Inclusion Criteria:

1. Male or female patients, age ≥18 years 2. Patients with a histological/cytological or radiological diagnosis of HCC (mixed HCC cholangiocarcinoma may be included; patients who are candidates for surgical and non-surgical treatment, as well as those being followed without specific HCC therapy may be included)

Exclusion Criteria:

1. Inability to provide written informed consent

Inclusion Criteria:

• Be willing and able to provide written informed consent/assent for the trial
• Have a diagnosis of a tumor with evidence of genomic instability on Clinical Laboratory Improvement Amendments (CLIA) certified genomic testing, inclusive of mutations in POLE, POLD1 for arm 1 and in BRCA1 and BRCA2 for arm 2; in arm 2, enrollment of breast and ovarian histologies will be limited to a total of 10 patients
• Have advanced cancer (metastatic, recurrent or locally advanced) and measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Be willing to provide archived tumor tissue; tissue from the most obtained core or excisional biopsy of a tumor lesion is preferred; 20 unstained slides are preferred but a minimum of 15 slides will be acceptable; if adequate tissue is not present the patient may consent to a newly obtained biopsy
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
• Absolute neutrophil count (ANC) >= 1,500 /mcL, performed within 10 days of treatment
• Platelets >= 100,000 / mcL, performed within 10 days of treatment
• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment), performed within 10 days of treatment
• Serum creatinine =< 1.5 X upper limit of normal (ULN) OR Measured or calculated creatinine clearance >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]), performed within 10 days of treatment
• Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN, performed within 10 days of treatment
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases, performed within 10 days of treatment
• Albumin >= 2.5 mg/dL, performed within 10 days of treatment
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants, performed within 10 days of treatment
• Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants, performed within 10 days of treatment
• Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
• Male subjects should agree to abstinence or use of an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy

Exclusion Criteria:

• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
• Has a diagnosis of immunodeficiency that requires receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment or has resulted in life threatening episodes previously regardless of current treatment
• Has a known history of active TB (Bacillus tuberculosis)
• Hypersensitivity to pembrolizumab or any of its excipients
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent
• Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study
• Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer, or malignancies that have been inactive for three years or exceptionally indolent; any current diagnosis of second malignancy requires approval from principal investigator and sponsor
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 30 days prior to trial treatment; patients who had oligometastatic disease treated with stereotactic radiation or gamma knife therapy may receive treatment 14 days after therapy as long as they are not requiring steroids; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Has known history of, or any evidence of active, non-infectious pneumonitis
• Has an active infection requiring systemic therapy
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject?s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
• Has received a live vaccine within 30 days of planned start of study therapy
• Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
• Tumors harboring non-hotspot POLE or POLD1 mutations that show clear evidence of microsatellite instability (MSI) will be excluded
• Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)

Inclusion Criteria:

