What is the role of Pembrolizumab (pembrolizumab) in treating cancer, specifically in adults with confirmed diagnoses of melanoma, non-small cell lung cancer, or head and neck squamous cell carcinoma, who have undergone previous treatments?

Pembrolizumab in Cancer Treatment

Pembrolizumab is FDA-approved and guideline-recommended as a highly effective immunotherapy across multiple cancer types, with treatment decisions primarily guided by tumor PD-L1 expression, microsatellite instability status (MSI-H/dMMR), and tumor mutational burden (TMB), demonstrating superior survival outcomes compared to chemotherapy in appropriately selected patients. 1

Melanoma

• Pembrolizumab is recommended as first-line treatment for unresectable or metastatic melanoma 2, 1
• Pembrolizumab demonstrated improved response rate, progression-free survival, and overall survival compared with ipilimumab in patients with one or fewer prior systemic therapies 2
• For adjuvant treatment, pembrolizumab is indicated for adult and pediatric patients (12 years and older) with Stage IIB, IIC, or III melanoma following complete resection 1

Non-Small Cell Lung Cancer (NSCLC)

First-Line Treatment

• For metastatic NSCLC with PD-L1 Tumor Proportion Score (TPS) ≥50% and no EGFR or ALK genomic aberrations, pembrolizumab monotherapy is the preferred first-line treatment 3, 2, 1
• For metastatic nonsquamous NSCLC without EGFR/ALK aberrations, pembrolizumab combined with pemetrexed and platinum chemotherapy is recommended as first-line treatment 2, 1
• For metastatic squamous NSCLC, pembrolizumab combined with carboplatin and either paclitaxel or paclitaxel protein-bound is recommended as first-line treatment 1
• Pembrolizumab monotherapy is indicated for Stage III NSCLC where patients are not candidates for surgical resection or definitive chemoradiation 1

Subsequent Therapy

• Pembrolizumab is recommended as subsequent therapy for metastatic NSCLC with PD-L1 TPS ≥1% after progression on platinum-based chemotherapy 3, 2
• In the KEYNOTE-010 trial, median overall survival was 10.4 months with pembrolizumab 2 mg/kg and 12.7 months with 10 mg/kg versus 8.5 months with docetaxel (HR 0.71 and 0.61 respectively, both P<.001) 3
• For patients with PD-L1 expression ≥50%, overall survival was 14.9 months with pembrolizumab 2 mg/kg and 17.3 months with 10 mg/kg versus 8.2 months with docetaxel 3
• Grade 3-5 treatment-related adverse events occurred in only 13-16% of pembrolizumab patients versus 35% with docetaxel 3, 2

Perioperative and Adjuvant Settings

• For resectable NSCLC (tumors ≥4 cm or node positive), pembrolizumab combined with platinum-containing chemotherapy is indicated as neoadjuvant treatment, then continued as monotherapy adjuvant treatment after surgery 1
• For adjuvant treatment following resection and platinum-based chemotherapy, pembrolizumab is indicated for Stage IB (T2a ≥4 cm), II, or IIIA NSCLC 1

Head and Neck Squamous Cell Carcinoma (HNSCC)

First-Line Treatment

• For metastatic or unresectable recurrent HNSCC with PD-L1 Combined Positive Score (CPS) ≥1, pembrolizumab combined with platinum and 5-FU is the primary recommendation 3, 4, 1
• For patients with PD-L1 CPS ≥20, pembrolizumab monotherapy is an alternative for those who do not require rapid tumor reduction, achieving median OS of 14.9 months versus 10.7 months with cetuximab-chemotherapy (HR 0.61, P=0.0007) 4
• For patients with PD-L1 CPS 1-19, pembrolizumab plus platinum plus 5-FU achieved median OS of 12.3 months versus 10.3 months with cetuximab-chemotherapy (HR 0.78, P=0.0086) 4
• Pembrolizumab monotherapy is indicated for first-line treatment in patients with PD-L1 CPS ≥1 1

