Last updated: October 9, 2026
KEYTRUDA, Merck & Co.’s pembrolizumab, is the largest oncology product by global sales and the company’s primary growth engine. Revenue rose from $21.2 billion in 2022 to $25.0 billion in 2023, an 18% increase. Growth has come from expanded use across tumor types, earlier-stage treatment, combination regimens, and international adoption.
The commercial risk is concentrated in the late 2020s. Merck identifies 2028 as the expected U.S. loss-of-exclusivity period for key pembrolizumab composition patents, although formulation, delivery, manufacturing, and method-of-use rights could affect the timing and scope of competitive entry. KEYTRUDA’s financial trajectory therefore depends on three variables: continued label expansion before 2028, conversion of intravenous treatment to longer-duration or subcutaneous formats, and the speed of biosimilar entry after core patent protection expires.
How large is the KEYTRUDA market?
KEYTRUDA is the leading PD-1/L1 immune checkpoint inhibitor by revenue and has one of the broadest oncology labels in the United States.
| Metric |
2022 |
2023 |
| KEYTRUDA global revenue |
$21.2 billion |
$25.0 billion |
| Year-over-year growth |
22% |
18% |
| Merck total revenue |
$59.3 billion |
$60.1 billion |
| KEYTRUDA share of Merck revenue |
Approximately 36% |
Approximately 42% |
Source: Merck & Co. annual reports.[1,2]
KEYTRUDA is approved in more than 20 cancer indications or disease settings, including non-small-cell lung cancer, melanoma, renal cell carcinoma, head and neck cancer, urothelial carcinoma, triple-negative breast cancer, cervical cancer, endometrial cancer, gastric cancer, esophageal cancer, colorectal cancer with certain biomarkers, and classical Hodgkin lymphoma.[3]
The product’s market is divided into four commercial segments:
- Metastatic and advanced disease, where KEYTRUDA competes with other checkpoint inhibitors and targeted therapies.
- Adjuvant treatment, which moves immunotherapy into earlier-stage disease after surgery.
- Neoadjuvant and perioperative treatment, particularly in lung, breast, and other solid tumors.
- Combination regimens, where KEYTRUDA is used with chemotherapy, targeted agents, or other immunotherapies.
Earlier-line treatment is strategically important because it increases the number of eligible patients and can lengthen treatment duration. It also raises payer scrutiny because treatment may be administered to patients with a higher probability of cure.
What drove KEYTRUDA revenue growth?
The principal growth drivers were new indications, higher treatment volumes, and expanded use in earlier disease.
Lung cancer expansion
Non-small-cell lung cancer remains one of the most important KEYTRUDA markets. The drug is used in metastatic disease and in perioperative settings. Its combination with chemotherapy and use in patients selected by PD-L1 expression or other clinical criteria have supported broad adoption.
The perioperative lung cancer market is commercially significant because it can add treatment before and after surgery, increasing total drug exposure per patient. This strategy also creates a larger addressable market than single-line metastatic treatment.
Breast cancer
KEYTRUDA has gained an important position in high-risk early-stage and metastatic triple-negative breast cancer. The early-stage indication is commercially relevant because treatment begins before surgery and continues after surgery. Merck’s competitive position depends on clinical outcomes, treatment duration, and the ability of physicians and payers to accept immunotherapy in earlier disease.
Gynecologic cancers
Endometrial and cervical cancer indications have expanded KEYTRUDA’s reach in tumors with meaningful unmet need. Merck has also pursued combination strategies, including use with lenvatinib in advanced endometrial cancer and other tumor types.
Biomarker-defined populations
KEYTRUDA benefits from biomarker-based prescribing in areas such as PD-L1 expression, microsatellite instability-high disease, mismatch-repair deficiency, and tumor mutational burden. Biomarkers can improve clinical positioning but reduce the addressable population in indications that require testing.
International growth
International sales have benefited from expanded reimbursement and regulatory approvals. Pricing outside the United States is generally lower, but overseas volume remains important because the product has broad approval and a large oncology population.
How does KEYTRUDA compare with competing immunotherapies?