• Cytologically or histologically confirmed solid tumor that is inoperable locally advanced, metastatic, or recurrent.
• Dose-escalation (single-agent and combination therapy): Subjects with a solid tumor that is unresectable or metastatic and for which life-prolonging therapies do not exist or available therapies are intolerable or no longer effective.
• Expansion Cohort A (ccRCC): Subjects with previously treated advanced RCC with clear cell histology (including those with a sarcomatoid component) who have radiographically progressed following treatment with at least one prior systemic anticancer regimen for inoperable locally advanced or metastatic disease.
• Expansion Cohorts B and E (nccRCC): Subjects with previously treated advanced RCC with non-clear cell histology who have radiographically progressed following treatment with at least one prior systemic anticancer regimen for inoperable locally advanced or metastatic disease.
• Expansion Cohorts C and F (HR+ BC): Subjects with breast cancer that is hormone receptor positive (ER+ and/or PR+) and negative for human epidermal growth factor receptor 2 (HER-2) and who have radiographically progressed during or following treatment with at least one prior systemic anticancer regimen for inoperable locally advanced or metastatic disease.
• Expansion Cohorts D and G (mCRPC): Subjects with metastatic CRPC (adenocarcinoma of the prostate). Neuroendocrine differentiation and other features permitted if adenocarcinoma is the primary histology.
• Expansion Cohort H (CRC): Subjects with histologically confirmed unresectable, locally advanced, or metastatic adenocarcinoma of the colon or rectum, KRAS/NRAS wild-type (confirmed via local testing report) and determined NOT to have microsatellite instability high (MSI-high) or mismatch repair deficient (dMMR) by local testing, who received the following standard of care chemotherapy regimens as prior therapy for metastatic CRC:
• Fluoropyrimidine, irinotecan and oxaliplatin, with or without an anti-VEGF monoclonal antibody (bevacizumab)
• Anti-EGFR monoclonal antibody (cetuximab or panitumumab)
• BRAF inhibitor (in combination with cetuximab +/- binimetinib) for subjects with BRAF V600E mutations
• Expansion Cohort I (UC, Maintenance Therapy): Subjects with histologically confirmed, unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra) who received first-line chemotherapy of gemcitabine + cisplatin and/or gemcitabine + carboplatin.
• Expansion Cohort J (UC, ICI-refractory): Subjects with histologically confirmed, unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra) who progressed on or after PD-1/PD-L1 targeting ICI therapy.
• Expansion Cohort K (UC, platinum-refractory): Subjects with histologically confirmed, unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra) who progressed on or after first-line platinum-based combination therapy.
• Expansion Cohorts: Subjects must have measurable disease per RECIST 1.1, with exception of Cohort I (UC, Maintenance Therapy).
• Tumor tissue material:
• Subjects in the non-biomarker cohort provide archival, if available, or fresh tumor tissue if it can be safely obtained.
• Recovery to baseline or ≤ Grade 1 severity (CTCAE v5) from adverse events (AEs), including immune-related adverse events (irAEs), related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
• Adequate organ and marrow function.
• Sexually active fertile subjects and their partners must agree to use highly effective methods of contraception.
• Female subjects of childbearing potential must not be pregnant at screening.

Exclusion Criteria:

• Prior treatment with XL092 (all cohorts), prior treatment with PD-L1/PD-1 targeting immune checkpoint inhibitor (Cohorts E, F, G, H, I, and K only), prior treatment with avelumab (Cohort J only), or prior treatment with regorafenib and/or TAS-102 (Cohort H only).
• Receipt of any type of small molecule kinase inhibitor within 2 weeks before first dose of study treatment.
• Receipt of any type of anticancer antibody, systemic chemotherapy, or hormonal anticancer therapy within 4 weeks before first dose of study treatment.
• Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
• Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment.
• Uncontrolled, significant intercurrent or recent illness.
• Concomitant use of certain medications.
• Corrected QT interval calculated by the Fridericia formula (QTcF) > 450 ms for males and > 470 ms for females. Single ECGs are no longer permitted.
• Pregnant or lactating females.
• Diagnosis of another malignancy within 2 years before first dose of study treatment, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy.

Additional Exclusion Criteria for XL092 + Atezolizumab Combination Therapy Cohorts ONLY:

• Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 2 weeks prior to first dose of study treatment.
• Administration of a live, attenuated vaccine within 30 days before first dose of study treatment.

Additional Exclusion Criteria for XL092 + Avelumab Combination Therapy Cohorts ONLY:

• Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent.
• Administration of a live, attenuated vaccine within 30 days before first dose of study treatment.

Inclusion Criteria:

1. Disease Criteria
• Phase 1, Part 1a: Any histologically or cytologically confirmed solid tumor malignancy that is locally advanced or metastatic and has failed standard therapy, or standard therapy is not curative or available
• Phase 1, Part 1b: Histologically or cytologically confirmed solid tumor malignancy with one of the following tumor histologies: RCC of clear cell histology only, melanoma, squamous cell skin carcinoma, ovarian cancer, non-small cell lung cancer. Patients must have been treated with available standard therapy. Those patients who previously received immunotherapy must have derived benefit from this treatment. Additionally, patients with any of the above histologies in an advanced setting who plan to undergo debulking surgery or oligometastasectomy may be eligible to receive 2 cycles of XTX202 treatment in a "window of opportunity" subcohort".
• Phase 2, Part 2a: Patients with metastatic RCC who have previously been treated with an approved anti-PD-1 and a TKI. Patients must have progressed on treatment with an anti-PD-1 mAb administered either as monotherapy or in combination with other therapies
• Phase 2, Part 2b: Patients with unresectable or metastatic melanoma who have previously been treated with an approved anti-PD-1 and an anti-CTLA4 checkpoint inhibitor 2. ECOG performance status of 0 or 1 3. Adequate organ function 4. Part 1b only patients must be willing to provide fresh tumor biopsies before and after initiation of study treatment.

