What Is Keytruda (Pembrolizumab)?
Keytruda is the brand name for pembrolizumab, a PD-1 checkpoint inhibitor immunotherapy developed by Merck that has fundamentally changed the landscape of oncology since its first FDA approval in 2014. It has since become one of the most widely approved cancer drugs in history — with indications spanning more than 20 distinct cancer types — and briefly became the world's top-selling pharmaceutical drug by revenue. Understanding Keytruda means understanding why harnessing the immune system to fight cancer has proved to be one of medicine's most important breakthroughs in decades.
How Checkpoint Inhibitors Work: Releasing the Brakes on T Cells
The immune system has built-in "checkpoint" mechanisms — molecular brakes that prevent T cells from becoming overactivated and attacking healthy tissue. These checkpoints evolved to prevent autoimmunity. Cancer cells, however, have learned to exploit these same checkpoints to evade immune attack. Specifically, many tumors express a protein called PD-L1 (programmed death ligand 1) on their surface. When PD-L1 on a cancer cell binds to PD-1 (programmed death protein 1) on a T cell, it sends an inhibitory signal that tells the T cell to stand down — essentially disguising the tumor as "self" to escape immune surveillance.
Pembrolizumab is a humanized monoclonal antibody that binds to PD-1 on T cells and blocks the interaction between PD-1 and its ligands (PD-L1 and PD-L2). By blocking this checkpoint, pembrolizumab "releases the brakes" — allowing tumor-infiltrating T cells to recognize and attack cancer cells that had previously evaded immune destruction. The result is not a direct toxic attack on cancer cells (as with chemotherapy) but rather restoration of the immune system's natural ability to eliminate aberrant cells.
FDA-Approved Cancer Types (Selected)
| Cancer Type | Notable Biomarker Requirement |
|---|---|
| Melanoma (unresectable or metastatic) | None required |
| Non-small cell lung cancer (NSCLC) | PD-L1 ≥1% (various settings) |
| Head and neck squamous cell carcinoma | PD-L1 CPS ≥1 |
| Classical Hodgkin lymphoma | None required |
| Urothelial carcinoma (bladder) | PD-L1 CPS ≥10 (certain settings) |
| Colorectal cancer | MSI-H or dMMR required |
| Gastric/GEJ adenocarcinoma | PD-L1 CPS ≥1 |
| Triple-negative breast cancer | PD-L1 CPS ≥10 |
| Cervical cancer | PD-L1 CPS ≥1 |
| Solid tumors (tumor-agnostic) | MSI-H/dMMR or TMB-H ≥10 mut/Mb |
The Biomarkers: Why Keytruda Works Better for Some Patients
PD-L1 expression
Because pembrolizumab works by blocking the PD-1/PD-L1 interaction, tumors that express more PD-L1 on their surface often (but not always) respond better to checkpoint inhibitor therapy. PD-L1 expression is tested using immunohistochemistry on tumor tissue and is typically reported as a Combined Positive Score (CPS) or Tumor Proportion Score (TPS), depending on the indication. High PD-L1 expression generally predicts better response, though some patients with low PD-L1 still respond and vice versa.
MSI-H / dMMR: The Tumor-Agnostic Approval
Microsatellite instability-high (MSI-H) and deficient mismatch repair (dMMR) tumors have defective DNA repair machinery, which causes them to accumulate large numbers of mutations and produce many abnormal proteins that the immune system can recognize. In 2017, Keytruda became the first cancer drug ever approved based on a genetic biomarker rather than tumor location — an accelerated approval covering any MSI-H or dMMR solid tumor regardless of where in the body it originated. This "tumor-agnostic" approval was a landmark in precision oncology.
Tumor mutational burden (TMB) is a measure of the total number of mutations in a tumor's genome. Like MSI-H, high TMB tumors may be more visible to the immune system due to the abundance of abnormal proteins they produce. In 2020, the FDA granted accelerated approval for pembrolizumab in adults with unresectable or metastatic TMB-high (≥10 mutations per megabase) solid tumors that have progressed following prior treatment, making TMB the second tumor-agnostic biomarker for checkpoint inhibitor use.
