Keytruda (Pembrolizumab) in Lung Cancer

Table of Contents

Abstract

Pembrolizumab (Keytruda) is a humanized monoclonal antibody targeting the programmed death-1 (PD-1) receptor, revolutionizing lung cancer therapy by enhancing T-cell–mediated anti-tumor immunity. It is approved for multiple indications in metastatic, unresectable, locally advanced, and adjuvant non–small cell lung cancer (NSCLC) and extensive-stage small cell lung cancer (ES-SCLC), either as monotherapy or in combination with chemotherapy. This review summarizes pharmacology, immunobiology, clinical trial evidence, biomarker considerations, immune-related adverse event (irAE) management, mechanisms of resistance, and guideline-based therapeutic positioning, reflecting NCCN-style academic rigor.

I. Introduction

Lung cancer remains the leading cause of cancer mortality worldwide. Historically, prognosis for advanced NSCLC and SCLC was poor, with limited survival benefit from cytotoxic chemotherapy or targeted therapy (in mutation-negative disease).

Immune checkpoint blockade, specifically PD-1/PD-L1 inhibition, represents a paradigm shift. Pembrolizumab demonstrated unprecedented improvement in overall survival (OS) and progression-free survival (PFS) in biomarker-selected populations and in combination with platinum chemotherapy.

II. Drug Class and Molecular Structure

Property	Description
Drug class	Immune checkpoint inhibitor (PD-1 inhibitor)
Type	Humanized IgG4 kappa monoclonal antibody
Source	Recombinant DNA technology
Target	PD-1 receptor on T lymphocytes
Modifications	Fc-region engineered to minimize ADCC/CDC, preventing T-cell depletion

III. Mechanism of Action

A. PD-1/PD-L1 Pathway

Tumor cells express PD-L1 to suppress T-cell activation. PD-1 on T-cells binds PD-L1 and PD-L2 → inhibits proliferation & cytokine release → immune evasion.

Pembrolizumab mechanism:

Binds PD-1 receptor
Blocks PD-1 interaction with PD-L1/PD-L2
Restores cytotoxic T-cell function
Promotes clonal expansion and tumor cell apoptosis

B. Immunological Effects

Effect	Outcome
↑ CD8+ T-cell tumor infiltration	Tumor killing
↑ IFN-γ, IL-2 secretion	Activation of immune response
Reversal of T-cell exhaustion	Sustained tumor control
Immune memory formation	Potential durable responses

IV. Indications in Lung Cancer

A. Non–Small Cell Lung Cancer (NSCLC)

Approved for:

Metastatic NSCLC (first-line and subsequent lines)
Locally advanced unresectable NSCLC (Stage III)
Adjuvant therapy in resected NSCLC

B. Small Cell Lung Cancer (SCLC)

Second-line treatment post-chemotherapy failure (historical; specific approvals evolved with trial updates)

V. Biomarkers for Pembrolizumab

A. PD-L1 Testing

Measured as Tumor Proportion Score (TPS)

PD-L1 TPS	Clinical significance
≥50%	Strong predictor of response to monotherapy
1–49%	May benefit, stronger with chemo + pembrolizumab
<1%	Limited benefit with monotherapy; chemo-IO preferred

B. Genomic Markers

Marker	Relevance
EGFR/ALK mutations	Poor IO benefit → targeted therapy preferred
TMB-high	Favors response (adjunctive biomarker)
KRAS-mutant	Higher responsiveness, especially KRAS-G12C
STK11/KEAP1 alterations	IO resistance trend

C. MSI-H / dMMR

Rare in lung cancer but predictive of strong IO response.

VI. Key Clinical Trials

1. KEYNOTE-024

2. KEYNOTE-042

PD-L1 ≥1% → benefit greatest in ≥50% subgroup.

3. KEYNOTE-189

4. KEYNOTE-407

Table: Survival Outcomes (Illustrative Research Values)

Trial	OS Benefit	PFS Benefit
KEYNOTE-024	↑ Median OS ~26–30 mo vs ~14–16	↑ PFS
KEYNOTE-042	Benefit driven by TPS ≥50%	Modest for TPS 1–49%
KEYNOTE-189	OS HR ≈0.49	Strong PFS benefit
KEYNOTE-407	OS HR ≈0.64	PFS improved

(values paraphrased academically; no direct quotations)

VII. Pharmacokinetics

Parameter	Description
Absorption	IV infusion
Distribution	Systemic, target-mediated
Half-life	~3–4 weeks
Steady-state	Reached by ~16 weeks
Metabolism	Proteolytic catabolism to peptides & amino acids
Clearance	Non-renal, non-hepatic dominant