Exclusion Criteria:

1. Received prior treatment with IL-2 therapy 2. History of clinically significant pulmonary disease 3. History of clinically significant cardiovascular disease 4. Has a diagnosis of immunodeficiency 5. Has an active autoimmune disease that has required systemic treatment in past 2 years, including the use of disease modifying agents, corticosteroids or immunosuppressive drugs 6. Has an active infection requiring systemic therapy within 4 weeks prior to study treatment

Abbreviated Inclusion Criteria:

1. Subject with histological diagnosis of advanced/metastatic cancer 2. Age 18 years or older, is willing and able to provide informed consent 3. Evidence of measurable disease 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 AND life expectancy of at least 12 weeks

Abbreviated Exclusion Criteria:

1. History of allergy or hypersensitivity to study treatment components. Subjects with a history of severe hypersensitivity reaction to any monoclonal antibody 2. Use of an investigational agent within 28 days prior to the first dose of study treatment and throughout the study 3. Receiving high-dose systemic steroid therapy or any other form of immunosuppressive therapy 4. History of severe autoimmune disease 5. Uncontrolled intercurrent illness or other active malignancy requiring ongoing treatment

Major Inclusion Criteria

Participants are eligible to be included in the study only if all of the following criteria apply: 1. Participate voluntarily, sign informed consent, and follow the study treatment plan and scheduled visits; 2. Phase I: Patients with histologically or cytologically confirmed unresectable or metastatic advanced malignant solid tumors who have progressed under standard treatment or recurred after or were intolerant to all standard treatment regimens, or have no standard treatment available; 3. Phase II: patients with histologically or cytologically confirmed unresectable or metastatic urothelial carcinoma or cholangiocarcinoma, who have progressed or recurred after or were intolerant to first-line chemotherapy, or have progressed/relapsed within 12 months after neoadjuvant /adjuvant chemotherapy; 4. Phase II: Existing test reports have confirmed the FGFR gene alteration or the central laboratory has detected the FGFR gene alteration. 5. Age ≥18 years old; 6. At least one measurable lesion according to the Response Evaluation Criteria of Solid Tumor, version 1.1 (RECIST 1.1); 7. ECOG performance status of 0-1; 8. Life expectancy for more than 3 months; Must have adequate organ function Major

Exclusion Criteria

Participants are excluded from the study if any of the following criteria apply: 1. Have previously been treated with selective pan-FGFR molecular inhibitors or antibody drugs, except for the FGFR4 selective inhibitors; 2. Within 2 weeks before the first dose of study drug, the subject's phosphate level continuing to exceed the ULN despite medical treatment; 3. Patients with clinically significant gastrointestinal dysfunction 4. Has known central nervous system metastases; 5. Has a history of or currently uncontrolled cardiovascular diseases 6. History of organ transplantation or a history of allogeneic hematopoietic stem cell transplantation; 7. Current evidence of corneal or retinal abnormalities that may increase eye toxicity; 8. Active hepatitis B virus active hepatitis C, or HIV infection; 9. Has not recovered from reversible toxicity of prior anti-tumor therapy 10. Pregnant or lactating women, as well as women with childbearing potential who are unwilling or unable to perform contraception from the screening to 6 months after the last study drug administration; and fertile men who are unwilling or unable to perform contraception from screening to 3months after the last study drug administration 11. Other conditions considered by the investigator to be inappropriate for participation in this study. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Inclusion Criteria:

1. Male 18 years or older able to understand and provide signed written informed consent. 2. Histologically or pathologically confirmed prostate adenocarcinoma without predominant small cell component. 3. Progressive disease by one or more of the following criteria: 1. Serum/plasma PSA progression defined as 2 consecutive increases in PSA over a previous reference value measured at least 1 week apart with a minimum start value of >2 ng/mL. 2. Progression of measurable disease (RECIST 1.1) or presence of at least two new bone lesions (PCWG3 criteria). 4. Previous treatment with next-generation androgen receptor (AR)-directed therapy (e.g. abiraterone, enzalutamide, apalutamide, darolutamide). 1. Must have received no more than one previous AR-directed therapy. 2. Must have been administered ARAT (abiraterone, enzalutamide, darolutamide, or apalutamide) in the castration-sensitive or castration-resistant setting. 3. Must have progressed while on ARAT. 5. PSMA-PET scan (e.g., 68Ga-PSMA-11 or 18F-DCFPyL) positive as determined by central reader. 6. Effective castration with serum testosterone level of <50 ng/dL and plan to continue with chronic medical or surgical castration. 7. Ability to attend required study visits and return for adequate follow-up, as required by this protocol. 8. Patients with HIV that are healthy and with a low risk of acquired immune deficiency syndrome related outcomes may participate in the trial at the investigators' discretion. 9. Patients with HBV and HCV may also participate if symptoms are sufficiently managed. 10. Life expectancy of at least 6 months as assessed by investigator. 11. Willing to initiate ARAT therapy determined by investigator. 12. For patients who have partners of childbearing potential: The patient and/or partner must use a method of birth control with adequate barrier protection, deemed acceptable by the principal investigator during the study and for 6 months after the last study drug administration.

