Pembrolizumab: A Comprehensive Oncological Review

I. Introduction to Pembrolizumab

A. Overview and Generic Information

Pembrolizumab, marketed internationally under the brand name Keytruda, is a cornerstone of modern cancer immunotherapy. It is a humanized monoclonal antibody designed to harness the patient's own immune system to combat various malignancies.[1]

• Generic Name: Pembrolizumab.[1]
• DrugBank ID: DB09037.[14]
• CAS Number: 1374853-91-4 [User Query].
• Type: Pembrolizumab is classified as a biotechnology-derived product (Biotech).[14]
• Brief Summary of Therapeutic Use: As a programmed death receptor-1 (PD-1) blocking antibody, Pembrolizumab is indicated for the treatment of numerous cancer types. Its primary function is to restore the immune system's ability to detect and destroy tumor cells.[1] Initial indications included advanced melanoma and non-small cell lung cancer, with subsequent approvals for head and neck cancer, Hodgkin's lymphoma, cervical cancer, and many others [User Query].
• Developer: Merck & Co., Inc. (known as MSD outside the United States and Canada) is the developer of Pembrolizumab.[4] Merck's extensive and ongoing KEYNOTE clinical trial program has been pivotal in establishing the broad efficacy and safety profile of Pembrolizumab across a multitude of cancer indications and treatment settings.[85]

B. Significance in Immuno-Oncology

Pembrolizumab achieved a landmark FDA approval on September 4, 2014, for patients with advanced melanoma, making it the first anti-PD-1 therapy to reach the U.S. market.[4] This heralded a new era in cancer treatment.

A particularly significant milestone was the FDA's approval of Pembrolizumab in 2017 for unresectable or metastatic solid tumors characterized by microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) biomarkers, irrespective of the tumor's tissue of origin. This was the first time a cancer drug was approved based on a tumor genetic feature rather than its location in the body, establishing Pembrolizumab as a "tissue-agnostic" therapy.[10]

The approval history of Pembrolizumab, particularly its tissue-agnostic indication for MSI-H/dMMR tumors, signifies a fundamental shift in how cancer is understood and treated. It underscores the growing importance of molecular biomarkers in guiding therapeutic decisions, moving beyond traditional anatomical classifications. Early cancer drug approvals were almost exclusively based on the primary site of the tumor. Pembrolizumab's initial approvals followed this model, for example, for melanoma.[15] The discovery that certain genetic alterations, like MSI-H/dMMR, render tumors susceptible to PD-1 blockade regardless of their anatomical origin, led to basket trials such as KEYNOTE-158.[23] The successful outcomes in these trials for MSI-H/dMMR tumors across various cancer types [59] prompted the FDA to grant a tissue-agnostic approval.[10] This precedent accelerates drug development for biomarker-defined populations, necessitates broader access to and adoption of comprehensive genomic profiling for cancer patients, and allows for more personalized treatment strategies. It also challenges the traditional organ-centric structure of oncology clinical trials and practice.

II. Molecular Profile and Pharmaceutical Characteristics

A. Description as a Humanized Monoclonal Antibody

Pembrolizumab is a humanized monoclonal antibody (mAb).[1] It was developed by grafting the complementarity-determining regions (CDRs), which are the antigen-binding portions, from a high-affinity murine anti-human PD-1 antibody onto a human immunoglobulin G (IgG) backbone.[4] This humanization process is critical in therapeutic antibody development to minimize the potential for an immune response against the antibody itself (anti-drug antibodies or ADAs) and to improve its pharmacokinetic profile, allowing for longer circulation and more effective engagement with its target.

B. Isotype: IgG4-kappa with S228P Fc Mutation

Pembrolizumab is specifically an IgG4-kappa isotype antibody.[3] A key feature of its design is the incorporation of a stabilizing S228P mutation in the Fc (Fragment crystallizable) region.[4]

The choice of the IgG4 isotype is significant because IgG4 antibodies naturally exhibit reduced effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), compared to other IgG subclasses like IgG1.[91] This characteristic is highly advantageous for a checkpoint inhibitor like Pembrolizumab. The primary therapeutic goal is to block the PD-1 receptor to restore T-cell function against tumor cells, not to directly kill the PD-1 expressing T-cells themselves, which could lead to undesirable immunosuppression or depletion of crucial effector immune cells. IgG4 antibodies are thus often described as immunologically "quieter" or "inert" in terms of their ability to trigger these cytotoxic mechanisms.[96]

The S228P (serine to proline at position 228) mutation in the hinge region of the IgG4 Fc domain is a critical engineering modification.[89] Wild-type IgG4 antibodies possess a unique property known as Fab-arm exchange (FAE) or "half-molecule exchange".[90] In this process, an IgG4 molecule can swap one of its Fab arms (a heavy chain-light chain pair responsible for antigen binding) with a Fab arm from another IgG4 molecule. This can occur in vivo, leading to the formation of bispecific antibodies that are functionally monovalent for each target and may have altered or reduced efficacy and a potentially shorter half-life due to instability.[90] The S228P mutation stabilizes the core hinge region and the inter-heavy chain disulfide bonds, effectively preventing this Fab-arm exchange.[89] This ensures that Pembrolizumab remains a stable, monospecific antibody that bivalently binds to its target, PD-1, thereby improving its stability and reducing therapeutic variability.[91]

The selection of the IgG4-S228P isotype is a deliberate and crucial molecular engineering strategy. This design ensures that Pembrolizumab effectively blocks PD-1 signaling to reinvigorate anti-tumor T-cell responses, while minimizing the risk of depleting these beneficial PD-1-expressing activated T cells through Fc-mediated effector functions. Furthermore, the S228P mutation ensures the antibody's structural integrity and consistent bivalent binding to PD-1, which is important for its therapeutic efficacy and predictable pharmacokinetic behavior. This contributes significantly to its overall therapeutic window and safety profile.

C. Structural Details

Pembrolizumab's structure is well-defined. It contains 32 cysteine residues.[4] The complete, correctly folded molecule is stabilized by a network of disulfide bonds: there are 4 interchain disulfide linkages (connecting the different polypeptide chains) and 23 intrachain disulfide bonds (within individual polypeptide chains).[4] These bonds are fundamental for maintaining the antibody's three-dimensional conformation, which is essential for its stability and antigen-binding capability. X-ray crystallography studies have revealed that Pembrolizumab is a compact molecule, a feature consistent with its relatively short hinge region characteristic of IgG4 antibodies.[89] Like other antibodies, the Fc domain of Pembrolizumab is glycosylated, specifically at the CH2 domain on both heavy chains. Interestingly, structural studies have shown that one of the CH2 domains in Pembrolizumab adopts an unusual conformation, rotated approximately 120° relative to what is typically observed in other antibody structures, with its glycan chain exposed to the solvent. This unique conformation is speculated to be influenced by the shorter hinge region of the IgG4 isotype.[89]

III. Mechanism of Action

A. Target: Programmed Death Receptor-1 (PD-1)

Pembrolizumab is a highly specific PD-1 blocking antibody.[1] PD-1 (CD279) is a critical immune checkpoint receptor. It is primarily expressed on the surface of activated T cells, but also on B cells, natural killer (NK) cells, and myeloid cells.[12] Under normal physiological conditions, PD-1 plays a crucial role in maintaining self-tolerance and modulating the duration and amplitude of immune responses, thereby preventing excessive immune activity that could lead to autoimmune damage.[2] In situations of chronic antigen exposure, such as in chronic infections or cancer, persistent PD-1 signaling can lead to T-cell exhaustion, a state of T-cell dysfunction characterized by reduced effector functions.[91]

B. Interaction with PD-1 Ligands (PD-L1 and PD-L2)

Pembrolizumab exerts its therapeutic effect by binding to the PD-1 receptor and physically obstructing its interaction with its two known ligands: Programmed Death-Ligand 1 (PD-L1, also known as B7-H1 or CD274) and Programmed Death-Ligand 2 (PD-L2, also known as B7-DC or CD273).[1] These ligands are expressed on various cell types, including antigen-presenting cells (APCs), and can be upregulated on tumor cells and other cells within the tumor microenvironment (TME), often in response to inflammatory signals like interferon-gamma (IFN-γ).[88] When PD-L1 or PD-L2 on tumor cells or other TME cells bind to PD-1 on T-cells, an inhibitory signal is transduced into the T-cell, leading to the downregulation of T-cell activity and the phenomenon of T-cell exhaustion.[88] Pembrolizumab binds to PD-1 with high affinity, and its binding epitope on PD-1 has a significant overlap with the binding site for PD-L1. This ensures a robust competitive blockade of the PD-1/PD-L1 interaction, which is crucial for its therapeutic action.[88]