KEYTRUDA competes primarily with Opdivo, Tecentriq, Imfinzi, Bavencio, and Libtayo. Its main commercial advantage is label breadth and the number of approved combination and perioperative uses.
| Product |
Sponsor |
Target |
Commercial position |
| KEYTRUDA |
Merck |
PD-1 |
Broadest oncology label and highest revenue |
| Opdivo |
Bristol Myers Squibb |
PD-1 |
Strong in lung, renal, gastrointestinal, and other cancers |
| Yervoy |
Bristol Myers Squibb |
CTLA-4 |
Primarily used in combination with Opdivo |
| Tecentriq |
Roche |
PD-L1 |
Established in lung, liver, and other cancers |
| Imfinzi |
AstraZeneca |
PD-L1 |
Strong position in lung cancer and biliary tract cancer |
| Libtayo |
Regeneron and Sanofi |
PD-1 |
Smaller commercial base, with strength in selected tumors |
KEYTRUDA’s advantage is not based only on mechanism. It is based on clinical development scale, regulatory execution, physician familiarity, combination partnerships, and a large body of survival data.
The competitive threat is stronger in indications where several checkpoint inhibitors have comparable efficacy. In those markets, pricing, convenience, treatment duration, supply reliability, and combination economics can influence market share.
What is the financial trajectory for KEYTRUDA?
KEYTRUDA has shifted Merck’s revenue mix toward oncology and offset declines in older products, including Januvia and Janumet.
| Year |
KEYTRUDA revenue |
Growth |
| 2020 |
Approximately $14.4 billion |
Approximately 30% |
| 2021 |
Approximately $17.2 billion |
Approximately 20% |
| 2022 |
Approximately $21.2 billion |
Approximately 22% |
| 2023 |
Approximately $25.0 billion |
Approximately 18% |
Source: Merck & Co. annual reports.[1,2]
Revenue growth has remained strong despite the product’s scale. A product generating more than $25 billion annually faces a mathematical challenge: maintaining double-digit growth requires several billion dollars of incremental sales each year.
Merck’s near-term growth levers include:
- Additional perioperative and adjuvant approvals.
- Expansion into earlier lines of therapy.
- Combination use with antibody-drug conjugates and targeted agents.
- Broader international reimbursement.
- Increased use in biomarker-defined tumors.
- New dosage and delivery formats.
- Lifecycle management that extends use beyond the core intravenous product.
Merck has not publicly disclosed KEYTRUDA’s product-level operating margin. The product has a high-value biologic profile, but profitability is reduced by clinical-development expense, manufacturing capacity, royalties or collaboration economics in certain combinations, rebates, and international pricing.
When does KEYTRUDA lose exclusivity?
The key U.S. loss-of-exclusivity date is generally identified as 2028 for pembrolizumab’s core composition-of-matter patent protection. The actual competitive timetable can differ by patent, product presentation, settlement, regulatory approval, and court outcome.
Key exclusivity elements
| Protection or right |
Strategic effect |
| Core antibody and composition patents |
Primary barrier to biosimilar competition |
| Manufacturing and cell-line technology |
Can complicate biosimilar development and comparability |
| Formulation patents |
May protect concentration, stability, or excipient combinations |
| Method-of-use patents |
Can delay or narrow competition in specific indications |
| FDA biologic exclusivity |
Provides regulatory protection separate from patent rights |
| Litigation settlements |
Can establish negotiated biosimilar entry dates |
Pembrolizumab was approved by the FDA in September 2014. The reference product received 12 years of reference-product exclusivity under the Biologics Price Competition and Innovation Act, but that exclusivity period has already expired. Patent protection, rather than regulatory exclusivity, is the main remaining barrier to U.S. biosimilar competition.[3,4]
What patents protect KEYTRUDA?
KEYTRUDA’s patent estate includes composition, antibody, formulation, manufacturing, and method-of-use claims. Public reporting has identified U.S. Patent No. 8,354,509 as a central pembrolizumab patent, with expiration generally reported in 2028 after applicable patent-term adjustments.[5]
The commercial protection is broader than one patent. Merck has pursued additional patents covering:
- Anti-PD-1 antibodies and binding properties.
- Cell lines and recombinant production.
- Pharmaceutical formulations.
