A Study of TAK-981 Given With Pembrolizumab in Participants With Select Advanced or Metastatic Solid Tumors

Inclusion Criteria:

1. Has a histologically or cytologically documented, advanced (metastatic and/orunresectable) cancer as listed below that is incurable: Note: Prior neoadjuvant oradjuvant therapy included in initial treatment may not be considered first- orlater-line standard of care treatment unless such treatments were completed lessthan 12 months prior to the current tumor recurrence. A. Non-squamous NSCLC for which prior standard first-line treatment containing ananti-programmed cell death protein 1/programmed cell death protein 1 ligand (PD-1/PD-L1) checkpoint inhibitor (CPI) alone or in combination has failed and thathas progressed on no more than 1 prior systemic therapy. In Phase 2, participantswith nonsquamous NSCLC must have not received more than 1 prior systemic therapy andmust not have presented with disease progression during the first 6 months oftreatment with first-line CPI/anti-PD-(1/L1)-containing therapy. Note: In Phase 1, participants with nonsquamous NSCLC and known drivermutations/genomic aberrations (e.g., epidermal growth factor receptor (EGFR), B-Rafproto-oncogene mutation V600E [BRAF V600E], and ROS proto-oncogene 1 [ROS1]sensitizing mutations, neurotrophic receptor tyrosine kinase [NRTK] gene fusions,and anaplastic lymphoma kinase [ALK] rearrangements) must have also shownprogressive disease after treatment with a commercially available targeted therapy.In Phase 2, participants with driver mutations are not eligible. B. CPI-naive cervical cancer (squamous cell carcinoma, adenosquamous carcinoma oradenocarcinoma of the cervix) participants for whom prior standard first-linetreatment has failed and who have received no more than 1 prior systemic line oftherapy for recurrent or Stage IVB cervical cancer. Note: The following cervicaltumors are not eligible: minimal deviation/adenoma malignum, gastric-typeadenocarcinoma, clear-cell carcinoma, and mesonephric carcinoma. Histologicconfirmation of the original primary tumor is required via pathology report. Note:First-line treatment must have consisted of platinum-containing doublet.Chemotherapy administered concurrently with primary radiation (e.g., weeklycisplatin) is not counted as a systemic chemotherapy regimen. C. CPI-naïve microsatellite stable-colorectal cancer (MSS-CRC) participants for whomprior standard first-line treatment has failed and who have progressed on no morethan 3 chemotherapy regimens. Note: Participants must have received prior treatment with fluoropyrimidine-,oxaliplatin-, and irinotecan-containing regimens if indicated. D. Unresectable Stage III or Stage IV cutaneous melanoma that has not received priortherapy in the metastatic setting. Note: Participants with acral melanoma are not eligible. Participants who havepresented with disease relapse after ≥6 months of the last dose of CPI orBRAF-mitogen-activated protein kinase kinase (MEK) inhibitor in the adjuvant settingare eligible. E. Squamous NSCLC for which prior standard first-line treatment containing ananti-PD-(1/L1) checkpoint inhibitor alone or in combination has failed. Participantmust have not received more than 1 prior systemic therapy and must not havepresented with disease progression during the first 6 months of treatment withfirst-line CPI/anti-PD-(1/L1)-containing therapy. F. Squamous or nonsquamous NSCLC for which prior standard first-line treatmentcontaining an anti-PD-(1/L1) checkpoint inhibitor alone or in combination has failedwithin 6 months from the initiation of the CPI. Participants must not have receivedmore than 1 prior systemic therapy in the metastatic setting. Note: Participants with driver mutations are not eligible.

2. Has at least 1 radiologically measurable lesion based on RECIST, Version 1.1. Tumorlesions situated in a previously irradiated area are considered measurable ifprogression has been demonstrated in such lesions.

3. Has a performance status of 0 or 1 on the Eastern Cooperative Group Oncology (ECOG)Performance Scale.

4. Has left ventricular ejection fraction (LVEF) ≥40%; as measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan.

5. Has recovered to Grade 1 or baseline from all toxicity associated with previoustherapy or have the toxicity established as sequela. Note: Has a neuropathy ≤Grade 2, any grade alopecia, or autoimmune endocrinopathies with stable replacementtherapy are permitted.