C. Restoration of Anti-Tumor T-Cell Activity

By effectively blocking the PD-1/PD-L1 and PD-1/PD-L2 interactions, Pembrolizumab disinhibits T-cells, thereby "releasing the brakes" on the immune system.[1] This blockade is particularly critical within the TME, where tumors often exploit the PD-1 pathway to evade immune surveillance. The most immediate and significant consequence is the reactivation of previously "exhausted" or anergic tumor-specific T-cells, especially cytotoxic CD8+ T lymphocytes (CTLs).[12] These reactivated T-cells regain their ability to proliferate, produce effector cytokines, and directly kill cancer cells.[2]

The enhanced T-cell activity following PD-1 blockade leads to an increased production and release of crucial pro-inflammatory cytokines, most notably IFN-γ and interleukin-2 (IL-2).[6] IFN-γ plays a multifaceted role in anti-tumor immunity: it can directly inhibit tumor cell proliferation, upregulate MHC molecule expression on tumor cells (making them more visible to T-cells), and further recruit and activate other immune cells, such as macrophages and NK cells, into the TME. IL-2 is a potent T-cell growth factor that promotes the proliferation and survival of activated T-cells.[88]

Beyond direct T-cell reactivation, Pembrolizumab can indirectly modulate other components of the immune system. For instance, it may enhance the antigen-presenting capabilities of dendritic cells (DCs) by promoting a more activated and mature state, which in turn facilitates more effective priming and expansion of tumor-antigen-specific T-cell populations.[88] This cascade of immune activation can lead to a broadening of the anti-tumor immune response and potentially the development of long-term immunological memory against the tumor, which could contribute to durable responses observed in some patients.[88]

D. Molecular Downstream Effects

The binding of PD-L1 or PD-L2 to PD-1 on T-cells initiates a downstream signaling cascade that inhibits T-cell activation and effector functions. A key event in this inhibitory signaling is the recruitment of phosphatases, such as SHP-1 (Src homology region 2 domain-containing phosphatase-1) and SHP-2, to the cytoplasmic tail of PD-1. These phosphatases dephosphorylate and inactivate key signaling molecules involved in T-cell receptor (TCR) and CD28 co-stimulatory signaling, such as ZAP70 and PI3K.[88] By blocking the PD-1 receptor, Pembrolizumab prevents the recruitment of these inhibitory phosphatases. This, in turn, allows for sustained phosphorylation and activation of TCR signaling components, leading to enhanced T-cell proliferation, cytokine production (e.g., IFN-γ, TNF-α), and cytotoxic activity against tumor cells.[88]

The mechanism of Pembrolizumab is not merely a simple "on-off" switch for T-cells but rather a complex immunomodulatory process. It involves the direct reactivation of exhausted effector cells, a significant shift in the cytokine milieu within the TME towards a more pro-inflammatory state, enhanced antigen presentation, and potentially the induction of durable immune memory. This multifaceted action likely contributes to its efficacy across a diverse range of tumor types. The efficacy of Pembrolizumab is often correlated with the presence of PD-L1 expression on tumor cells or immune cells within the TME, or with a high tumor mutational burden (TMB) or MSI-H/dMMR status, as these factors can indicate a pre-existing, albeit suppressed, anti-tumor immune response that can be unleashed by PD-1 blockade. The cytokine cascade initiated by T-cell reactivation, while crucial for its therapeutic effect, is also understood to be a primary driver of the unique spectrum of immune-related adverse events associated with checkpoint inhibitors.

IV. Pharmacokinetics and Pharmacodynamics

A. Absorption and Distribution

Pembrolizumab is administered via intravenous (IV) infusion, ensuring immediate and complete bioavailability.[3] Following administration, it exhibits a relatively small volume of distribution at steady-state, reported as approximately 6.0 L with a coefficient of variation (CV) of 20% [3] or 7.7 L.[12] This is characteristic of monoclonal antibodies and indicates limited extravascular distribution, meaning the drug primarily resides within the bloodstream and interstitial fluid rather than extensively penetrating tissues. As a protein, Pembrolizumab does not specifically bind to plasma proteins in the conventional sense of small molecule drugs.[3]

B. Metabolism and Elimination

Like other therapeutic monoclonal antibodies, Pembrolizumab is not metabolized by cytochrome P450 enzymes or other hepatic/renal pathways typically involved in small molecule drug metabolism.[3] Instead, it is presumed to be catabolized into smaller peptides and amino acids through general protein degradation pathways, likely involving phagocytosis by cells of the reticuloendothelial system.[3] Its clearance (CL) is time-dependent, being approximately 23% lower at steady-state (geometric mean, 195 mL/day [CV%: 40%]) compared to the clearance after the first dose (252 mL/day [CV%: 37%]).[3] Another source reports a clearance of 0.22 L/day.[12] This decrease in clearance over time is not considered clinically significant.[3]

C. Half-life and Steady-State

Pembrolizumab has a long terminal half-life, reported at steady-state to be approximately 22 days (CV: 32%) [3] or 26 days.[98] Due to this long half-life, steady-state concentrations are typically achieved by 16 weeks of repeated dosing with an every 3-week regimen, resulting in a systemic accumulation of approximately 2.1-fold.[3] Pharmacokinetic parameters such as peak concentration (Cmax) and area under the plasma concentration-time curve (AUC) increase proportionally with dose within the clinically evaluated and efficacious range.[3]

D. Pharmacodynamics

Pharmacodynamic studies have shown that Pembrolizumab effectively engages its target, the PD-1 receptor. Maximum serum target engagement, assessed by PD-1 receptor occupancy on peripheral T-cells, is achieved at trough concentrations resulting from doses of 1 mg/kg every 3 weeks or higher.[13] Mechanism-based translational models incorporating pharmacokinetic and pharmacodynamic data predicted that robust clinical activity would be observed at doses of 2 mg/kg every 3 weeks or its equivalent.[13] Extensive modeling and simulation analyses of dose/exposure relationships for efficacy and safety have indicated no clinically significant differences between the 200 mg every 3 weeks, 2 mg/kg every 3 weeks, and 400 mg every 6 weeks dosing regimens.[3] Recent research into a subcutaneous formulation of Pembrolizumab (co-formulated with berahyaluronidase alfa) has demonstrated noninferior pharmacokinetics compared to the intravenous formulation, along with consistent efficacy and safety profiles, potentially offering increased patient convenience.[99]

The pharmacokinetic profile of Pembrolizumab, particularly its long half-life, underpins the rationale for its every 3-week or every 6-week dosing schedules. These extended dosing intervals can significantly improve patient convenience and adherence compared to more frequent administrations. The observation that PD-1 receptor saturation is achieved at relatively low doses suggests that further dose escalation beyond the established therapeutic range is unlikely to yield greater efficacy and could potentially increase the risk of toxicity. The development of flat-dose regimens (e.g., 200 mg every 3 weeks or 400 mg every 6 weeks) across most adult indications, rather than weight-based dosing, simplifies clinical practice, reduces the potential for dosing errors, and may minimize drug wastage. This is supported by the consistent pharmacokinetic and pharmacodynamic profiles observed across a wide range of patient body weights. The ongoing development of a subcutaneous formulation further reflects a commitment to enhancing patient experience and optimizing healthcare resource utilization.[99]

E. Special Populations

Pharmacokinetic analyses have generally shown no clinically important differences in Pembrolizumab clearance based on age, sex, race, tumor type, or tumor burden.[3] Similarly, mild to moderate renal impairment or mild hepatic impairment do not appear to significantly alter Pembrolizumab pharmacokinetics, and thus dose adjustments are typically not required in these populations.[3] However, data in patients with severe renal or moderate to severe hepatic impairment are limited. While most studies indicate no overall differences in safety or effectiveness in elderly patients (≥65 years), some reports suggest a trend towards an increased frequency of severe adverse events in patients aged ≥75 years, particularly in the adjuvant melanoma setting.[3]

V. Regulatory History and Approved Indications

Pembrolizumab has a broad and expanding list of approved indications globally, reflecting its significant impact across various cancer types.