Immune-Related Adverse Events (irAEs)
Because pembrolizumab releases the immune system's brakes, the immune system can — in some patients — begin attacking healthy tissue. These immune-related adverse events (irAEs) can affect virtually any organ system and are distinct from the side effects seen with traditional chemotherapy:
IMMUNE-RELATED ADVERSE EVENTS: Pembrolizumab can cause severe and potentially life-threatening immune reactions including pneumonitis (lung inflammation — symptoms: new or worsening cough, shortness of breath, chest pain), colitis (diarrhea, abdominal pain, blood in stool), hepatitis (elevated liver enzymes, jaundice), endocrinopathies (hypothyroidism, hyperthyroidism, adrenal insufficiency, type 1 diabetes), nephritis, and severe skin reactions. Many irAEs are treated with corticosteroids; severe cases may require permanent discontinuation of pembrolizumab. Patients should report any new or unusual symptoms to their oncology team promptly — even those that seem unrelated to cancer treatment.
The frequency and severity of irAEs varies by indication, patient characteristics, and immune status. Endocrine irAEs (particularly hypothyroidism) often require long-term hormone replacement even after pembrolizumab is stopped, because the immune system can permanently damage glands. Pneumonitis and colitis, while less common, can be severe and require aggressive management.
How Keytruda Differs from Chemotherapy
Traditional chemotherapy targets rapidly dividing cells — killing cancer cells but also harming healthy rapidly dividing cells (hair follicles, GI tract lining, bone marrow), which produces the classic chemotherapy side effects of hair loss, nausea, fatigue, and infection risk. Pembrolizumab does not work this way at all. It does not directly damage cancer cells. Instead, it enables the immune system to recognize and attack them. This means:
- No hair loss from pembrolizumab itself (though combination regimens with chemotherapy will still cause it)
- Different and sometimes delayed responses — some patients experience tumor growth before response (pseudoprogression) or respond very late
- Potentially durable responses in some patients, even after stopping therapy, because activated immune memory persists
- Side effects that reflect immune activation rather than cytotoxicity (the irAEs described above)
Want to look up Keytruda's full side effect profile or interactions?
Explore Drug EncyclopediaFrequently Asked Questions
Keytruda (pembrolizumab) has FDA approval for over 20 cancer types, including melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, classical Hodgkin lymphoma, urothelial (bladder) cancer, colorectal cancer with MSI-H/dMMR, gastric cancer, cervical cancer, triple-negative breast cancer, endometrial cancer, biliary tract cancer, esophageal cancer, and any solid tumor with high tumor mutational burden (TMB-H) or MSI-H/dMMR regardless of tumor origin (tumor-agnostic approvals). The specific setting (first-line, second-line, with or without chemotherapy) and any biomarker requirements vary by indication.
Keytruda's side effects differ fundamentally from chemotherapy. Because it activates the immune system, the main risks are immune-related adverse events (irAEs) — the immune system attacking healthy organs. Common irAEs include hypothyroidism, skin rash, and fatigue. More serious but less common irAEs include pneumonitis (lung inflammation), colitis (gut inflammation), hepatitis (liver inflammation), and various endocrine gland disorders including adrenal insufficiency and type 1 diabetes. Any new or unusual symptom while on Keytruda — even something that seems unrelated to cancer — should be reported to the oncology team promptly, as irAEs can progress quickly without treatment.
Chemotherapy drugs directly kill cells that are dividing rapidly — which includes cancer cells but also healthy cells like hair follicles and gut lining. This produces the familiar side effects of hair loss, nausea, mouth sores, and increased infection risk. Keytruda does not directly kill cancer cells. Instead, it removes the molecular "off switch" that prevents immune T cells from attacking the tumor. This allows the immune system to do the work of eliminating cancer cells. Because the mechanism is fundamentally different, Keytruda's side effects are also fundamentally different — they reflect immune system overactivation rather than cellular toxicity. Some patients achieve durable, long-term responses on pembrolizumab that persist even after the drug is stopped.