant alone and in combination with pembrolizumab. Disease response, pharmacodynamics, and response biomarkers will also be assessed.

Key Inclusion Criteria:

• Male and female adult patients 18 years of age or older on day of signing informed consent.
• Patients must have a histologically confirmed advanced, metastatic, or progressive Microsatellite Stable (MSS) Colorectal Cancer (CRC) per institutional standards.
• Patient has received at least two prior lines of therapy for advanced or metastatic CRC, at least one of which included fluorouracil.
• Highly effective birth control.
• Measurable disease.
• Accessible tumor that can be safely accessed for multiple core biopsies and patient is willing to provide tissue from newly obtain biopsies before and during treatment.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Adequate organ function.
• Able to swallow and absorb oral tablets.

Key Exclusion Criteria:

• 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
• Current use of NSAIDs, COX-2 inhibitors and aspirin products within 3 days (preferably 7 days) before treatment initiation or at anytime during the study unless used for management of AE.
• History of severe hypersensitivity reactions to chimeric or humanized antibodies
• Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to treatment, or 5 half-lives, whichever is shorter.
• 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 the first dose of study drug.
• Known additional malignancy that is progressing or has required active treatment within the past 3 years.
• Known active CNS metastases and/or carcinomatous meningitis.
• Active autoimmune disease that has required systemic treatment in past 2 years.
• History of non-infectious pneumonitis that required steroids or has current pneumonitis.
• Active infection requiring systemic therapy.
• Recent (within the last 12 months) or current GI ulcer, colitis or non-immune colitis.
• Known history of human immunodeficiency virus (HIV) infection, Hepatitis B, or active Hepatitis C virus infection.
• Clinically significant (i.e. active) cardiovascular disease
• Allogeneic tissue/solid organ transplant
• Medical conditions requiring concomitant administration of strong CYP3A4 or P glycoprotein inhibitors or inducers.