Pembrolizumab Efficacy in Cancer Treatment
Pembrolizumab demonstrates significant survival benefit and durable responses across multiple cancer types, with the strongest evidence in urothelial carcinoma where it improves overall survival to 10.3 months versus 7.4 months with chemotherapy (p=0.002), and in cervical cancer where it extends 24-month overall survival to 53.0% versus 41.7% with placebo when combined with chemotherapy. 1, 2
Urothelial Carcinoma: Category 1 Evidence
Pembrolizumab has the highest level of evidence in urothelial carcinoma among all checkpoint inhibitors. In the phase III KEYNOTE-045 trial, pembrolizumab as second-line therapy after platinum-based chemotherapy demonstrated superior median overall survival of 10.3 months compared to 7.4 months with chemotherapy (HR 0.73, p=0.002), with significantly fewer grade 3-5 adverse events (15.0% vs 49.4%). 1 This represents the only checkpoint inhibitor with category 1 evidence for this indication, while all other PD-1/PD-L1 inhibitors have only category 2 evidence. 1
For first-line treatment in cisplatin-ineligible patients, pembrolizumab achieved an overall response rate of 29% with 7% complete responses in the KEYNOTE-052 trial. 1 The NCCN recommends pembrolizumab as preferred second-line therapy and as first-line for cisplatin-ineligible patients with PD-L1 combined positive score ≥10. 3
Common pitfall: While pembrolizumab is FDA-approved regardless of PD-L1 status in the second-line setting, response rates are higher in PD-L1 positive tumors. However, the newer combination of enfortumab vedotin plus pembrolizumab has become the preferred first-line option with superior overall survival of 31.5 versus 16.1 months compared to platinum-based chemotherapy (HR 0.47), and this combination requires no PD-L1 testing. 4
Cervical Cancer: Significant Survival Improvement
In the KEYNOTE-826 trial, adding pembrolizumab to chemotherapy with or without bevacizumab significantly improved outcomes in persistent, recurrent, or metastatic cervical cancer. Among patients with PD-L1 combined positive score ≥1, median progression-free survival was 10.4 months versus 8.2 months with placebo (HR 0.62, p<0.001), and 24-month overall survival was 53.0% versus 41.7% (HR 0.64, p<0.001). 2
The benefit was consistent across PD-L1 subgroups, with similar improvements seen in the intention-to-treat population and in patients with PD-L1 combined positive score ≥10. 2 The most common grade 3-5 adverse events were anemia (30.3%) and neutropenia (12.4%). 2
Biomarker-Directed Indications
MSI-H/dMMR Tumors: Tumor-Agnostic Approval
Pembrolizumab received FDA approval for MSI-H or dMMR solid tumors regardless of tumor type, representing the first biomarker-based approval independent of tumor site. 1 In the phase II study across 15 cancer types, the overall response rate was 39.6%, with 78% of responders maintaining response for ≥6 months. 1
For pancreatic cancer specifically, pembrolizumab showed an objective response rate of 62% in 6 patients with dMMR tumors (2 complete responses, 3 progressive disease). 1 In the KEYNOTE-158 study of noncolorectal MSI-H/dMMR tumors, the overall response rate was 34.3%, with median progression-free survival of 4.1 months and median overall survival of 23.5 months. 1
TMB-High Tumors
Pembrolizumab is approved for TMB-high tumors (≥10 mutations/megabase) that have progressed after prior therapy. 1, 5 In vulvar cancer with TMB-high status, the objective response rate was approximately 17% versus 3.4% in non-TMB-high disease. 1
PD-L1 Expression
PD-L1 expression correlates with improved response rates across tumor types. In non-small cell lung cancer, patients with PD-L1 expression ≥50% achieved a response rate of 45.2%, with median progression-free survival of 6.3 months. 6 In head and neck squamous cell carcinoma with PD-L1 combined positive score ≥1, pembrolizumab monotherapy achieved median overall survival of 12.3 months versus 10.3 months with cetuximab plus chemotherapy (HR 0.78, p=0.0171). 7
Critical caveat: PD-L1 testing methodology matters. The combined positive score (number of PD-L1-staining cells divided by total viable tumor cells, multiplied by 100) is the validated metric for pembrolizumab in most indications. 5, 2
Vulvar Cancer: Limited but Promising Data
In the KEYNOTE-158 trial of 101 patients with advanced vulvar squamous cell carcinoma, the overall response rate was 10.9% overall, with median progression-free survival of 2.1 months and median overall survival of 6.2 months. 1 Interestingly, the response rate was 28.6% in PD-L1-negative patients versus 9.5% in PD-L1-positive patients, though numbers were small. 1
Safety Profile
Pembrolizumab demonstrates a favorable safety profile compared to chemotherapy, with grade 3-4 treatment-related adverse events occurring in 9-18% of patients across studies. 1, 5 The most common adverse events are fatigue, pruritus, and decreased appetite. 6 Immune-related adverse events include pneumonitis, colitis, hepatitis, endocrinopathies, and skin reactions. 5
Important safety consideration: In patients ≥75 years treated with pembrolizumab plus enfortumab vedotin, the incidence of fatal adverse reactions was 7% versus 4% in younger patients. 7
Duration of Response
A key advantage of pembrolizumab is durability of response. In urothelial carcinoma, the median duration of response was 20.9 months in the KEYNOTE-045 trial. 1 In non-small cell lung cancer, median duration of response was 12.5 months. 6 Among responders in various tumor types, 64.1% maintained response for ≥12 months. 8
Dosing and Administration
The standard dose is 200 mg intravenously every 3 weeks for up to 35 cycles (approximately 2 years). 7 An alternative regimen of 400 mg every 6 weeks is approved for solid tumors based on pharmacokinetic modeling showing similar exposure. 7 Steady-state concentrations are reached by 16 weeks. 7