A Study of Modakafusp Alfa (TAK-573) Given by Itself and Together With Pembrolizumab in Adults With Advanced or Metastatic Solid Tumors

Open to people ages 18 years and up

1. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
2. For both the dose escalation and expansion cohort phases of the study, eligible participants must have histologically confirmed advanced (locoregionally recurrent, not amenable to curative therapy) or metastatic solid tumors.
3. Measurable disease per RECIST v1.1. At least 1 target lesion amenable for biopsy is required for enrollment in phase 1b. A minimum of 1 target lesion for response assessment is required for enrollment in phase 2. A separate lesion amenable for biopsy is required for enrollment in phase 2 for cohorts I and II post futility analysis and for all participants (safety lead-in and expansion) with subgroup III melanoma.

4. Phase 1b Dose Escalation: Participants with histologically confirmed advanced locally (locoregionally recurrent, not amenable to curative therapy) or metastatic solid tumors.

   Phase 2 Dose Expansion: The combination cohorts, including participants in the safety-lead phase, will enroll participants with unresectable/metastatic melanoma in the following subgroups: I. Unresectable/metastatic histologically confirmed cutaneous melanoma with primary resistance to no more than 2 prior lines of anti-PD1 containing treatments in the metastatic setting. II. Unresectable/metastatic histologically confirmed cutaneous melanoma with acquired resistance to no more than 2 prior lines of anti-PD1 containing treatments in the metastatic setting. III. Unresectable/metastatic histologically confirmed cutaneous melanoma naive to prior anti-PD1 containing treatments in the metastatic setting.

5. Participants with BRAF V600E mutant melanoma may have received prior BRAF inhibitor therapy.
6. For the expansion cohorts I and II, there is no limitation of total number of prior line(s) of therapy, but the number of prior line(s) containing anti-PD1 must be ≤2 in the metastatic setting.
7. For the expansion cohort III, participants who received an anti-PD-1 treatment in the adjuvant setting must have completed that treatment at least 6 months prior to enrollment and must not have progressed on the anti-PD1 adjuvant treatment.
8. Primary resistance is defined as a best response of PD or SD less than (<) 6 months to an anti-PD1 alone or in combination with other agents (that is, CTLA4) in the initial anti-PD1 containing treatment.
9. Acquired resistance is defined as a progression following a best response of CR, PR or SD>6 months to a prior anti-PD1 alone or in combination with other agents (that is, CTLA4).

1. Persistent toxicity from previous treatments that has not resolved to less than or equal to (<=) CTCAE version 5.0 Grade 1 prior to administration of modakafusp alfa, except for alopecia, Grade 2 neuropathy, and Grade 2 asthenia/fatigue, or autoimmune endocrinopathies with stable replacement therapy.
2. History of any of the following <=6 months before first dose modakafusp alfa: New York Heart Association (NYHA) Grade III or IV congestive heart failure, unstable angina, myocardial infarction, unstable symptomatic ischemic heart disease, any ongoing symptomatic cardiac arrhythmias of Grade >2, pulmonary embolism, or symptomatic cerebrovascular events, or any other serious cardiac condition (example, symptomatic pericardial effusion or restrictive cardiomyopathy). Chronic, stable atrial fibrillation on stable anticoagulant therapy, including low molecular-weight heparin, is allowed.
3. Baseline QT interval with Fridericia's correction (QTcF) greater than (>) 480 millisecond (msec) (Grade >=2), history of congenital long QT syndrome, or torsades de pointes.
4. Patients with acral lentiginous melanoma are excluded in phase 2 except for the safety lead-in phase.
5. Ongoing or active infection.
6. Known history of human immunodeficiency virus (HIV) infection or any other relevant congenital or acquired immunodeficiency. Testing during screening period is required only if indicated by specific local regulations or investigator's criteria.
7. Known hepatitis B (HBV) surface antigen seropositive or detectable hepatitis C infection viral load. Note: Participants with a positive HBV core antibody can be enrolled but must have an undetectable hepatitis B viral load.
8. Autoimmune disease requiring systemic immunosuppressive therapy. Participants with immune mediated endocrine deficiency from previous therapy with stable hormone replacement are exceptions.