pembrolizumab

Overview

Pembrolizumab (trade name Keytruda) is a humanized monoclonal antibody that targets the programmed cell death 1 (PD-1) receptor, a key immune checkpoint protein expressed on the surface of cytotoxic T cells, regulatory T cells, and natural killer (NK) cells. By binding PD-1, pembrolizumab blocks its interaction with the inhibitory ligands Programmed Death-Ligand 1 (PD-L1) and PD-L2, which are frequently overexpressed on tumor cells and within the tumor microenvironment. This blockade effectively releases a brake on T-cell-mediated immune surveillance, restoring the capacity of cytotoxic T cells to recognize and destroy cancer cells. Pembrolizumab belongs to the broader class of immune checkpoint inhibitors (ICIs) and is structurally related in mechanism to other anti-PD-1 agents such as nivolumab and cemiplimab, as well as anti-PD-L1 therapies and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitors.

Since receiving initial FDA approval, pembrolizumab has become one of the most broadly approved oncology drugs in history, with indications spanning non-small cell lung cancer (NSCLC), melanoma, head and neck squamous cell carcinoma (HNSCC), urothelial carcinoma, gastric and gastroesophageal junction (GEJ) cancers, biliary tract cancer, colorectal cancer, triple-negative breast cancer (TNBC), hepatocellular carcinoma (HCC), cervical cancer, and tumors defined by tissue-agnostic biomarkers such as high tumor mutational burden (TMB-high) and mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) status. Its mechanism of action is intimately tied to biomarker expression — most notably PD-L1 combined positive score (CPS) and tumor proportion score (TPS) — which serve as critical patient selection tools in both clinical trials and routine practice.

Focus of Latest Publications

Recent publications demonstrate pembrolizumab's expanding role across multiple solid tumor types, primarily in combination regimens and adjuvant settings. In metastatic urothelial carcinoma, enfortumab vedotin combined with pembrolizumab has emerged as a preferred first-line approach, with real-world data supporting its efficacy and safety compared to alternative platinum-based strategies. For renal cell carcinoma, adjuvant pembrolizumab improves disease-free and overall survival in resected clear-cell disease, and combination with the hypoxia-inducible factor 2α inhibitor belzutifan shows promise for patients at high recurrence risk. Pembrolizumab plus lenvatinib combinations are being evaluated for metastatic renal cell carcinoma and anaplastic thyroid carcinoma, while chemotherapy combinations including pembrolizumab demonstrate benefit in triple-negative breast cancer (particularly when added to neoadjuvant chemotherapy), gastric and gastroesophageal junction adenocarcinomas, and non-small cell lung cancer. Early-phase trials are exploring pembrolizumab with novel agents targeting tumor microenvironment features, including HPK1 inhibitors, live biotherapeutic products, and anti-PD-L1 sacituzumab tirumotecan.

Real-world effectiveness studies reveal that pembrolizumab's clinical outcomes vary considerably across patient populations and treatment contexts. First-line pembrolizumab monotherapy in metastatic non-small cell lung cancer with high PD-L1 expression demonstrates measurable benefit in routine practice, as do adjuvant regimens in high-risk renal cell carcinoma following surgery. Second-line pembrolizumab for metastatic urothelial carcinoma shows durable responses in selected patients, though real-world outcomes diverge from trial populations. Comparative effectiveness analyses indicate pembrolizumab-based combinations often achieve numerically superior survival compared to alternative first-line strategies, though real-world evidence suggests smaller effect sizes than randomized trials. Emerging analytic methods, including regression discontinuity in time approaches, help mitigate unmeasured confounding and provide estimates more closely aligned with trial data.

Biomarker-driven patient selection increasingly shapes pembrolizumab efficacy. Mismatch repair deficiency and high tumor mutational burden associate with improved responses in colorectal and rare cancers, while PD-L1 combined positive score ≥10 predicts benefit, though responses occur across biomarker-negative subsets. tumor microenvironment characteristics, including baseline CD8+ T cell density and regulatory T cell localization, demonstrate greater predictive power than genomic assays alone. artificial intelligence-guided analysis of pretreatment and on-treatment biopsies may refine outcome prediction in rare tumors. Broader gene representation by whole-exome sequencing improves accuracy of tumor mutational burden assessment for pembrolizumab patient selection compared to targeted gene panels, particularly for patients near the clinical threshold. PDCD1 single nucleotide polymorphisms and early pembrolizumab plasma levels after the first treatment cycle may serve as prognostic markers for progression-free and overall survival in metastatic lung adenocarcinoma.

Concomitant medications and tumor-related factors significantly impact pembrolizumab efficacy and tolerability. Proton pump inhibitor use associates with reduced overall and progression-free survival in urothelial carcinoma and other solid tumors, though probiotics may partially restore effectiveness in esophageal cancer patients receiving concurrent PPIs. Dosage switching from 200 mg every 3 weeks to 400 mg every 6 weeks produces variable pharmacokinetic effects and may influence immune-related adverse event rates in non-small cell lung cancer. Pre-existing interstitial lung abnormalities increase pneumonitis risk in chemo-naive patients receiving pembrolizumab plus platinum-based chemotherapy, requiring careful patient selection. Quality of life assessments in recurrent or metastatic head and neck cancer demonstrate pembrolizumab's longitudinal effects on patient-reported outcomes beyond traditional efficacy measures.

