What criteria make a patient with advanced or metastatic cancer, such as melanoma, non-small cell lung cancer, or renal cell carcinoma, a candidate for treatment with checkpoint inhibitors like pembrolizumab (pembrolizumab), nivolumab (nivolumab), or ipilimumab (ipilimumab)?

Candidacy for Checkpoint Inhibitors

Patients with advanced or metastatic solid tumors—particularly melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), urothelial carcinoma, and microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) cancers—are candidates for checkpoint inhibitors when they have adequate performance status (ECOG 0-2), no active autoimmune disease requiring immunosuppression, and disease that has progressed on or after standard therapies (or as first-line in specific contexts). 1, 2

FDA-Approved Indications by Cancer Type

Melanoma

• Unresectable or metastatic melanoma in treatment-naïve patients: nivolumab, pembrolizumab, or ipilimumab/nivolumab combination are approved 1, 2
• Adjuvant therapy for completely resected Stage IIB, IIC, III, or IV melanoma in patients ≥12 years: nivolumab and pembrolizumab are approved 1, 2
• Patients do NOT require PD-L1 testing for melanoma, as checkpoint inhibitors are effective regardless of PD-L1 status 3

Non-Small Cell Lung Cancer

• First-line metastatic NSCLC with PD-L1 ≥1% and no EGFR/ALK alterations: nivolumab plus ipilimumab 1
• First-line metastatic NSCLC with PD-L1 ≥50% and no EGFR/ALK alterations: pembrolizumab monotherapy 2
• Second-line metastatic NSCLC after platinum-based chemotherapy: nivolumab (category 1), pembrolizumab (category 1 if PD-L1 ≥1%), or atezolizumab (category 1) 4
• Patients with EGFR or ALK genomic alterations must have disease progression on FDA-approved targeted therapy before receiving checkpoint inhibitors 1, 2

Renal Cell Carcinoma

• First-line intermediate or poor-risk advanced RCC: nivolumab plus ipilimumab or nivolumab plus cabozantinib 1
• Second-line advanced RCC after prior anti-angiogenic therapy: nivolumab monotherapy 1

Colorectal Cancer

• MSI-H or dMMR metastatic colorectal cancer that has progressed after fluoropyrimidine, oxaliplatin, and irinotecan: pembrolizumab or nivolumab (with or without ipilimumab) in patients ≥12 years 4, 1, 2
• Pembrolizumab is approved for any MSI-H/dMMR solid tumor that has progressed after prior treatment with no satisfactory alternatives 2

Other Approved Indications

• Urothelial carcinoma: nivolumab, pembrolizumab, atezolizumab, avelumab, or durvalumab in various settings 4, 1, 2
• Head and neck squamous cell carcinoma: nivolumab or pembrolizumab after platinum-based therapy 4, 1, 2
• Classical Hodgkin lymphoma: nivolumab or pembrolizumab after relapse post-transplant 4, 1, 2
• Hepatocellular carcinoma: nivolumab plus ipilimumab after sorafenib 1
• Esophageal squamous cell carcinoma: nivolumab or pembrolizumab in various settings 1, 2

Essential Patient Selection Criteria

Performance Status Requirements

• ECOG performance status 0-2 is required for most checkpoint inhibitor therapy 4
• Patients with ECOG PS 3-4 should receive best supportive care rather than checkpoint inhibitors 4
• Performance status serves as a negative prognostic marker with hazard ratio of 1.5 for worse outcomes 3

Exclusionary Criteria

• Active autoimmune disease requiring systemic immunosuppression is a contraindication 4, 1, 2
• Concurrent immunosuppressive medications (except physiologic corticosteroid replacement) exclude patients 4
• Active HIV, hepatitis B, or hepatitis C infection were exclusion criteria in pivotal trials 2
• History of severe hypersensitivity to other monoclonal antibodies is a contraindication 2

Disease Tempo Considerations for Treatment Selection

• Low-volume, asymptomatic metastatic disease favors checkpoint immunotherapy as first-line, as there is time for durable immune response to develop 4
• Rapidly progressive or symptomatic disease may favor BRAF-targeted therapy (if BRAF-mutated melanoma) or clinical trial enrollment, as checkpoint inhibitor responses can take longer to emerge 4
• Elevated LDH (particularly >2× upper limit of normal) is a negative prognostic marker for both targeted and immunotherapies 3

Biomarker Testing Requirements

Required Testing

• BRAF V600 mutation testing is required in all unresectable stage III or metastatic melanoma patients to determine eligibility for BRAF/MEK inhibitor combinations, regardless of whether immunotherapy is planned first 3
• MSI-H/dMMR testing should be performed in colorectal cancer to identify candidates for checkpoint inhibitors 4
• PD-L1 testing is required for pembrolizumab in NSCLC (≥1% for second-line, ≥50% for first-line monotherapy) but NOT routinely recommended for melanoma 4, 3, 2

Biomarkers That Do NOT Exclude Patients

• PD-L1-negative status does not exclude melanoma patients from anti-PD-1 therapy, as PD-L1-negative patients still achieve 20% response rates 3
• BRAF wild-type melanoma is equally eligible for checkpoint inhibitors as BRAF-mutant disease 4

Critical Clinical Pitfalls to Avoid

Sequencing Errors

• Do not use ipilimumab monotherapy as first-line in treatment-naïve melanoma patients, as it is inferior to anti-PD-1 monotherapy or combination therapy 4, 5
• Do not rechallenge with the same checkpoint inhibitor class after clear progression (e.g., pembrolizumab after nivolumab failure), as cross-resistance is expected 4, 5
• Do not use checkpoint inhibitors in EGFR/ALK-positive NSCLC until progression on targeted therapy 4, 1

Toxicity Management Preparedness

• Grade 3-4 immune-related adverse events occur in 10-27% with anti-CTLA-4 monotherapy, 12-20% with anti-PD-1 monotherapy, and 50-60% with nivolumab/ipilimumab combination 4
• Treatment-related deaths occur in up to 2% of patients, varying by checkpoint inhibitor 4
• Patients must be counseled on the need for proactive monitoring and prompt intervention with immune suppression for immune-related adverse events 4

Contraindications to Combination Therapy

• Nivolumab/ipilimumab combination should be reserved for patients who can tolerate higher toxicity risk, as grade 3-4 immune-related adverse events approach 65% 6
• Patient selection for combination therapy must consider overall health, medical history, concomitant therapies, comorbidities, and compliance with toxicity monitoring 4

Special Populations

Brain Metastases

• Patients with stable, treated brain metastases are eligible for checkpoint inhibitors 4
• Active, symptomatic brain metastases were exclusion criteria in most pivotal trials 2

Pediatric Patients

• Checkpoint inhibitors are approved for patients ≥12 years with melanoma or MSI-H/dMMR colorectal cancer 1, 2

Prior Therapy Requirements

• No prior ipilimumab was required in KEYNOTE-006 for melanoma 2
• Progression on ipilimumab (≥2 doses at 3 mg/kg or higher) was required in KEYNOTE-002 2
• Prior platinum-based chemotherapy is required for second-line NSCLC indications 4