- High-concentration or extended-stability formulations.
- Dosing regimens.
- Combination treatments.
- Specific cancer indications.
- Biomarker-selected patient populations.
The practical value of secondary patents varies. A composition patent can block a biosimilar broadly. A method-of-use patent may be difficult to enforce against a biosimilar that uses a skinny label excluding the patented indication. Formulation claims may matter most when a biosimilar seeks to copy the same concentration, excipient system, or delivery profile.
Are there KEYTRUDA biosimilar or Paragraph IV challenges?
KEYTRUDA is a biologic, so biosimilar litigation is governed primarily by the BPCIA rather than the small-molecule Hatch-Waxman Paragraph IV process. The FDA does not list KEYTRUDA in the Orange Book because the Orange Book covers approved drug products and patents under the small-molecule framework. Biologic reference products are tracked through the Purple Book.[4,6]
A biosimilar applicant can challenge patent protection through the BPCIA patent-dispute process. The applicant may also file declaratory actions or pursue other litigation strategies, depending on the disclosure and negotiation sequence.
The principal post-2028 competitive scenarios are:
| Scenario |
Likely commercial effect |
| No biosimilar at launch |
Merck retains sales for longer, but pricing pressure remains limited |
| One biosimilar |
Moderate price erosion and hospital-account pressure |
| Several biosimilars |
Faster discounting, formulary substitution, and share loss |
| Interchangeable biosimilar competition |
Greater substitution potential at the pharmacy or payer level, depending on product and channel |
| Patent settlement |
Negotiated entry date and possible limits on indications or presentations |
No conventional Paragraph IV generic launch should be expected for KEYTRUDA. The relevant competitors are FDA-approved biosimilars, not chemically synthesized generics.
What is the FDA and Orange Book status of KEYTRUDA?
KEYTRUDA is FDA-approved as an intravenous biologic containing pembrolizumab. It is administered by infusion, typically every three or six weeks depending on the indication and dosing regimen.[3]
| Regulatory issue |
Status |
| Active ingredient |
Pembrolizumab |
| Drug class |
Anti-PD-1 monoclonal antibody |
| Dosage form |
Intravenous infusion |
| U.S. regulatory pathway |
Biologics License Application |
| FDA reference-product status |
Reference product for biosimilar purposes |
| Orange Book listing |
Not applicable as a biologic |
| Purple Book relevance |
Identifies reference-product and biosimilar information |
| Original U.S. approval |
September 2014 |
The most important regulatory risk is indication-specific. A biosimilar may obtain approval for some, but not all, reference-product indications. Patent-protected methods of use may be omitted from the biosimilar label.
What formulation and delivery patents could extend KEYTRUDA’s life cycle?
Merck’s largest lifecycle opportunity is a more convenient formulation or administration schedule. Intravenous infusion creates operational burden for hospitals and patients. A subcutaneous or otherwise simplified presentation could improve convenience, reduce infusion-chair use, and create differentiation from first-wave biosimilars.
A lifecycle product can produce several outcomes:
- Switching before biosimilar entry, if physicians and payers adopt the new format.
- Retention of patients in Merck’s franchise, even after intravenous pembrolizumab faces competition.
- New patent positions, particularly around formulation, delivery device, dosing, or combination with a delivery technology.
- Potential payer resistance, if the new presentation carries a significant premium without a clear total-cost benefit.
Formulation patents generally do not eliminate biosimilar risk. They can shift competition from the original intravenous product to a separate presentation, but biosimilar developers may pursue the original formulation or develop their own delivery systems.
What manufacturing and intellectual-property barriers affect biosimilars?
Pembrolizumab biosimilar development requires more than reproducing the amino-acid sequence. Developers must establish analytical similarity, pharmacokinetic comparability, immunogenicity, and, depending on FDA requirements and extrapolation strategy, a sufficient clinical package.
Manufacturing barriers include:
- Mammalian-cell expression and process control.
- Control of aggregation and product-related impurities.
- Glycosylation and other quality attributes.
- High-dose formulation stability.
- Aseptic filling and cold-chain logistics.
- Commercial-scale capacity.
- Regulatory comparability after process changes.