A. FDA Approval Timeline and Key Indications

The U.S. Food and Drug Administration (FDA) first approved Pembrolizumab (Keytruda) on September 4, 2014, for the treatment of patients with unresectable or metastatic melanoma following ipilimumab therapy and, if BRAF V600 mutation positive, a BRAF inhibitor.[4] This marked the entry of the first anti-PD-1 therapy into the U.S. market.

Since its initial approval, Pembrolizumab has received numerous additional approvals for a wide range of malignancies, often accompanied by specific biomarker requirements (e.g., PD-L1 expression, MSI-H/dMMR status). A summary of key FDA-approved indications is presented in Table 1.

Table 1: Key FDA Approved Indications for Pembrolizumab (KEYTRUDA)

(Illustrative list based on provided data; not exhaustive. Dates are approximate year of first approval for the specified context.)

Indication	Specific Patient Population & Setting	Biomarker Requirement (if any)	Approval Year (Approx.)	Special Designations Noted
Melanoma	Unresectable or metastatic	None specified	2014	Breakthrough Therapy
	Adjuvant treatment, Stage IIB, IIC, or III (following complete resection)	None specified	2021 (IIB/IIC)	Priority Review
Non-Small Cell Lung Cancer (NSCLC)	Metastatic, PD-L1 TPS ≥1%, progression on/after platinum-chemo	PD-L1 TPS ≥1%	2015	Accelerated Approval
	Metastatic, first-line, PD-L1 TPS ≥50%, no EGFR/ALK aberrations	PD-L1 TPS ≥50%	2016	Breakthrough Therapy
	Metastatic non-squamous, first-line, in combination with pemetrexed and platinum chemotherapy	None for combo	2017 (Accel.), 2018 (Full)	Priority Review (sBLA)
	Metastatic squamous, first-line, in combination with carboplatin and paclitaxel/nab-paclitaxel	None for combo	2018
	Adjuvant treatment, Stage IB (T2a ≥4 cm), II, or IIIA, following resection and platinum-based chemotherapy	None specified	2023
Head and Neck Squamous Cell Cancer (HNSCC)	Recurrent or metastatic, disease progression on/after platinum-chemo	None specified	2016
	Metastatic or unresectable, recurrent, first-line, single agent	PD-L1 CPS ≥1	2019
	Metastatic or unresectable, recurrent, first-line, in combination with platinum and fluorouracil (FU)	None for combo	2019
Classical Hodgkin Lymphoma (cHL)	Adult, relapsed or refractory	None specified	2017	Breakthrough Therapy, Priority Review
	Pediatric, refractory or relapsed after ≥2 lines of therapy	None specified	2017
Primary Mediastinal Large B-Cell Lymphoma (PMBCL)	Adult and pediatric, refractory or relapsed after ≥2 prior lines of therapy	None specified	2018
Urothelial Carcinoma	Locally advanced or metastatic, progression during/following platinum-chemo or within 12 months of neoadjuvant/adjuvant platinum-chemo	None specified	2017
	Locally advanced or metastatic, not eligible for cisplatin-chemo (first-line)	PD-L1 CPS ≥10	2017	Accelerated Approval
	Locally advanced or metastatic, first-line, in combination with enfortumab vedotin	None for combo	2023
	BCG-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with CIS +/- papillary tumors, ineligible for/elected not to undergo cystectomy	None specified	2020
Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Solid Tumors (Tissue-Agnostic)	Adult and pediatric, unresectable or metastatic, progressed following prior treatment, no satisfactory alternatives	MSI-H or dMMR	2017 (Accel.), 2023 (Full)	Breakthrough Therapy
MSI-H/dMMR Colorectal Cancer (CRC)	Unresectable or metastatic, first-line	MSI-H or dMMR	2020	Breakthrough Therapy
Gastric/Gastroesophageal Junction (GEJ) Adenocarcinoma	Locally advanced unresectable or metastatic HER2-positive, first-line, in combination with trastuzumab and fluoropyrimidine/platinum-chemo	HER2-positive, PD-L1 CPS ≥1	2021 (Accel.), 2025 (Full)	Orphan Drug, Priority Review
	Locally advanced unresectable or metastatic HER2-negative, first-line, in combination with fluoropyrimidine/platinum-chemo	PD-L1 CPS ≥1	2023
Esophageal Cancer	Locally advanced or metastatic, not amenable to surgical resection or definitive chemoradiation, in combination with platinum/fluoropyrimidine-chemo (first-line)	PD-L1 CPS ≥10 (for squamous)	2021
Cervical Cancer	Persistent, recurrent, or metastatic, PD-L1 CPS ≥1, in combination with chemotherapy +/- bevacizumab	PD-L1 CPS ≥1	2021
	FIGO 2014 Stage III-IVA, in combination with chemoradiotherapy	None specified	2024
Hepatocellular Carcinoma (HCC)	Previously treated with sorafenib (secondary to hepatitis B)	None specified	2018
Merkel Cell Carcinoma (MCC)	Adult and pediatric, recurrent locally advanced or metastatic	None specified	2018
Renal Cell Carcinoma (RCC)	Advanced, first-line, in combination with axitinib	None for combo	2019
	Advanced, first-line, in combination with lenvatinib	None for combo	2021	Breakthrough Therapy
	Adjuvant treatment, intermediate-high or high risk of recurrence following nephrectomy +/- resection of metastatic lesions	None specified	2021	Priority Review
Endometrial Carcinoma	Advanced, MSI-H or dMMR, progression following prior systemic therapy, not candidates for curative surgery/radiation	MSI-H or dMMR	2022
	Advanced, not MSI-H/dMMR, in combination with lenvatinib, progression following prior systemic therapy, not candidates for curative surgery/radiation	Not MSI-H/dMMR	2019 (Accel.), 2021 (Full)	Breakthrough Therapy
	Primary advanced or recurrent, in combination with carboplatin and paclitaxel, then single-agent	None for combo	2024
Cutaneous Squamous Cell Carcinoma (cSCC)	Recurrent or metastatic, not curable by surgery or radiation	None specified	2020
	Locally advanced, not curable by surgery or radiation	None specified	2021
Triple-Negative Breast Cancer (TNBC)	High-risk early-stage, neoadjuvant with chemotherapy, then adjuvant monotherapy	None specified	2021	Breakthrough Therapy
	Locally recurrent unresectable or metastatic, PD-L1 CPS ≥10, in combination with chemotherapy	PD-L1 CPS ≥10	2020 (Accel.), 2021 (Full)	Priority Review
Biliary Tract Cancer (BTC)	Locally advanced unresectable or metastatic, in combination with gemcitabine and cisplatin	None for combo	2023
Malignant Pleural Mesothelioma (MPM)	Unresectable advanced or metastatic, first-line, in combination with pemetrexed and platinum chemotherapy	None for combo	2024

Sources for Table 1: User Query,.[6]

B. EMA Approval Timeline and Key Indications

The European Medicines Agency (EMA) granted its initial marketing authorization for Keytruda on July 17, 2015, for advanced (unresectable or metastatic) melanoma.[4] Similar to the FDA, the EMA has subsequently expanded Pembrolizumab's indications. A summary of key EMA-approved indications is presented in Table 2.

Table 2: Key EMA Approved Indications for Pembrolizumab (KEYTRUDA)

(Illustrative list based on provided data; not exhaustive. Dates reflect initial approval or last update for the indication context.)