VIII. Dosing and Administration

Example regimens:

200 mg IV every 3 weeks
400 mg IV every 6 weeks

IX. Immune-Related Adverse Events (irAEs)

System-Specific

System	Toxicity
Pulmonary	Pneumonitis
GI	Colitis, diarrhea
Endocrine	Hypothyroidism, adrenal insufficiency, hypophysitis
Hepatic	Hepatitis, ↑ transaminases
Dermatologic	Rash, pruritus
Renal	Nephritis

irAE Management (NCCN-style)

Grade	Management
Grade 1	Continue therapy, monitor
Grade 2	Hold drug, start prednisone 0.5–1 mg/kg
Grade 3–4	Discontinue permanently, high-dose steroids (1–2 mg/kg) ± infliximab/mycophenolate

X. Resistance Mechanisms

Mechanism	Description
Primary immune resistance	STK11/KEAP1 alterations, cold tumors
Adaptive resistance	Upregulation of alternative checkpoints (TIGIT, LAG-3, TIM-3)
Tumor microenvironment	Treg infiltration, MDSCs, suppressive cytokines
Genetic loss	Beta-2 microglobulin → antigen presentation loss

XI. Place in Therapy According to Guidelines

Clinical Setting	Preferred Strategy
PD-L1 ≥50%	Pembrolizumab monotherapy
Any PD-L1 (no driver mutation)	Pembrolizumab + chemo
Driver-mutated lung cancer (EGFR/ALK/ROS1)	Targeted therapy first

Also used in:

Stage III consolidation (with chemoradiation alternatives)
Adjuvant therapy post-surgery in high-risk disease

XII. Future Directions

Combination with TIGIT inhibitors (e.g., tiragolumab – ongoing research)
Neoadjuvant and perioperative strategies
Personalized IO based on TMB & immune signatures
Integrating circulating tumor DNA (ctDNA) for minimal residual disease monitoring

XIII. Conclusion

Pembrolizumab represents a cornerstone of modern lung cancer therapy, demonstrating survival benefit across molecular profiles, PD-L1 strata, and treatment settings. Deep understanding of immunobiology, predictive biomarkers, toxicity management, and clinical trial evidence is essential for optimal therapeutic strategy.

Checkpoint immunotherapy transformed lung cancer from a historically fatal disease into one where durable long-term survival is achievable for selected patients

Keytruda (Pembrolizumab): A Complete Medical & Pharmacology-Based Overview

Introduction

Keytruda (generic name: Pembrolizumab) is a humanized monoclonal antibody belonging to the class of immune checkpoint inhibitors. It selectively blocks the Programmed Death-1 (PD-1) receptor on T-lymphocytes, reactivating anti-cancer immune responses. Keytruda has revolutionized oncology, particularly in non-small-cell lung cancer (NSCLC), melanoma, renal cancers, head & neck cancers, and hematologic malignancies.

It represents a paradigm shift from traditional cytotoxic chemotherapy toward precision immunotherapy.

Pharmacological Classification

Category	Details
Drug Class	Immune Checkpoint Inhibitor
Type	Humanized Monoclonal Antibody (IgG4-κ)
Target	PD-1 receptor on T-cells
Administration Route	Intravenous (IV infusion)
Molecular Weight	~149 kDa

Mechanism of Action

Cancer cells express PD-L1 to bind PD-1 on T-cells, suppressing immune activation. This creates immune tolerance and tumor escape.

Keytruda works by:

Binding to PD-1 receptor on T-cells
Blocking PD-L1 / PD-L2 interaction
Restoring T-cell cytotoxic activity
Enhancing tumor cell recognition & killing

Simplified Concept: Keytruda removes the “brakes” on the immune system, allowing T-cells to attack cancer.

Indications

Keytruda is FDA-approved for multiple cancers:

1. Lung Cancer

Non-small-cell lung cancer (NSCLC)
Small-cell lung cancer (SCLC)
First-line or second-line therapy
Alone or in combination with platinum chemotherapy
Strongest benefit in high PD-L1 expression tumors

2. Melanoma

Advanced/unresectable melanoma
Adjuvant therapy post-surgery

3. Head and Neck Squamous Cell Carcinoma (HNSCC)

4. Hodgkin Lymphoma

5. Urothelial Carcinoma

6. Renal Cell Carcinoma (in combination therapy)

7. Colorectal Cancer

Especially MSI-H (Microsatellite Instability-High) or dMMR tumors

8. Other Cancers

Cervical cancer
Gastric cancer
Endometrial cancer
Hepatocellular carcinoma
Esophageal cancer
Tumor-agnostic indications (TMB-High, MSI-H)

Dosing

Typical dosing regimens:

Form	Dose	Frequency
IV infusion	200 mg	Every 3 weeks
IV infusion	400 mg	Every 6 weeks

Infuse over 30 minutes.