Second-Line Treatment

• For recurrent or metastatic HNSCC progressing on or after platinum-containing chemotherapy, pembrolizumab monotherapy is recommended regardless of PD-L1 status 4, 1
• Pembrolizumab demonstrated median OS of 8.4 months in the KEYNOTE-040 trial 4
• Grade 3-4 adverse events occurred in only 9% of pembrolizumab patients compared to 35.1% with standard chemotherapy 4

Rare Head and Neck Cancers

• Pembrolizumab may be offered to patients with TMB-high (≥10 mutations/megabase) recurrent or metastatic rare head and neck cancers (e.g., salivary, sinonasal) 3
• Response rates were 29% in TMB-high tumors versus 6% in non-TMB-high tumors 3
• For recurrent or metastatic salivary gland cancers with PD-L1 expression ≥1%, pembrolizumab may be offered 3
• In the KEYNOTE-028 study, 12% of patients with PD-L1-positive salivary gland cancers achieved partial response 3

Colorectal Cancer

MSI-H/dMMR Colorectal Cancer

• Pembrolizumab is recommended as first-line therapy for unresectable or metastatic MSI-H or dMMR colorectal cancer 2, 5
• For second- or third-line therapy in metastatic MMR-deficient colorectal cancer, pembrolizumab is a recommended treatment option 3
• In phase II studies, immune-related objective response rate was 40% in dMMR colorectal cancer versus 0% in MMR-proficient colorectal cancer 3, 5
• The 20-week immune-related progression-free survival rate was 78% in dMMR colorectal cancer versus 11% in MMR-proficient disease 3
• Median progression-free survival and overall survival were not reached in dMMR colorectal cancer versus 2.2 and 5.0 months respectively in MMR-proficient disease (HR 0.10, P<.001) 3
• In the KEYNOTE-177 trial, pembrolizumab demonstrated superior PFS (16.5 vs 8.2 months; HR 0.60) and improved OS (77.5 vs 36.7 months; HR 0.73) compared to chemotherapy 2
• Grade 3-5 adverse events occurred in only 22% of pembrolizumab patients versus 66-67% with chemotherapy 2

Important Caveat

• Pembrolizumab is NOT recommended for metastatic colorectal cancer with high TMB (≥10 mutations/megabase) who have proficient mismatch repair 2
• Patients who experience disease progression on pembrolizumab should not be offered nivolumab, and vice versa 3

Urothelial Cancer

• Pembrolizumab combined with enfortumab vedotin is indicated for locally advanced or metastatic urothelial cancer 1
• Pembrolizumab monotherapy is indicated for locally advanced or metastatic urothelial carcinoma in patients who are not eligible for platinum-containing chemotherapy 5, 1
• Pembrolizumab is also indicated for patients with disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy 1

Biomarker Testing Requirements

PD-L1 Testing

• PD-L1 testing should be performed at diagnosis to inform first-line or second-line pembrolizumab use 2
• For NSCLC, use Tumor Proportion Score (TPS) with ≥1% considered positive and ≥50% considered high 3, 1
• For HNSCC, use Combined Positive Score (CPS) with ≥1% considered positive and ≥20% considered high 4, 1
• PD-L1 testing uses FDA-approved companion diagnostic tests specific to pembrolizumab 3, 1

MSI/MMR Testing

• Microsatellite instability (MSI) or mismatch repair (MMR) status should be determined before initiating therapy for colorectal cancer patients 2, 5
• MSI-H/dMMR testing is recommended across tumor types as pembrolizumab is FDA-approved for any MSI-H tumor 3, 1
• In KEYNOTE-158, response to pembrolizumab in MSI-H/dMMR cancers was 34.3% with OS of 23.5 months 3

Tumor Mutational Burden (TMB)