Indication	Specific Patient Population & Setting	Biomarker Requirement (if any)	Approval/Update Year (Approx.)
Melanoma	Advanced (unresectable or metastatic), adults and adolescents ≥12 years	None specified	2015
	Adjuvant treatment, Stage IIB, IIC or III, adults and adolescents ≥12 years, post-resection	None specified	2021 (Update for IIB/IIC)
Non-Small Cell Lung Cancer (NSCLC)	Neoadjuvant (with chemo) then adjuvant (monotherapy) for resectable NSCLC at high risk of recurrence	See SmPC section 5.1	2022 (Update)
	Adjuvant treatment, high risk of recurrence post-resection and platinum-chemo	See SmPC section 5.1	2023 (Update)
	First-line metastatic, PD-L1 TPS ≥50%, no EGFR/ALK mutations	PD-L1 TPS ≥50%, no EGFR/ALK	2016
	First-line metastatic non-squamous, in combination with pemetrexed and platinum chemotherapy, no EGFR/ALK mutations	No EGFR/ALK	2018
	First-line metastatic squamous, in combination with carboplatin and paclitaxel/nab-paclitaxel	None for combo	2019
	Locally advanced or metastatic, PD-L1 TPS ≥1%, post-chemo (EGFR/ALK+ should have received targeted therapy)	PD-L1 TPS ≥1%	2017
Classical Hodgkin Lymphoma (cHL)	Relapsed or refractory, adult and pediatric ≥3 years, failed ASCT or ≥2 prior therapies if ASCT not option	None specified	2017
Urothelial Carcinoma	Locally advanced or metastatic, post-platinum chemotherapy	None specified	2017
	Locally advanced or metastatic, cisplatin-ineligible, first-line	PD-L1 CPS ≥10	2017
	First-line unresectable or metastatic, in combination with enfortumab vedotin	None for combo	2024 (Update)
Head and Neck Squamous Cell Cancer (HNSCC)	First-line metastatic or unresectable recurrent, monotherapy or combination with platinum/5-FU	PD-L1 CPS ≥1	2019
	Recurrent or metastatic, PD-L1 TPS ≥50%, progressing on/after platinum-chemo	PD-L1 TPS ≥50%	2017
Renal Cell Carcinoma (RCC)	First-line advanced, in combination with axitinib	None for combo	2019
	First-line advanced, in combination with lenvatinib	None for combo	2022 (Update)
	Adjuvant treatment, increased risk of recurrence post-nephrectomy +/- resection of metastases	See SmPC section 5.1	2022 (Update)
MSI-H/dMMR Cancers	Colorectal (CRC), first-line metastatic	MSI-H or dMMR	2021
	Colorectal (CRC), unresectable or metastatic, after prior fluoropyrimidine-based combination	MSI-H or dMMR	2021
	Endometrial, Gastric, Small Intestine, Biliary (advanced/recurrent, post-prior therapy)	MSI-H or dMMR	2021 (Update)
Oesophageal Carcinoma	First-line locally advanced unresectable or metastatic, in combination with platinum/fluoropyrimidine-chemo	PD-L1 CPS ≥10	2021
Triple-Negative Breast Cancer (TNBC)	Locally advanced or early-stage, high risk of recurrence, neoadjuvant (with chemo) then adjuvant (monotherapy)	See SmPC section 5.1	2022 (Update)
	Locally recurrent unresectable or metastatic, PD-L1 CPS ≥10, no prior chemo for metastatic disease, in combination with chemotherapy	PD-L1 CPS ≥10	2021
Endometrial Carcinoma (EC)	First-line primary advanced or recurrent, in combination with carboplatin and paclitaxel	None for combo	2024 (Update)
	Advanced or recurrent, progression on/following prior platinum-chemo, not candidate for curative surgery/radiation, in combination with lenvatinib	None for combo	2021
Cervical Cancer	FIGO 2014 Stage III-IVA locally advanced, in combination with chemoradiotherapy	None specified	2024 (Update)
	Persistent, recurrent, or metastatic, PD-L1 CPS ≥1, in combination with chemotherapy +/- bevacizumab	PD-L1 CPS ≥1	2022 (Update)
Gastric/GEJ Adenocarcinoma	First-line locally advanced unresectable or metastatic HER2-positive, PD-L1 CPS ≥1, in combination with trastuzumab and fluoropyrimidine/platinum-chemo	HER2-positive, PD-L1 CPS ≥1	2021
	First-line locally advanced unresectable or metastatic HER2-negative, PD-L1 CPS ≥1, in combination with fluoropyrimidine/platinum-chemo	HER2-negative, PD-L1 CPS ≥1	2023 (Update)
Biliary Tract Carcinoma (BTC)	First-line locally advanced unresectable or metastatic, in combination with gemcitabine and cisplatin	None for combo	2023 (Update)
Malignant Pleural Mesothelioma (MPM)	First-line unresectable non-epithelioid, in combination with platinum and pemetrexed	None specified	2024 (Update)

Sources for Table 2:.[3]

C. Special Regulatory Designations

Pembrolizumab has received multiple special designations from regulatory authorities, reflecting its potential to address unmet medical needs and its significant clinical benefits.

• FDA Breakthrough Therapy Designation: This designation is intended to expedite the development and review of drugs for serious or life-threatening conditions where preliminary clinical evidence indicates substantial improvement over available therapies.[78] Pembrolizumab has received this for:
• Advanced Melanoma (2013 - first cancer drug to receive this designation).[52]
• NSCLC (EGFR/ALK negative, progressed on/after platinum chemotherapy - October 2014).[32]
• Relapsed/Refractory cHL (April 2016).[55]
• MSI-H Metastatic CRC (November 2015).[60]
• Hepatocellular Carcinoma (HCC) (first-line, in combination with Lenvima - July 2019).[78]
• Renal Cell Carcinoma (RCC) (in combination with Lenvima - January 2018).[78]
• Endometrial Carcinoma (non-MSI-H/pMMR, in combination with Lenvima - July 2018).[78]
• High-Risk Early-Stage TNBC (neoadjuvant, in combination with chemotherapy).[79]
• Recurrent or metastatic HNSCC (PD-L1 CPS ≥1, first-line, in combination with petosemtamab - February 2025).[17]
• FDA Priority Review: This designation is granted to drugs that, if approved, would offer significant improvements in safety or effectiveness for serious conditions. It shortens the FDA review timeline. Pembrolizumab has received Priority Review for several applications, including:
• Adjuvant Melanoma (Stage IIB/IIC - granted August 2021).[61]
• NSCLC (First-line, combination with chemotherapy for metastatic non-squamous).[54]
• cHL (Relapsed/Refractory, sBLA with PDUFA date March 15, 2017).[66]
• HNSCC (Resectable, locally advanced, perioperative treatment, PDUFA date June 23, 2025).[20]
• FDA Orphan Drug Designation: This designation is granted to drugs intended for the treatment, prevention, or diagnosis of a rare disease or condition. Pembrolizumab received this for:
• Advanced Melanoma (late 2012).[52]
• HER2-positive Gastric/GEJ Adenocarcinoma (first-line combination therapy).[19]

The numerous Breakthrough Therapy and Priority Review designations granted to Pembrolizumab underscore its substantial clinical advancements and the significant unmet medical needs it addresses across a spectrum of difficult-to-treat cancers. This accelerated pathway has been instrumental in bringing this transformative therapy to patients more rapidly than would have occurred under standard review timelines, fundamentally altering treatment paradigms. The pattern of receiving these designations for diverse indications highlights the consistent and compelling early clinical data generated by the KEYNOTE program, demonstrating Pembrolizumab's potential for major therapeutic advances. This regulatory success reflects both the drug's innovative mechanism and the FDA's commitment to expediting access to promising new cancer treatments.

VI. Clinical Efficacy Across Major Indications

The clinical development program for Pembrolizumab, primarily through the extensive series of KEYNOTE trials, has established its efficacy across a multitude of cancer types and settings. The following sections summarize key findings from pivotal trials.