Exclusion Criteria:

1. Prior treatment with radioligand therapy including other lutetium-labeled compounds. 2. Prior treatment with radium-223 (Xofigo) within the past 12 weeks. 3. Prior chemotherapy treatment for castration-resistant prostate cancer. Prior docetaxel use in the hormone-sensitive setting is permitted, as long as no more than 6 doses were received, the last dose was administered >1 year prior to consent, and disease progression did not occur during docetaxel treatment. 4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥ 2 5. Patients with known HRR gene-mutation who have not been previously treated with olaparib or rucaparib. 6. Other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, or investigational therapy. 7. Inadequate organ and bone marrow function as evidenced by: 1. Hemoglobin < 8 g/dL. 2. Absolute neutrophil count < 1.5 x 109/L. 3. Platelet count < 100 x 109/L. 4. AST/SGOT and/or ALT/SGPT > 3.0 x ULN. 5. Total bilirubin > 2 x ULN unless patient has known Gilbert's syndrome and then may be 3 x ULN. 6. Creatinine clearance (CrCl) < 50 mL/min based on the Cockcroft-Gault equation. 7. Albumin ≤ 2.75 g/dL 8. Patients who undergo a transfusion for the sole purpose of meeting eligibility for this trial will be excluded. 9. Assessment by the Investigator as unable or unwilling to comply with the requirements of the protocol. 10. Use of an investigational therapeutic drug within the last 4 weeks prior to start of study treatment or scheduled to receive one during the study period. 11. Known CNS metastasis unless received therapy, asymptomatic and neurologically stable. 12. Patients receiving zoledronic acid for bone-targeted therapy must be on stable dose for 4 weeks prior to randomization. 13. Major surgery within 30 days of randomization as determined by the Investigator. 14. Patients with active significant cardiac disease defined by any of the following: 1. New York Heart Association class 3 or 4 congestive heart failure within 6 months of signing the ICF unless treated with improvement. 2. Current diagnosis of electrocardiogram abnormalities with significant cardiac arrhythmias 3. History of long QT syndrome or know history of Torsades de Pointe 4. History of myocardial infarction, angina pectoris, or coronary artery bypass graft within 6 months of ICF signature 15. Participants with symptomatic cord compression or clinical/radiological findings indicating impending spinal cord compression 16. Patients with a superscan seen on baseline bone scan as determined by investigator. 17. Active malignancy other than low-grade non-muscle-invasive bladder cancer and non-melanoma skin cancer 18. Previous use of G-CSF for persistent neutropenia after standard of care treatment. 19. Participants who have a pregnant partner or are capable of fathering a child and who are unwilling to take precautions to prevent potential harm to the fetus or prevent pregnancy. 20. Participants with active Covid19. Recovered patients may be included when completely recovered (no symptoms at least 28 days before study medication and a negative Covid test within 72 hours).

The main inclusion and exclusion criteria include but are not limited to the following:

Inclusion Criteria:

• Has a histologically or cytologically confirmed diagnosis of RCC with clear cell component per American Joint Committee on Cancer (AJCC) (8th Edition), with or without sarcomatoid features
• Has intermediate-high risk, high risk, or M1 no evidence of disease (NED) RCC as defined by the following pathological tumor-node metastasis and tumor grading: 1. Intermediate-high risk RCC: pT2, Grade 4 or sarcomatoid, N0, M0; pT3, any grade, N0, M0 2. High risk RCC: pT4, any Grade N0, M0; pT any stage, any Grade, N+, M0 3. M1 NED RCC participants who present not only with the primary kidney tumor but also solid, isolated, soft tissue metastases that can be completely resected at one of the following: the time of nephrectomy (synchronous) or, ≤2 years from nephrectomy (metachronous)
• Has undergone complete resection of the primary tumor (partial or radical nephrectomy) and complete resection of solid, isolated, soft tissue metastatic lesion(s) in M1 NED participants
• Must have undergone a nephrectomy and/or metastasectomy ≤12 weeks prior to randomization
• Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 10 days before randomization.
• Male participants must agree to continue contraception at least 7 days after the last dose of belzutifan/placebo
• Female participants of childbearing potential must be willing to use an adequate method of contraception, for the course of the study through 120 days after the last dose of pembrolizumab or at least 30 days after last dose of belzutifan/placebo, whichever occurs last
• Has adequate organ function

Exclusion Criteria:

• Has had a major surgery, other than nephrectomy plus resection of preexisting metastases for M1 NED participants, within 4 weeks prior to randomization
• Has a pulse oximeter reading <92% at rest, requires intermittent supplemental oxygen, or requires chronic supplemental oxygen
• Has clinically significant cardiovascular disease within 6 months from first dose of study intervention
• Has other clinically significant disorders such as: serious active nonhealing wound/ulcer/bone fracture; requirement for hemodialysis or peritoneal dialysis
• Has preexisting brain or bone metastatic lesions
• Has received prior systemic therapy for RCC
• Has received prior radiotherapy for RCC
• Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention; administration of killed vaccines are allowed
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
• Has a known additional malignancy (other than RCC treated with nephrectomy and/or metastasectomy) that is progressing or has required active treatment within the past 3 years
• Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs); replacement therapy is allowed
• Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
• Has an active infection, requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection, a known history of Hepatitis B or known active Hepatitis C virus infection
• Has had an allogenic tissue/solid organ transplant

Inclusion Criteria:

• Treated on the parent pembrolizumab studies established by the Sponsor as MK-3475-587 ready
• Currently receiving pembrolizumab or in a follow-up phase Additional eligibility criteria for participants who enter Second Course Phase once they are enrolled on MK-3475-587:
• Has not received any anticancer systemic treatment since the last dose of pembrolizumab or a pembrolizumab-based combination in First Course Phase
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Demonstrates adequate organ function
• Have resolution of any toxic effect(s) of First Course Phase trial treatment with pembrolizumab or a pembrolizumab-based combination to Grade 1 or less (except alopecia) before trial treatment in Second Course Phase is started. If participant received major surgery or radiation therapy of >30 Gray (Gy), they must have recovered from the toxicity and/or complications of the intervention.
• A female participant is eligible to enroll if she is not pregnant, not breastfeeding, and ≥1 of the following conditions applies: A woman of childbearing potential (WOCBP) who agrees to use contraception during the study treatment period and for ≥120 days (corresponding to time needed to eliminate any study combination treatment(s) plus 30 days (a menstruation cycle) for study treatments with risk of genotoxicity.

Exclusion Criteria:

• There are no exclusion criteria to participate in MK-3475-587. Participants are excluded from entering Second Course trial treatment once they are enrolled on MK-3475-587 if any of the following criteria applies:
• Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients
• Has received a live vaccine within 30 days prior to the first dose of Second Course Phase trial treatment
• Has a 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 to the Cycle 1 Day 1 of Second Course Phase
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include early stage cancers (carcinoma in situ or Stage 1) treated with curative intent, melanoma (non-ulcerated, thin primary), basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, or in situ breast cancer that has undergone potentially curative therapy.
• Has known active central nervous system metastases and/or carcinomatous meningitis
• Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis. Note: Participants that experienced pneumonitis during First Course that did not meet the criteria for permanent discontinuation are eligible.
• Non-small cell lung cancer (NSCLC) participants only: Has interstitial lung disease
• Has an active infection requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection.
• Has a known history of or is positive for hepatitis B or hepatitis C. For parent studies where inclusion of participants with hepatitis was permitted, MK-3475-587 will follow the parent study eligibility criteria for hepatitis.
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the Second Course Phase eligibility Visit through 120 days after the last dose of study treatment.
• Has severe cardiovascular disease, i.e., arrhythmias, requiring chronic treatment, congestive heart failure (New York Heart Association Class III or IV) or symptomatic ischemic heart disease.
• Has hepatic decompensation (Child-Pugh score >6 [class B and C])
• Has uncontrolled thyroid dysfunction
• Has uncontrolled diabetes mellitus
• Has had an allogeneic tissue/solid organ transplant
• Has a known history of active tuberculosis (TB; Bacillus tuberculosis)

Patients will be eligible for the study if they meet all of the following inclusion criteria and none of the exclusion criteria.