• TMB testing (≥10 mutations/megabase threshold) may guide pembrolizumab use in rare cancers when PD-L1 testing is unavailable 3, 4
• TMB-high status is associated with better response rates (29% vs 6% in non-TMB-high) 3

Dosing and Administration

• Standard dosing is pembrolizumab 200 mg intravenously every 3 weeks 2, 1
• Alternative dosing of 400 mg every 6 weeks is FDA-approved for solid tumors 1
• Treatment should continue until disease progression, unacceptable toxicity, or up to 24 months 2, 1, 6
• Treatment may be prolonged beyond 24 months if disease is controlled and toxicity is acceptable 2

Response Assessment and Timing

• Median time to response is approximately 3 months, coinciding with first assessment at 12 weeks 2
• Late responses can occur more than one year after starting treatment 2
• Initial partial responses may become complete responses with continued treatment 2
• Complete responses are highly durable, with 88% persisting after median follow-up of 30 months 2

Critical Clinical Considerations

Pseudoprogression

• Progressive disease may be observed initially before response (pseudoprogression), requiring careful clinical assessment before discontinuing therapy 2
• In MSI-H/dMMR colorectal cancer, initial progressive disease may occur in 29% of cases despite overall survival benefit 2
• A subset of patients treated beyond RECIST v1.1 progression show meaningful benefit: 24.4% of melanoma patients, 11.6% of NSCLC patients, and 13.2% of urothelial cancer patients achieved 30% reduction in tumor burden post-progression 7

Treatment Beyond Progression

• Most patients show stable target lesion dynamics in the post-progression period (64.8-75.9% across tumor types) 7
• Second-course pembrolizumab achieved objective response rate of 27.3% in HNSCC patients 8

Subsequent Therapy After Pembrolizumab

• For NSCLC patients with progression after first-line pembrolizumab, platinum-based chemotherapy is recommended as second-line treatment 2
• Progression-free survival on next-line therapy (PFS2) was improved after pembrolizumab in PD-L1 CPS ≥20 (HR 0.64) and CPS ≥1 (HR 0.79) HNSCC populations 8

Safety Profile

Common Adverse Events

• Grade 3-5 treatment-related adverse events occur in approximately 13-16% of patients, significantly lower than chemotherapy (35%) 3, 2
• Pembrolizumab is generally well-tolerated across all cancer types 2, 5, 6
• Most common immune-related adverse events affect the skin 3

Serious Immune-Related Adverse Events

• Serious adverse reactions occur in 21-41% of patients, many immune-mediated 3
• Pneumonitis occurs in approximately 3-7% of patients and is one of the most serious side effects 3
• Other immune-related adverse events include colitis, hepatitis, endocrinopathies, and skin reactions 5
• Treatment-related deaths occurred in approximately 1% of patients across studies 3

Pediatric Considerations

• Adverse reactions occurring at ≥10% higher rate in pediatric patients include pyrexia (33%), vomiting (29%), headache (25%), abdominal pain (23%), decreased lymphocyte count (13%), and decreased white blood cell count (11%) 1
• Laboratory abnormalities more common in pediatric patients include leukopenia (30%), neutropenia (28%), thrombocytopenia (22%), and Grade 3 anemia (17%) 1

Geriatric Considerations

• Elderly patients (>65 years) show equivalent efficacy and no difference in toxicity compared to younger patients 2
• No overall differences in safety or effectiveness were observed between elderly and younger patients across multiple cancer types 1
• Patients 75 years or older treated with pembrolizumab in combination with enfortumab vedotin experienced higher incidence of fatal adverse reactions (7% vs 4% in younger patients) 1

Immunogenicity

• The incidence of treatment-emergent anti-drug antibodies (ADAs) is low at 1.8% in advanced tumors and 3.4% in adjuvant melanoma 9
• Only 0.5% of patients developed neutralizing antibodies 9
• Presence of ADAs did not impact pembrolizumab exposure, safety profile, or efficacy 9