A. Melanoma

• KEYNOTE-001 (Phase 1b): This early trial provided foundational evidence for Pembrolizumab's activity in advanced melanoma.[34] In a cohort of 655 patients (both treatment-naive and previously treated), the overall response rate (ORR) was 33% [33], with 10% achieving a complete response (CR).[80] Responses were notably durable, with a median duration of response (DOR) not reached and 73% of responses ongoing at data cutoff; the longest response was 66 months.[100] The 5-year overall survival (OS) was 34% for all patients and 41% for treatment-naive patients, with median OS of 23.8 months and 38.6 months, respectively.[34] The 5-year progression-free survival (PFS) rates were 21% (all patients) and 29% (treatment-naive).[34] The safety profile was considered tolerable, with treatment-related adverse events (TRAEs) in 86% of patients and Grade 3/4 TRAEs in 17%.[34]
• KEYNOTE-002 (Phase 2): This trial focused on patients with ipilimumab-refractory advanced melanoma (n=540).[68] Pembrolizumab demonstrated superior PFS compared to chemotherapy (HR 0.57 for 2 mg/kg dose, HR 0.50 for 10 mg/kg dose; P<0.0001 for both). The 6-month PFS rates were 34% (2 mg/kg) and 38% (10 mg/kg) for Pembrolizumab, versus 16% for chemotherapy.[69] ORR was also significantly higher with Pembrolizumab (21-25%) compared to chemotherapy (4%).[69] Median DOR was not reached with Pembrolizumab versus 37 weeks for chemotherapy.[69] Pembrolizumab was associated with fewer Grade 3-5 AEs (11-14%) compared to chemotherapy (26%).[69]
• KEYNOTE-006 (Phase 3): This pivotal trial compared Pembrolizumab to ipilimumab in patients with unresectable Stage III or IV advanced melanoma who were ipilimumab-naive.[35] Long-term follow-up (10 years) demonstrated sustained survival benefits for Pembrolizumab. Median OS was 32.7 months for Pembrolizumab versus 15.9 months for ipilimumab (HR 0.71).[35] The 10-year OS rate was 34.0% with Pembrolizumab versus 23.6% with ipilimumab.[35] Median modified PFS was 9.4 months versus 3.8 months (HR 0.64) [35], with 10-year mPFS rates of 22.0% versus 12.8%, respectively.[35] ORR was approximately 36-37% for Pembrolizumab versus 13% for ipilimumab.[80] The safety profile was generally manageable and favorable compared to ipilimumab.

B. Non-Small Cell Lung Cancer (NSCLC)

• KEYNOTE-010 (Phase 2/3, Previously Treated, PD-L1 TPS ≥1%): Compared to docetaxel, Pembrolizumab improved OS (HR 0.53 for PD-L1 TPS ≥50%; HR 0.69 for PD-L1 TPS ≥1%).[70] At 36 months, OS rates for PD-L1 TPS ≥50% were 34.5% (Pembrolizumab) vs 12.7% (docetaxel), and for PD-L1 TPS ≥1% were 22.9% vs 11.0%.[70] Responses were durable, and second-course treatment showed benefit.[70] Pembrolizumab had fewer Grade 3-5 TRAEs (16%) compared to docetaxel (37%).[70]
• KEYNOTE-024 (Phase 3, First-Line, PD-L1 TPS ≥50%): Pembrolizumab monotherapy was compared to platinum-based chemotherapy.[37] Median OS was 26.3 months with Pembrolizumab versus 13.4 months with chemotherapy (HR 0.62).[37] The 5-year OS rate was 31.9% versus 16.3%, respectively.[37] Median PFS was 7.7-10.3 months for Pembrolizumab versus 5.5-6.0 months for chemotherapy (HR 0.50).[37] ORR was 46.1% versus 31.1%, with a median DOR of 29.1 months versus 6.3 months.[37] The safety profile was manageable.[38]
• KEYNOTE-189 (Phase 3, First-Line, Metastatic Nonsquamous, regardless of PD-L1 expression): This trial evaluated Pembrolizumab plus pemetrexed and platinum chemotherapy versus placebo plus pemetrexed-platinum.[39] The combination significantly improved OS, with a median of 22.0 months versus 10.6-10.7 months for chemotherapy alone (HR 0.56-0.60).[39] The 5-year OS rate was 19.4% versus 11.3%.[39] Median PFS was also improved (8.8-9.0 months vs 4.9 months; HR 0.48-0.52) [39], with 5-year PFS rates of 7.5% versus 0.6%.[39] ORR was 48.3% versus 19.9% [39], with a median DOR of 12.7 months versus 7.1 months.[39] Safety was manageable, with Grade 3-5 AEs occurring in 71.9% of the combination arm versus 66.8% in the chemotherapy-alone arm.[40]

C. Head and Neck Squamous Cell Carcinoma (HNSCC)

• KEYNOTE-048 (Phase 3, First-Line, Recurrent/Metastatic): This trial compared Pembrolizumab monotherapy and Pembrolizumab plus chemotherapy to the EXTREME regimen (cetuximab + platinum + 5-FU).[41]
• Pembrolizumab monotherapy showed improved OS in patients with PD-L1 CPS ≥20 (median OS 14.9 vs 10.7 months; HR 0.61) and PD-L1 CPS ≥1 (median OS 12.3 vs 10.3 months; HR 0.74-0.78).[41]
• Pembrolizumab plus chemotherapy demonstrated superior OS in the total population (median OS 13.0 vs 10.7 months; HR 0.71-0.77), PD-L1 CPS ≥1 (median OS 13.6 vs 10.4 months; HR 0.64-0.65), and PD-L1 CPS ≥20 (median OS 14.7 vs 11.0 months; HR 0.60-0.62).[41] ORR for Pembro+Chemo in CPS ≥20 was 42.9-43.7% vs 38.2% for EXTREME, with median DOR of 7.1 vs 4.2 months.[41]
• Safety: Pembrolizumab monotherapy had a favorable safety profile. Pembrolizumab plus chemotherapy had comparable safety to the EXTREME regimen.[41]

D. Classical Hodgkin Lymphoma (cHL)

• KEYNOTE-087 (Phase 2, Relapsed/Refractory): Showed an ORR of 71.9% by blinded independent central review (BICR), with a CRR of 27.6%.[72] The median DOR was 16.5 months.[72] The safety profile was consistent with previous reports, with common TRAEs including hypothyroidism, pyrexia, and fatigue.[73]
• KEYNOTE-204 (Phase 3, Relapsed/Refractory): Pembrolizumab was compared to brentuximab vedotin (BV).[43] Pembrolizumab demonstrated superior PFS with a median of 13.2 months versus 8.3 months for BV (HR 0.65; P=0.00271).[43] The 12-month PFS rate was 53.9% for Pembrolizumab versus 35.6% for BV.[43] ORR was 65.6% for Pembrolizumab and 54.2% for BV, with CR rates of 24.5% and 24.2%, respectively.[43] Median DOR was longer with Pembrolizumab (20.7 months vs 13.8 months).[43] Grade 3-5 TRAEs occurred in 19.6% of Pembrolizumab patients versus 25.0% of BV patients; one death (pneumonia) was reported with Pembrolizumab.[43]

E. Urothelial Carcinoma

• KEYNOTE-045 (Phase 3, Second-Line, Platinum-Refractory): Pembrolizumab was compared to investigator's choice of chemotherapy (paclitaxel, docetaxel, or vinflunine).[47] Pembrolizumab showed a longer median OS (10.1-10.3 months vs 7.2-7.4 months; HR 0.71-0.73).[47] The 5-year OS rate was 14.9% versus 8.7%.[82] ORR was 21.1-21.9% for Pembrolizumab versus 11.0-11.4% for chemotherapy.[48] Median DOR was notably longer with Pembrolizumab (29.7 months vs 4.4 months).[47] Pembrolizumab had a more favorable safety profile, with lower rates of any grade TRAEs (60.9-62.0% vs 90.2-90.6%) and Grade ≥3 TRAEs (16.5-16.9% vs 50.2%).[48]
• KEYNOTE-052 (Phase 2, First-Line, Cisplatin-Ineligible): This single-arm study showed an ORR of 28.6-28.9%, with a CRR of 8.9-9.5%.[47] The median DOR was 30.1-33.4 months.[47] Median OS was 11.3 months [81], with 5-year follow-up data also available.[109] Patients with PD-L1 CPS ≥10 or lymph node-only disease had better outcomes.[81] The safety profile was consistent with known data, with no new signals.[47]
• KEYNOTE-057 (Phase 2, BCG-Unresponsive NMIBC):
• Cohort A (CIS +/- papillary tumors): Achieved a CRR of 41% at 3 months, with 46% of responders maintaining response for ≥12 months.[74]
• Cohort B (papillary tumors without CIS): Showed a 12-month disease-free survival (DFS) rate of 43.5%, with a median DFS of 7.7 months. Patients with PD-L1 CPS ≥10 had a higher 12-month DFS rate (54.1%) compared to those with CPS <10 (39.4%).[74] Safety was manageable, with Grade 3/4 TRAEs in 14% of Cohort B patients.[74]