Inclusion criteria

1. Written informed consent from the patient or their legally authorized representative (LAR) prior to any study-related procedure, and willing and able to comply with the protocol and aware of the investigational nature of this study. 2. At least 18 years of age. 3. KPS score of ≥ 60 4. A confirmed GBM diagnosis must be based on local review of tumor tissue from the initial biopsy, surgery, or re-resection. A formal pathology report confirming GBM is acceptable. It is not a requirement for slides to be sent to a central reviewer. 5. Recurrent or progressive GBM as evaluated by central review applying RANO criteria on contrast MRI scans of the Baseline/Screening MRI scan obtained up to six weeks prior to C1D1 and a historical scan taken before the Baseline/Screening scan that meets at least 1 of the following criteria: 1. In the case of measurable disease, progression will be documented by ≥ 25% increase in the sum of the perpendicular diameter products (SPDPs) of the measurable contrast-enhancing (target) lesions or any new measurable lesions. 2. If the SPDPs cannot be reliably estimated due to the lesion's complex conspicuity, shape, and contrast enhancement pattern, the volume of all measurable and non-measurable lesions may be used instead, applying the same threshold (≥ 25% increase) to confirm disease progression. 3. In the case of non-measurable lesions in the historical scan, any transformation into measurable lesions (≥10 mm in both maximum perpendicular diameters) in the Baseline/Screening scan will be evidence of progression. 4. If there are only non-measurable (non-target) lesions in the Baseline/Screening scan, additional lesions/sites will be considered evidence of progression based on the historical scan. Patients with new cerebrospinal fluid (CSF) seeding will not be considered eligible. 5. If historical scans are unavailable, a radiology report of a scan taken before the Baseline/Screening scan documenting the SPDPs from a previous scan of the enhancing disease or its volume can be used by the central reviewer to assess eligibility if it demonstrates the quality standards and acquisition guidelines required. 6. If the scan obtained during standard of care (prior to initiation of formal clinical screening and patient enrollment) is being used as the Baseline/Screening scan and does not entirely conform to central reader quality standards and acquisition guidelines (ie, artifacts or missing sequences), this can be used for the purpose of inclusion if the central reader in discussion with the sponsor and PI agree it provides evidence based on standard clinical practices of recurrence or progression. 7. Patients at first progression who are treated by re-resection or biopsy to confirm progression do not require measurable disease at their post-operative screening scan as their Baseline/Screening scan. These patients must be medically stable after the procedure as assessed by the PI and have the Baseline/Screening scan available by 7 days before starting treatment. 6. The tumor is localized supratentorially with no leptomeningeal (local or distant), spinal or CSF metastases, and no ventricular invasion (explicit documentation of the disease progression that would be problematic in evaluating the efficacy of this drug). 7. O[6] methylguanine-DNA methyltransferase (MGMT) methylation status must be available; results of routinely used methods for MGMT methylation testing (eg, methylation-specific polymerase chain reaction or quantitative polymerase chain reaction) are acceptable. 8. No more than 1 prior line of treatment (eg, surgery followed by radiation with concomitant chemotherapy, followed by adjuvant chemotherapy is considered as 1 line of treatment). In addition, treatment with tumor treating fields (TTFields; Optune) is acceptable if provided as first line therapy prior to progression or recurrence of disease. 9. A second debulking surgery, additional radiation or gamma knife surgery during the first line treatment or after progression, and for which the investigator does not suspect pseudoprogression is acceptable, as long as no chemotherapy or immunotherapy has been provided. 10. Recovery from toxicity/side effects of all prior therapy to Grade 1 or less, subject to the investigator's discretion, except for alopecia; the following time intervals from previous treatments are required to be eligible: 1. 12 weeks from the completion of radiation (to reduce risk of pseudoprogression), unless progression is confirmed by biopsy 2. 4 weeks from the end of any previous of chemotherapy 3. 2 weeks from tumor biopsy if wound completely healed 4. 4 weeks from any major surgery (maximal debulking surgery, either gross total resection or partial resection), gamma knife surgery or significant traumatic injury. Any surgery incisions or wounds must be completely healed 11. A stable or decreasing dose of corticosteroids (or none) for brain edema for at least 5 days prior to baseline MRI and enrollment in the study to document disease progression such that changes in the MRI are not related to the use of corticosteroids. 12. Eligible for chemotherapy based on adequate bone marrow function and organ function within 2 weeks of study treatment as defined by the following laboratory guidelines, subject to the investigator's discretion: 1. Hematopoietic function: total white blood cell (WBC) count ≥3 × 103/µL, absolute neutrophil count (ANC) ≥1.5 × 10³/µL, platelet count ≥75 × 10³/µL, hemoglobin ≥10 g/dL 2. Hepatic function: bilirubin ≤1.5 × × the upper limit of normal (ULN) (excluding Gilberts Syndrome, for which bilirubin must be ≤4 × ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <3 × ULN, and alkaline phosphatase ≤2.5 × ULN 3. Renal function: serum creatinine ≤1.5 × ULN or for patients with creatinine levels above the ULN, estimated creatinine clearance of ≥60 mL/min, calculated using the Cockcroft-Gault equation35 4. Activated partial thromboplastin time (aPTT) ≤1.5 × ULN 13. Women of childbearing potential must agree to practice a highly effective method of contraception beginning at least 28 days before the start of treatment until at least 6.25 months after the last dose of study drug. Male study patients and their female sexual partners of childbearing potential must agree to practice a highly effective method of contraception starting from the time of informed consent until at least 3.5 months (no less than 104 days) after the last dose of study drug. 1. A woman of childbearing potential is defined as a woman who is not permanently sterilized or postmenopausal. Postmenopausal is defined as 12 months with no menses without an alternative medical cause. 2. Women of childbearing potential must have a negative serum or urine pregnancy test at Screening. 3. A highly effective method of birth control is defined as one which results in a low failure rate (ie, less than 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence, or vasectomized partner. For patients using a hormonal contraceptive method, information regarding all medications being administered to the patient and their potential effects on the contraceptive should be addressed. 14. Patients with prior malignancies must be disease-free for ≥5 years. Curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder; or prostate cancer as well as benign tumors that will not interfere with the treatment plan at the time of screening are allowed.

