This is a Phase 1a/1b, dose-escalation/expansion, consecutive-cohort, open-label study to evaluate the safety, tolerability, PK, PD, and preliminary evidence of antitumor activity of PLN-101095 in combination with pembrolizumab (the study treatment regimen) in adult participants with advanced or metastatic solid tumors for which pembrolizumab is indicated but have documented disease progression (refractory [primary resistance]) or relapsed [secondary resistance]) after at least 3 months from the start of treatment with pembrolizumab.

The study will consist of 2 main parts:

• Part 1: Consecutive dose-escalation cohorts using a Bayesian optimal interval (BOIN) dose escalation design with accelerated titration
• Part 2: Dose-expansion cohorts using Simon's 2-stage design

Inclusion Criteria:

1. Has histologically or cytologically confirmed advanced or metastatic solid tumor
2. Have received ≥12 weeks of continuous anti-PD-1 or anti-PD-L1 treatment administered as monotherapy or in combination with other anticancer therapies
3. Have demonstrated documented prior clinical benefit, defined as CR or PR at any time during treatment, or SD lasting ≥6 months (Part 2 only)
4. Must have subsequently developed radiographic disease progression while receiving anti-PD-1 or anti-PD-L1 treatment or within ≤12 weeks after the last dose of such treatment
5. At least 1 measurable lesion, as defined by RECIST v1.1
6. Estimated survival of ≥3 months
7. Have adequate bone marrow and organ function.
8. A female participant is eligible to participate if she is not pregnant, not breastfeeding

Exclusion Criteria:

1. Any immune-related medical conditions that would put participants at greater risk when receiving pembrolizumab
2. Has a known additional malignancy that is progressing or has required active treatment within the past 2 years
3. Has received prior radiotherapy within 2 weeks for palliative bone-directed therapy and 4 weeks for all other radiotherapy
4. Has undergone major surgery within 4 weeks prior to the first dose of study treatment or has not adequately recovered from surgery or related complications
5. Has a diagnosis of immunodeficiency or use of systemic steroids >10 mg/day
6. Has an active autoimmune disease that has required systemic treatment in the past 2 years
7. Has known active CNS metastases (brain and/or leptomeningeal metastases)
8. Has significant cardiac disease
9. Has an active infection requiring systemic therapy (including uncontrolled HIV, Hepatitis B and C)
10. Has received a live or live-attenuated vaccine within 30 days or a non-live vaccine within 7 days prior to the first dose of PLN-101095