F. Cervical Cancer

• KEYNOTE-028 (Phase 1b, Advanced, PD-L1+): ORR was 17% (all partial responses), with a median DOR of 5.4 months.[21] TRAEs occurred in 75% of patients, with Grade 3 TRAEs in 5 patients; no Grade 4 TRAEs or deaths were observed.[21]
• KEYNOTE-158 (Phase 2 Basket, Previously Treated Advanced): In the cervical cancer cohort (n=98), the ORR was 12.2%. All responses occurred in patients with PD-L1-positive tumors (ORR 14.6% in PD-L1+).[23] Median DOR was not reached.[23] Median OS was 9.4 months overall and 11.0 months in the PD-L1-positive population.[23] TRAEs occurred in 65.3% of patients, with Grade 3-4 TRAEs in 12.2%.[23]
• KEYNOTE-826 (Phase 3, First-Line, Persistent, Recurrent, or Metastatic): This trial evaluated Pembrolizumab plus chemotherapy with or without bevacizumab versus placebo plus chemotherapy with or without bevacizumab.[25] The addition of Pembrolizumab resulted in improved OS: median 26.4 months vs 16.8 months in the all-comer population. For PD-L1 CPS ≥1, median OS was 28.6 vs 16.5 months, and for PD-L1 CPS ≥10, median OS was 29.6 vs 17.4 months.[25] PFS was also improved (median 10.4 vs 8.2 months for all-comers).[25] ORR was higher and DOR was longer with the Pembrolizumab combination.[25] Grade ≥3 TRAEs were reported in 69.1% of the Pembrolizumab arm versus 65% in the placebo arm.[25]

G. MSI-H/dMMR Solid Tumors (including Colorectal Cancer - CRC)

• KEYNOTE-177 (Phase 3, First-Line, MSI-H/dMMR mCRC): Pembrolizumab was compared to standard chemotherapy +/- bevacizumab/cetuximab.[31]
• Median PFS was significantly improved with Pembrolizumab (16.5 months vs 8.2 months; HR 0.60).[50] The 2-year PFS rate was 48.3% vs 18.6%.[50]
• Median OS was 77.5 months with Pembrolizumab versus 36.7 months with chemotherapy (HR 0.73), despite an effective crossover rate of 62% from the chemotherapy arm to subsequent PD-(L)1 inhibitor therapy.[110] The 5-year OS rates were 54.8% versus 44.2%.[110] Initial OS data did not show statistical significance due to the high crossover rate.[51]
• ORR was 43.8% (11% CR) for Pembrolizumab versus 33.1% (3.9% CR) for chemotherapy.[50]
• Median DOR was substantially longer with Pembrolizumab (75.4 months, with some earlier reports stating "not reached") compared to 10.6 months for chemotherapy.[50]
• Pembrolizumab was associated with fewer Grade 3-5 TRAEs (22%) compared to chemotherapy (66-67%).[50]
• Pooled Analysis (KEYNOTE-158, -164, -051 for MSI-H/dMMR solid tumors): This analysis supported the tissue-agnostic approval. The ORR was 33.3% (CR 10.3%), with a median DOR of 63.2 months. Notably, 77% of responders had a response lasting 12 months or longer, and 39% had responses lasting 36 months or longer.[59]

The consistent demonstration of efficacy, particularly durable responses and improved overall survival in many settings, across a wide array of tumor types, underscores the broad applicability and profound impact of PD-1 blockade with Pembrolizumab. The benefit is often more pronounced in biomarker-selected populations (e.g., PD-L1 high expression, MSI-H/dMMR status). This pattern of success in numerous KEYNOTE trials has fundamentally changed the standard of care for many advanced cancers. The long-term survival data emerging from these trials provide hope for durable remission in a subset of patients. The success in biomarker-defined populations reinforces the critical importance of molecular testing in guiding personalized treatment decisions in oncology.

Table 3: Summary of Efficacy from Key Pivotal Trials (KEYNOTE series)

Trial ID	Cancer Type	Setting	Patient Population (Key Characteristics)	Pembrolizumab Arm Details	Comparator Arm Details	Median OS (Pembro vs Comp) (HR; 95% CI)	Median PFS (Pembro vs Comp) (HR; 95% CI)	ORR (Pembro vs Comp) (%)	Key Safety Summary (Pembro Arm)
KEYNOTE-006	Melanoma	Advanced, Ipilimumab-Naive	Unresectable Stage III/IV	Pembrolizumab 10 mg/kg q2w or q3w	Ipilimumab 3 mg/kg q3w	32.7 vs 15.9 mo (HR 0.71) (10-yr) 35	9.4 vs 3.8 mo (HR 0.64) (10-yr) 35	~36-37 vs ~13 80	Favorable vs Ipilimumab
KEYNOTE-024	NSCLC	First-Line, Metastatic	PD-L1 TPS ≥50%, no EGFR/ALK	Pembrolizumab 200 mg q3w	Platinum-based Chemo	26.3 vs 13.4 mo (HR 0.62) (5-yr) 37	7.7-10.3 vs 5.5-6.0 mo (HR 0.50) 37	46.1 vs 31.1 37	Manageable toxicity 38
KEYNOTE-189	NSCLC	First-Line, Metastatic Nonsquamous	No EGFR/ALK, regardless of PD-L1	Pembrolizumab + Pemetrexed/Platinum	Placebo + Pemetrexed/Platinum	22.0 vs 10.6-10.7 mo (HR 0.56-0.60) (5-yr) 39	8.8-9.0 vs 4.9 mo (HR 0.48-0.52) (5-yr) 39	48.3 vs 19.9 39	Grade 3-5 AEs: 71.9% 40
KEYNOTE-048	HNSCC	First-Line, Recurrent/Metastatic	PD-L1 CPS ≥20 (for Pembro mono & Pembro+Chemo vs EXTREME)	Pembro mono; Pembro + Chemo	EXTREME regimen	P-mono: 14.9 vs 10.7 mo (HR 0.61); P+C: 14.7 vs 11.0 mo (HR 0.60-0.62) 41	PFS2 improved 42	P+C: 43-44 vs 38 41	P-mono favorable; P+C comparable to EXTREME 41
KEYNOTE-204	cHL	Relapsed/Refractory	Post-ASCT or ASCT-ineligible	Pembrolizumab 200 mg q3w	Brentuximab Vedotin (BV) 1.8 mg/kg q3w	OS data immature at interim 44	13.2 vs 8.3 mo (HR 0.65) 43	65.6 vs 54.2 43	Grade 3-5 TRAEs: 19.6% (1 death) 43
KEYNOTE-045	Urothelial Ca	Second-Line, Platinum-Refractory	Advanced	Pembrolizumab 200 mg q3w	Chemo (Paclitaxel, Docetaxel, or Vinflunine)	10.1-10.3 vs 7.2-7.4 mo (HR 0.71-0.73) (5-yr) 47	PFS not significantly different 48	21.1-21.9 vs 11.0-11.4 48	Fewer TRAEs vs Chemo (Grade ≥3: ~17% vs ~50%) 48
KEYNOTE-052	Urothelial Ca	First-Line, Cisplatin-Ineligible	Advanced	Pembrolizumab 200 mg q3w	Single-arm study	Median OS 11.3 mo (5-yr data) 47	N/A	28.6-28.9 47	No new safety signals 47
KEYNOTE-826	Cervical Ca	First-Line, Persistent/Recurrent/Metastatic	PD-L1 CPS ≥1 (primary); All-comers	Pembrolizumab + Chemo +/- Bevacizumab	Placebo + Chemo +/- Bevacizumab	All-comers: 26.4 vs 16.8 mo 25	All-comers: 10.4 vs 8.2 mo 25	Higher ORR 25	Grade ≥3 TRAEs: 69.1% 25
KEYNOTE-177	MSI-H/dMMR CRC	First-Line, Metastatic	MSI-H or dMMR	Pembrolizumab 200 mg q3w	Chemo +/- Bevacizumab/Cetuximab	77.5 vs 36.7 mo (HR 0.73) (5-yr, post-crossover) 110	16.5 vs 8.2 mo (HR 0.60) 50	43.8 vs 33.1 50	Fewer Grade 3-5 TRAEs (22% vs 66-67%) 50

Abbreviations: OS=Overall Survival, PFS=Progression-Free Survival, ORR=Objective Response Rate, HR=Hazard Ratio, CI=Confidence Interval, mo=months, q2w=every 2 weeks, q3w=every 3 weeks, Ca=Cancer, Chemo=Chemotherapy, Pembro=Pembrolizumab, Comp=Comparator, R/M=Recurrent/Metastatic, Adjuv=Adjuvant, Met=Metastatic, Adv=Advanced, Pop=Population, Plat=Platinum, Uro=Urothelial, MSI-H=Microsatellite Instability-High, dMMR=Mismatch Repair Deficient.