Duration varies by malignancy; may continue up to 24 months in responsive cases.

Pharmacokinetics

Parameter	Description
Absorption	IV only (complete bioavailability)
Distribution	Wide into extravascular space
Metabolism	Proteolytic catabolism (reticuloendothelial system)
Half-life	~22–26 days
Elimination	Monoclonal antibody degradation pathways

No renal/hepatic dose adjustment usually needed.

Clinical Efficacy Highlights

Improves overall survival (OS) and progression-free survival (PFS) in many cancers
Particularly effective in high PD-L1 tumors
Produces durable, long-term responses unlike chemotherapy

In some trials, 5-year survival doubled vs chemotherapy in NSCLC.

Adverse Effects

Common Side Effects

Category	Examples
General	Fatigue, fever, weight loss
GI	Nausea, diarrhea
Respiratory	Cough, dyspnea
Skin	Rash, pruritus
Musculoskeletal	Arthralgia

Immune-Related Adverse Events (irAEs)

These are the most critical and unique toxicities.

Organ	Condition
Lungs	Pneumonitis
GI	Colitis
Endocrine	Hypothyroidism, hyperthyroidism, adrenal insufficiency, diabetes
Liver	Hepatitis
Kidney	Nephritis
Skin	Severe dermatitis, vitiligo
Nervous system	Neuropathies

Management

Mild (Grade 1–2) → corticosteroids, symptomatic care
Severe (Grade 3–4) → high-dose IV steroids, treatment discontinuation

Monitoring thyroid, liver, kidney, glucose, and respiratory symptoms is essential.

Contraindications

Known hypersensitivity to pembrolizumab
Caution in autoimmune diseases
Avoid during pregnancy/breastfeeding

Drug Interactions

Immunosuppressants (e.g., steroids, methotrexate) may reduce efficacy
No major CYP-mediated interactions (monoclonal antibody)

Advantages

Selective immune activation
Durable cancer control
Better tolerated than chemotherapy in many cases
Tumor-agnostic FDA approvals

Limitations

Not effective in all patients
Expensive therapy
Response may take time (immune activation period)
Risk of immune-mediated toxicity

Biomarker-Based Use

Required Tests

PD-L1 expression level
Microsatellite instability (MSI-H)
Tumor mutation burden (TMB)
Driver mutation screening (EGFR/ALK in NSCLC)

High PD-L1 (≥50%) predicts strong response.

Latest Advances & Research

Combination therapy (immunotherapy + chemotherapy/targeted drugs)
Neoadjuvant & adjuvant use in early cancers
Expanding tumor-agnostic approvals
Research in pancreatic, ovarian, prostate cancers

Patient Counseling Points

Therapy boosts immune system—it does not “kill” cancer directly
Report symptoms early: cough, diarrhea, severe fatigue, fever
Continue regular lab tests & imaging
Maintain hydration & nutrition
Avoid pregnancy during treatment

Conclusion

Keytruda (Pembrolizumab) is a groundbreaking immuno-oncology drug that has transformed cancer treatment by enabling the immune system to recognize and destroy tumor cells. It demonstrates superior outcomes in multiple cancers, particularly when guided by biomarker testing like PD-L1 and MSI-H.

Despite immune-related toxicities and high cost, it remains a cornerstone of modern oncology with expanding indications and ongoing research.

External referances

“Pembrolizumab for the treatment of PD-L1 positive advanced or metastatic non-small cell lung cancer” — a full review article. PMC

“The 5-year outcomes of the KEYNOTE-024 trial” — data on first-line pembrolizumab in NSCLC with PD-L1 ≥ 50 %. PMC

“Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer” (NEJM article) — evidence of pembrolizumab + chemo. nejm.org

“Immune checkpoint inhibitors in non-small cell lung cancer” — overview of the role of pembrolizumab in NSCLC treatment algorithms. PMC

Official clinical trial resource page for Keytruda. keytrudahcp.com

Clinical trials listing for pembrolizumab (via NCI). Cancer.gov