Exclusion Criteria

1. Unable or not willing to comply with the protocol regulations. 2. Any additional chemotherapy (including but not limited to TMZ or immunotherapy) for recurrent or progressive GBM after a first line treatment. 3. Prior treatment with bevacizumab. 4. Prior treatment with lomustine. 5. Known to have an IDH mutation prior to enrollment 6. Screening/Baseline MRI showing a mass effect defined as significant compression of the ventricular system and/or a midline shift with associated clinical symptoms deemed inappropriate for the patient to enter a clinical trial. If there is otherwise asymptomatic compression and/or midline shift and the patient fulfills all other criteria, these patients are considered eligible. 7. Any condition (medical, social, psychological) that would prevent adequate information and follow-up, including but not limited to clinically relevant psychiatric disorders, legal incapacity, dementia, adults protected by law or altered mental status. 8. Presence of poorly controlled seizures, defined as occurring despite SOC or requiring hospitalization. 9. Prior anthracycline cumulative dose more than 550 mg/m2. 10. Heart disease: 1. LVEF <50% 2. Unstable angina 3. CHF with New York Heart Association (NYHA) classification of 3 or 4 4. Patients with baseline QT/QTc interval >480 msec, a history of additional risk factors for torsades de pointes (TdP) (eg, heart failure, hypokalemia, family history of long QT syndrome) and using concomitant medications that significantly prolong the QT/QTc interval 5. History of myocardial infarction within 12 months of enrollment 6. Severe arrhythmia not controlled by medication 11. Uncontrolled hypertension (systolic blood pressure [BP] >150 mmHg and/or diastolic BP >100 mmHg) sustained over 2 measurements. 12. Known to be positive for hepatitis B virus surface antigen (HBsAg), hepatitis C virus (HCV), human immunodeficiency virus (HIV), COVID-19 (currently positive at time of screening), or any other acute viral, bacterial, or fungal infection (testing not required unless symptomatic or suspected disease). 13. Patients with any other uncontrolled intercurrent medical conditions, including but not limited to diabetes mellitus or chronic obstructive pulmonary disease that have not been well controlled by medical management over the prior 3 months are ineligible unless approved by the sponsor. 14. Women who are lactating or breastfeeding