VII. Safety and Tolerability Profile

The use of Pembrolizumab, while offering significant therapeutic benefits, is associated with a unique spectrum of adverse events, primarily immune-related, stemming from its mechanism of action.

A. Overview of Common Adverse Events

The most frequently reported adverse reactions vary depending on whether Pembrolizumab is administered as a single agent or in combination with other therapies.

• Monotherapy [3]: Commonly observed adverse events (≥20% of patients) include fatigue, musculoskeletal pain, rash, diarrhea, pyrexia (fever), cough, decreased appetite, pruritus (itching), dyspnea (shortness of breath), constipation, pain, abdominal pain, nausea, and hypothyroidism. The EMA SmPC highlights fatigue (31%), diarrhoea (22%), and nausea (20%) as the most frequent with monotherapy, mostly Grade 1 or 2 in severity.
• Combination Therapy [3]: When Pembrolizumab is used in combination, the adverse event profile generally includes those seen with monotherapy plus toxicities associated with the combination partner(s). For example, with chemotherapy, common AEs include nausea, anemia, fatigue, diarrhea, constipation, vomiting, neutropenia, and alopecia. When combined with tyrosine kinase inhibitors (TKIs) like axitinib or lenvatinib, common AEs include diarrhea, hypertension, hypothyroidism, fatigue, and palmar-plantar erythrodysesthesia.

B. Detailed Discussion of Immune-Related Adverse Events (irAEs)

The core mechanism of Pembrolizumab involves enhancing the body's immune response, which can lead to immune-mediated adverse reactions (irAEs). These irAEs can affect any organ system or tissue and may occur at any time during or even after discontinuation of treatment. Multiple irAEs can also occur simultaneously. Severe or fatal cases have been reported.[3]

• Immune-Mediated Pneumonitis: Inflammation of the lungs is a serious irAE. The FDA label reports an incidence of 3.4% (fatal in 0.1%), while the EMA SmPC notes 4.2% (fatal in 0.1%). Management involves corticosteroids and withholding or permanently discontinuing Pembrolizumab based on severity.[3]
• Immune-Mediated Colitis: Inflammation of the colon, often presenting as diarrhea. The FDA label indicates an incidence of 1.7%, and the EMA SmPC reports 2.1%. Management includes corticosteroids and dose modifications.[3]
• Immune-Mediated Hepatitis (and Hepatotoxicity with combinations): Liver inflammation can occur. The FDA label notes an incidence of 0.7% with monotherapy, with higher rates of liver enzyme elevations when combined with axitinib. The EMA SmPC reports a 1.0% incidence. Corticosteroids and dose adjustments are key to management.[3]
• Immune-Mediated Endocrinopathies: These are relatively common irAEs.
• Hypophysitis: Inflammation of the pituitary gland. Incidence: FDA 0.6%; EMA 0.7%. Management involves corticosteroids, hormone replacement, and dose modifications.[3]
• Thyroid Disorders: Including thyroiditis, hyperthyroidism, and hypothyroidism. Hypothyroidism is common (FDA: 8%; EMA: 12.3%), as is hyperthyroidism (FDA: 3.4%; EMA: 5.2%). Management includes hormone replacement and monitoring; severe hyperthyroidism may require withholding treatment.[3]
• Type 1 Diabetes Mellitus: Can occur, sometimes presenting with diabetic ketoacidosis. Incidence (FDA): 0.2%. Requires insulin and withholding Pembrolizumab for severe hyperglycemia.[3]
• Adrenal Insufficiency: Incidence: FDA 0.8%; EMA 1.0%.[3]
• Immune-Mediated Nephritis with Renal Dysfunction: Kidney inflammation. Incidence: FDA 0.3%; EMA 0.5%. Management includes corticosteroids and dose modifications.[3]
• Immune-Mediated Dermatologic Adverse Reactions: Severe skin reactions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS), can occur. Incidence of severe reactions: FDA 1.4%; EMA 1.7%. Management involves corticosteroids and dose adjustments.[3]
• Immune-Mediated Myocarditis: Rare but potentially fatal inflammation of the heart muscle. Requires permanent discontinuation and corticosteroid administration.[3]
• Immune-Mediated Neurological Toxicities: Includes meningitis, encephalitis, myelitis, Guillain-Barré syndrome, and myasthenic syndrome. Severe cases warrant permanent discontinuation and corticosteroids.[3]
• Other Clinically Significant irAEs: A range of other irAEs affecting various organ systems have been reported at lower frequencies (<1% unless noted by FDA), including uveitis, arthritis (1.5% FDA), myositis/polymyositis, rhabdomyolysis, pancreatitis, hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, sarcoidosis, immune thrombocytopenic purpura, and solid organ transplant rejection.[3]

C. Management Strategies for irAEs

The successful use of Pembrolizumab relies heavily on the early identification and appropriate management of irAEs.[3]

• Monitoring: Patients should be closely monitored for signs and symptoms. Baseline and periodic evaluation of liver enzymes, creatinine, and thyroid function are recommended. For patients with TNBC receiving neoadjuvant therapy, blood cortisol monitoring is also advised.[6]
• General Approach: For suspected irAEs, a thorough workup is necessary to confirm the diagnosis and exclude other causes, such as infection. Treatment decisions are based on the severity of the reaction. Generally, for Grade 2 (moderate) irAEs, Pembrolizumab is withheld. For Grade 3 (severe) irAEs that recur, or for any Grade 4 (life-threatening) irAE, Pembrolizumab is permanently discontinued (exceptions exist for endocrinopathies manageable with hormone replacement).[3]
• Corticosteroid Therapy: Systemic corticosteroids (e.g., prednisone 1-2 mg/kg/day or equivalent) are the cornerstone of managing moderate to severe irAEs. Once the irAE improves to Grade 1 or less, corticosteroids should be tapered gradually over at least one month.[3]
• Other Immunosuppressants: If irAEs are not adequately controlled with corticosteroids, the use of other systemic immunosuppressive agents may be considered.[3]
• Patient Education: Patients are typically provided with an alert card detailing the risks of irAEs, symptoms to watch for, and instructions to contact their physician immediately if they occur. Self-treatment of irAEs is discouraged.[3]

D. Infusion-Related Reactions

Infusion-related reactions, including hypersensitivity and anaphylaxis, can occur. Mild to moderate reactions may be managed by interrupting or slowing the infusion rate. Severe or life-threatening reactions necessitate permanent discontinuation of Pembrolizumab.[3]

E. Warnings, Precautions, and Contraindications

• FDA [6]:
• While no explicit "Black Box Warning" is detailed in the provided snippets for general use, the prescribing information emphasizes the potential for severe and fatal immune-mediated adverse reactions.
• No specific contraindications are listed in the provided snippets for general use.[6]
• A significant warning exists regarding increased mortality when Pembrolizumab is added to a thalidomide analogue plus dexamethasone for the treatment of multiple myeloma; this combination is not recommended outside of controlled clinical trials.[6]
• Embryo-fetal toxicity is a concern (Pregnancy Category D), and women of reproductive potential should be counseled on the risks and the need for effective contraception.[6]
• EMA [3]:
• The primary contraindication listed is hypersensitivity to Pembrolizumab or any of its excipients.[3]
• Warnings are extensive and cover the spectrum of irAEs, infusion-related reactions, and complications related to allogeneic hematopoietic stem cell transplantation (HSCT).[3]

The distinct safety profile of Pembrolizumab, characterized by irAEs, necessitates a departure from traditional chemotherapy toxicity management. Effective use requires heightened clinician awareness, proactive patient monitoring, and adherence to established guidelines for irAE management. This specialized approach is critical to maximizing the therapeutic benefits of Pembrolizumab while mitigating potential risks.

