A Study to Investigate the Safety, Pharmacokinetics, and Preliminary Effectiveness of GSK4418959 Alone or in Combination With Other Anti-cancer Agents in Participants With Solid Tumors

Inclusion Criteria:

Parts 1, 2, and 3 inclusion criteria:

• Has a histologically diagnosed advanced (unresectable, metastatic or recurrent)solid tumor

• Has a known dMMR/MSI-H status as determined by a certified local laboratory at thetime of Pre-screening or has an unknown Mismatch repair (MMR)/ MicrosatelliteInstability (MSI) status at the time of Pre-screening and MMR/MSI status will bedetermined by central reference laboratory

• Provides an archival or fresh (preferred) formalin fixed, paraffin embedded (FFPE)sample

• Intends to receive GSK4418959 (alone or in combination with PD-1 inhibitor, asdetermined between Investigator and sponsor) as next line of treatment

• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

• Is expected to have a minimum of 3 months life expectancy

• Has adequate organ function, as defined in the protocol

Parts 1 and 3 inclusion criteria:

• Has histologically diagnosed advanced (unresectable, metastatic or recurrent) solid tumor and has exhausted all standard of care treatment options

Part 2 inclusion criteria:

• Has histologically diagnosed advanced (unresectable, metastatic or recurrent)Colorectal cancer (CRC) or Endometrial cancer (EC)

• Has received at least 1 but no more than 3 lines of systemic anticancer therapy fortheir advanced (unresectable, metastatic or recurrent) disease including at leastone line of Immune checkpoint inhibitors (ICI) therapy

• Has measurable disease (i.e., at least 1 target lesion) during the Screening periodper RECIST 1.1, as determined by the investigator

Exclusion Criteria:

Parts 1, 2, and 3 exclusion criteria:

• Has not recovered (i.e., to Grade ≤1 or to baseline) from prior anticancertherapy-induced AEs

• Has received prior treatment with a WRN inhibitor

• Is unable to swallow and retain orally administered study treatment

• Has symptomatic uncontrolled brain or leptomeningeal metastases

• Has a known additional malignancy that progressed or required active treatmentwithin the last 2 years because reoccurrence of another malignancy would confoundinterpretation by RECIST 1.1 criteria. Exceptions include basal cell carcinoma ofthe skin, squamous cell carcinoma of the skin that has undergone potentiallycurative therapy, or in situ cancer that is considered to be low risk forprogression by the investigator

• Has any impairment of gastrointestinal function or gastrointestinal disease that maysignificantly alter the absorption of study drugs

• Has severe liver fibrosis

• Has cirrhosis or current unstable liver or biliary disease

• Has known hypersensitivity to any of the study interventions or any of theirexcipients

• Has known WRN syndrome

• Has an active autoimmune disease that has required systemic treatment in the past 2years

Part 3 exclusion criteria:

• Has experienced any of the following with prior immunotherapy: any immune mediatedadverse events (imAE) of Grade ≥3, immune-related severe neurologic events of anygrade, exfoliative dermatitis of any grade (Stevens-Johnson Syndrome, toxicepidermal necrolysis, or Drug rash with eosinophilia and systemic signs syndrome [DRESS] syndrome), or myocarditis of any grade. Non-clinically significantlaboratory abnormalities are not exclusionary

• Has any history of interstitial lung disease or pneumonitis