Emerging research identifies mechanisms of therapeutic resistance and potential strategies to enhance pembrolizumab activity. Dysbiosis of the gut microbiome contributes to immunotherapy resistance across solid tumors, and live biotherapeutic products represent one approach to microbiome modulation. Cancer cell plasticity, mediated through STAT3 and CD44 imbalance in urothelial carcinoma, impairs pembrolizumab responses and represents a potential therapeutic target. Combination approaches pairing pembrolizumab with antagonists of immunosuppressive receptors (LILRB1/2 and KIR3DL1) show preliminary promise in overcoming PD-(L)1 resistance. Tumor-agnostic reimbursement frameworks increasingly support pembrolizumab access for rare and ultra-rare cancers lacking disease-specific checkpoint inhibitor indications, such as angiosarcoma, gestational trophoblastic disease, and adrenocortical carcinoma, where subset of patients derive substantial durable benefit despite low baseline biomarker prevalence.

Key Publications

• NEWJul First-Line Enfortumab Vedotin Plus Pembrolizumab vs Gemcitabine Plus Cisplatin for Metastatic Urothelial Carcinoma. (JAMA network open, 2026, PMID 42384383): "Enfortumab vedotin plus pembrolizumab (EV/P) recently emerged as the preferred first-line treatment regimen for metastatic urothelial carcinoma (mUC), but evidence outside trial settings is relatively limited."
• NEWJul Adjuvant Pembrolizumab plus Belzutifan for Renal-Cell Carcinoma. (The New England journal of medicine, 2026, PMID 42384869): "Adjuvant pembrolizumab improves disease-free and overall survival among patients with resected clear-cell renal-cell carcinoma."
• NEWJan Real-world Implementation of Adjuvant Pembrolizumab for High-risk Clear-cell Renal Cell Carcinoma After Surgery. (In vivo (Athens, Greece), 2026, PMID 42379743): "Adjuvant pembrolizumab is an important postoperative treatment option for selected patients with high-risk clear-cell renal cell carcinoma."
• NEWJun Pharmacokinetic variability with pembrolizumab dosage switching and its impact on immune-related adverse events in patients with non-small cell lung cancer. (Journal for immunotherapy of cancer, 2026, PMID 42373128): "The impact of concentration changes when switching from 200 mg every 3 weeks (Q3W) to Q6W on immune-related adverse events (irAEs) remains unclear."
• NEWJul Real-world Comparison of Avelumab Maintenance and Enfortumab Vedotin Plus Pembrolizumab in Metastatic Urothelial Carcinoma. (Anticancer research, 2026, PMID 42373274): "This study aimed to determine whether avelumab maintenance following platinum-based chemotherapy offers comparable or superior survival outcomes to EVP."
• NEWJul Impact of Proton Pump Inhibitors on Immune-related Adverse Events and Efficacy During Pembrolizumab Monotherapy. (Anticancer research, 2026, PMID 42373280): "Concomitant proton pump inhibitors (PPIs) have been inversely correlated with efficacy, including overall survival (OS) and progression-free survival (PFS), in patients with urothelial carcinoma receiving pembrolizumab."
• NEWJul Bayesian Analysis to Refine East Asian Subgroup Estimates in the CLEAR Trial (Lenvatinib Plus Pembrolizumab vs. Sunitinib) for Advanced Renal Cell Carcinoma. (Anticancer research, 2026, PMID 42373289): "This study aimed to refine estimates of lenvatinib plus pembrolizumab (Len/Pembro) efficacy in East Asian patients with advanced renal cell carcinoma (aRCC) in the CLEAR trial using Bayesian borrowing from Western Europe and North America (WENA), and to assess safety while preserving region-specific toxicity."
• NEWJun Artificial intelligence-guided analysis of the tumor microenvironment predicts response to pembrolizumab in rare tumors. (Journal for immunotherapy of cancer, 2026, PMID 42342409): "We investigated whether artificial intelligence (AI)-powered analyses of pretreatment and on-treatment biopsies may inform treatment outcomes to pembrolizumab."
• NEWJun Efficacy and toxicity of neoadjuvant chemotherapy versus chemo-immunotherapy in triple-negative breast cancer patients with and without germline BRCA mutations. (Breast cancer research and treatment, 2026, PMID 42329463): "The addition of pembrolizumab (KN522) to neoadjuvant doxorubicin, cyclophosphamide (AC), carboplatin and paclitaxel (TC) has significantly improved survival, albeit with increased toxicity."
• NEWJun [Translated article] Real world outcomes of first-line pembrolizumab in metastatic non-small-cell lung cancer. (Farmacia hospitalaria : organo oficial de expresion cientifica de la Sociedad Espanola de Farmacia Hospitalaria, 2026, PMID 42285782): "To describe the effectiveness and safety of pembrolizumab in routine clinical practice as first-line treatment for advanced/metastatic non-small cell lung cancer (NSCLC) with PD-L1 expression ≥50% and without EGFR or ALK alterations."