Table 4: Common and Significant Immune-Related Adverse Events (irAEs) of Pembrolizumab

Organ System/irAE Type	FDA Incidence (All Grades %) (Fatal %)	EMA Incidence (All Grades %) (Fatal %)	Median Time to Onset (Approx.)	Key Management Principles (General)
Pneumonitis	3.4 (0.1) 6	4.2 (0.1) 3	3.9 months 3	Withhold G2; Permanently discontinue G3/4 or recurrent G2. Administer corticosteroids. 3
Colitis	1.7 (<0.1 for G4) 6	2.1 (<0.1 for G4) 3	4.3 months 3	Withhold G2/3; Permanently discontinue G4 or recurrent G3. Administer corticosteroids. 3
Hepatitis (Monotherapy)	0.7 (<0.1 for G4) 6	1.0 (<0.1 for G4) 3	3.5 months 3	Withhold or discontinue based on LFT elevations. Administer corticosteroids. Specific guidance for combo with axitinib. 3
Nephritis	0.3 (<0.1 for G4) 6	0.5 (<0.1 for G4) 3	4.2 months 3	Withhold G2; Permanently discontinue G3/4. Administer corticosteroids. 3
Endocrinopathies
Hypophysitis	0.6 (<0.1 for G4) 6	0.7 3	5.9 months 3	Withhold G2; Withhold or discontinue G3/4. Hormone replacement. Corticosteroids for symptomatic. 3
Thyroid Disorders	Hyper: 3.4; Hypo: 8.0 6	Hyper: 5.2; Hypo: 12.3 3	Hyper: 1.4 mo; Hypo: 3.4 mo 3	Monitor thyroid function. Manage with hormone replacement as needed. Withhold for severe hyperthyroidism. 3
Type 1 Diabetes	0.2 6	N/A in summary table 3	Variable	Administer insulin. Withhold for G≥3 hyperglycemia/ketoacidosis. 3
Adrenal Insufficiency	0.8 6	1.0 3	5.4 months 3	Withhold G2; Withhold or discontinue G3/4. Hormone replacement. 3
Dermatologic Reactions (Severe)	1.4 6	1.7 3	2.8 months 3	Withhold G3; Permanently discontinue G4 or SJS/TEN. Administer corticosteroids. 3
Myocarditis	<1 (can be fatal) 6	<1 (can be fatal) 3	Variable	Permanently discontinue for G3/4. Administer high-dose corticosteroids. 3
Infusion-Related Reactions	0.2 (Severe/Life-threatening) 6	N/A in summary table 3	During/shortly after infusion	Interrupt or slow rate for mild/moderate; Permanently discontinue for severe/life-threatening. 3

G=Grade. N/A=Not available in the summarized table format in the snippet. LFT=Liver Function Tests. SJS/TEN=Stevens-Johnson syndrome/Toxic Epidermal Necrolysis. Incidence data is a general summary; refer to full prescribing information for specific combination therapy data.

VIII. Dosing and Administration

A. Recommended Dosing Regimens

The dosing of Pembrolizumab has been standardized for most indications to simplify clinical practice.

• Adults: The generally recommended dose is either 200 mg administered intravenously every 3 weeks or 400 mg intravenously every 6 weeks.[3] These regimens are considered to provide comparable exposure and efficacy based on pharmacokinetic and pharmacodynamic modeling.[3]
• Pediatric Patients: For approved pediatric indications, such as classical Hodgkin lymphoma (cHL) in patients aged 3 years and older and melanoma in patients aged 12 years and older, the recommended dose is 2 mg/kg (up to a maximum of 200 mg) intravenously every 3 weeks.[3]
• Dose Modifications: Dose adjustments for Pembrolizumab itself (i.e., dose reduction) are generally not recommended. Instead, management of adverse reactions involves withholding or permanently discontinuing treatment based on the type and severity of the toxicity, often in conjunction with corticosteroid administration as detailed in Section VII.C.[3] Specific guidelines exist for managing toxicities when Pembrolizumab is used in combination with other agents like axitinib or lenvatinib.[6]

B. Administration Guidelines

Pembrolizumab is administered as an intravenous infusion over a period of 30 minutes.[3] Standard protocols for the preparation and handling of monoclonal antibodies should be followed. This includes reconstitution of lyophilized powder (if applicable for the formulation used) and dilution in a compatible intravenous solution prior to administration.

IX. Conclusion and Future Perspectives

A. Summary of Pembrolizumab's Role in Oncology

Pembrolizumab has unequivocally revolutionized the treatment landscape for a multitude of cancers, firmly establishing immunotherapy, and specifically PD-1 blockade, as a cornerstone of modern oncology. Its efficacy, characterized by durable responses and improved overall survival in many instances, has been consistently demonstrated across an extensive range of tumor types and clinical settings—from metastatic disease to adjuvant and neoadjuvant scenarios. The approval of Pembrolizumab for tissue-agnostic indications, such as MSI-H/dMMR solid tumors, represents a paradigm shift towards personalized medicine, where treatment is guided by molecular biomarkers rather than solely by the anatomical site of the cancer's origin. This has not only provided new hope for patients with previously limited options but has also spurred a transformation in diagnostic practices, emphasizing the need for comprehensive genomic profiling.

B. Ongoing Research and Potential Future Directions

The journey of Pembrolizumab is far from complete, with active research continuing to explore its full potential.

• Novel Combinations: A significant area of investigation involves combining Pembrolizumab with other therapeutic modalities. These include other immune checkpoint inhibitors, targeted therapies (such as TKIs like lenvatinib and axitinib, or other novel agents), chemotherapy, radiotherapy, and emerging immunotherapies like oncolytic viruses or novel cytokine-based therapies (e.g., denfivontinib [114]). The rationale is to overcome primary or acquired resistance to PD-1 blockade and to enhance the depth and durability of anti-tumor responses.
• Expansion to Earlier Lines of Therapy: Building on its success in advanced disease, Pembrolizumab is increasingly being evaluated and approved for use in earlier stages of cancer, including neoadjuvant (pre-operative) and adjuvant (post-operative) settings. The aim here is to improve cure rates and prevent disease recurrence in patients with localized but high-risk disease. Numerous KEYNOTE trials have already led to approvals in these settings for various cancers like melanoma, NSCLC, and TNBC.
• Biomarker Development: While PD-L1 expression and MSI-H/dMMR status are established biomarkers, there is a pressing need for more refined predictive biomarkers. Research is focused on identifying signatures within the tumor microenvironment, host immune factors, and tumor genomics/transcriptomics that can more accurately predict which patients are most likely to benefit from Pembrolizumab, who may require combination strategies, or who are at higher risk of irAEs.
• Understanding and Overcoming Resistance: Mechanisms of primary and acquired resistance to PD-1 blockade are a major focus of research. This involves investigating the role of the tumor microenvironment, alternative immune checkpoints, tumor escape mutations, and metabolic factors that may limit T-cell function.
• Optimizing Treatment Duration and Managing Long-Term Effects: As more patients achieve long-term survival with Pembrolizumab, questions regarding the optimal duration of therapy and the management of chronic or late-onset irAEs become increasingly important. Studies are exploring de-escalation strategies or fixed-duration treatments for responders.
• Novel Formulations and Delivery Methods: The development of subcutaneous formulations of Pembrolizumab, as demonstrated by studies with co-formulations like berahyaluronidase alfa [99], aims to improve patient convenience, reduce healthcare resource utilization, and potentially allow for home-based administration in the future.

The trajectory of Pembrolizumab illustrates a dynamic interplay between scientific discovery, innovative clinical trial design, and evolving regulatory landscapes. Its success has not only provided a powerful new weapon against cancer but has also deepened the understanding of tumor immunology, paving the way for the next generation of immunotherapeutic strategies. The future of Pembrolizumab likely lies in more personalized and combination-oriented approaches, tailored to individual patient and tumor characteristics, with a continued emphasis on maximizing efficacy while carefully managing its unique safety profile. The ongoing research will be crucial in further refining its role and extending its benefits to an even broader population of cancer patients.

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