6. Demonstrate adequate organ function as described below:

A. Platelet count ≥75.0 × 10^9/L. B. Absolute neutrophil count (ANC) ≥1.0 × 10^9/L. C. Hemoglobin ≥85 g/L (red blood cell [RBC] transfusion allowed ≥14 days before assessment).

D. Calculated creatinine clearance ≥30 mL/min using the Cockcroft-Gault formula.

E. Aspartate aminotransferase (AST, GOT) and alanine aminotransferase (ALT, GPT) ≤3.0 times the upper limit of normal (ULN), <5.0 times the ULN if liver enzyme elevations are due to liver metastases; bilirubin ≤1.5 times the ULN. Participants with Gilbert's syndrome may have a bilirubin level >1.5 times the ULN, per discussion between the investigator and the medical monitor.

Exclusion Criteria:

1. History of uncontrolled brain metastasis (evidence of progression by imaging over aperiod of 4 weeks and/or neurologic symptoms that have not returned to baseline).Participant with treated brain metastases are allowed provided they areradiologically stable, without evidence of progression for at least 4 weeks byrepeat imaging, clinically stable, and without requirement of steroid treatment forat least 14 days prior to first dose of study treatment. Note: For asymptomaticparticipants, screening brain imaging is not required.

2. Second malignancy within the previous 3 years, except treated basal cell orlocalized squamous skin carcinomas, localized prostate cancer, cervical carcinoma insitu, resected colorectal adenomatous polyps, breast cancer in situ, or othermalignancy for which the participant is not on active anticancer therapy.

3. Major surgery ≤14 days from the first dose of study drug and not recovered fullyfrom any complications from surgery.

4. History of immune-related AEs related to treatment with immune CPIs that requiredtreatment discontinuation.

5. Receiving or requires the continued use of medications that are known to be strongor moderate inhibitors and inducers of cytochrome P-450 (CYP) 3A4/5 and strongP-glycoprotein (Pgp) inhibitors.

6. Baseline prolongation of the QT interval corrected using Fridericia's formula (QTcF) (e.g., repeated demonstration of QTcF interval >480 milliseconds (ms), history ofcongenital long QT syndrome, or torsades de pointes).

7. Has a history of autoimmune disease requiring systemic immunosuppressive therapywith daily doses of prednisone >10 mg/day or equivalent doses, or any other form ofimmunosuppressive therapy. Hormone replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for thyroid, adrenal or pituitaryinsufficiency) for endocrinopathies are not considered prohibited forms of systemictreatment of an autoimmune disease.

8. Has a history of noninfectious pneumonitis that required steroids or a history ofinterstitial lung disease.

9. Has an evidence of active, non-infectious pneumonitis.

10. Has a history of allogeneic tissue or solid organ transplant.

11. Has an active infection requiring systemic therapy.

12. Has a known history of human immunodeficiency virus (HIV) infection or any otherrelevant congenital or acquired immunodeficiency.

13. Has a known hepatitis B virus surface antigen seropositive or detectable hepatitis Cinfection viral load. Note: Participants who have positive hepatitis B core antibodyor hepatitis B surface antigen antibody can be enrolled but must have anundetectable hepatitis B viral load.

14. History of any of the following ≤6 months before first dose: congestive heartfailure New York Heart Association Grade III or IV, unstable angina, myocardialinfarction, unstable symptomatic ischemic heart disease, uncontrolled hypertensiondespite appropriate medical therapy, ongoing symptomatic cardiac arrhythmias >Grade 2, pulmonary embolism or symptomatic cerebrovascular events, or any other seriouscardiac condition (e.g., pericardial effusion or restrictive cardiomyopathy).Chronic atrial fibrillation on stable anticoagulant therapy is allowed.

15. Psychiatric illness/social circumstances that would limit compliance with studyrequirements and substantially increase the risk of AEs or has compromised abilityto provide written informed consent.