These barriers can delay entry, but they do not provide permanent exclusivity. Large biosimilar companies and contract manufacturers already have relevant monoclonal-antibody capabilities.
What litigation and settlement risks affect KEYTRUDA?
The most important legal risk will be patent litigation initiated after biosimilar applicants disclose their products under the BPCIA. Litigation could address:
- Core composition claims.
- Antibody-binding claims.
- Formulation and concentration claims.
- Manufacturing claims.
- Treatment methods.
- Combination therapies.
- Patent-term adjustments and terminal disclaimers.
- Whether a biosimilar’s label induces infringement.
A settlement could allow entry before the full expiry of every asserted patent. The financial effect would depend on the agreed date, the covered presentations, and whether the biosimilar can launch for unpatented indications.
The absence of a traditional Orange Book listing makes the litigation path less standardized than for products such as Keytruda’s small-molecule competitors. Merck’s risk assessment must therefore account for the full patent portfolio and BPCIA procedure rather than a single Orange Book patent-listing date.
How much revenue is exposed to loss of exclusivity?
At the 2023 revenue level, more than $25 billion in annual sales were associated with KEYTRUDA. The amount exposed in 2028 will depend on growth through the end of the decade, international patent terms, new presentations, and the proportion of revenue protected by indication-specific rights.
A simple erosion framework illustrates the exposure:
| Post-entry erosion |
Annual revenue retained from a $25 billion base |
| 20% loss |
$20.0 billion |
| 40% loss |
$15.0 billion |
| 60% loss |
$10.0 billion |
| 80% loss |
$5.0 billion |
This is a scenario analysis, not a forecast. Biologic erosion is often slower than small-molecule erosion because manufacturing is complex, physician substitution is less automatic, and payers may use contracting rather than mandatory substitution. The rate can accelerate when several biosimilars launch together and obtain broad payer coverage.
The more material exposure is incremental revenue. If KEYTRUDA reaches a higher sales base before 2028, even moderate percentage erosion can produce a larger absolute decline.
How does KEYTRUDA compare with Merck’s post-2028 growth products?
Merck is developing a portfolio intended to reduce dependence on KEYTRUDA. The principal categories include:
- Winrevair, or sotatercept, in pulmonary arterial hypertension.
- Capvaxive, a pneumococcal vaccine.
- Gardasil and Gardasil 9.
- Lagevrio, subject to COVID-19 demand volatility.
- Oncology combinations and follow-on immunotherapies.
- Business-development assets and licensing transactions.
KEYTRUDA remains materially larger than most individual products in the portfolio. Merck’s business-development strategy has therefore focused on assets capable of reaching multibillion-dollar sales or reinforcing the oncology franchise.
The company’s ability to replace KEYTRUDA revenue will depend on launch timing, clinical differentiation, reimbursement, and whether new products carry durable patent protection.
What generic launch risks exist for KEYTRUDA?
The principal launch risks are:
- A biosimilar entrant obtaining broad FDA approval.
- Multiple biosimilars launching within a short period.
- Payer-led switching in hospital and oncology networks.
- Discounting by large biosimilar manufacturers.
- Merck’s failure to shift patients to new formulations.
- Narrow patent claims that protect only individual indications.
- Court rulings invalidating or limiting asserted patents.
- Settlement agreements permitting entry before the nominal patent expiry date.
Merck has countervailing advantages: a large clinical evidence base, established oncology relationships, global manufacturing, contracting scale, and a broad label. Those advantages can slow share loss but cannot fully prevent price competition once a clinically interchangeable or highly substitutable biosimilar market develops.
Key Takeaways
- KEYTRUDA generated approximately $25.0 billion in global revenue in 2023, up from $21.2 billion in 2022.
- Pembrolizumab is Merck’s dominant product and represented roughly 42% of company revenue in 2023.
- Growth is driven by lung cancer, triple-negative breast cancer, perioperative treatment, gynecologic cancers, biomarker-selected populations, and international expansion.
- The core U.S. patent estate is generally expected to lose primary protection around 2028.
- KEYTRUDA is a biologic, so biosimilar and BPCIA litigation are more relevant than conventional Paragraph IV generic litigation.
- KEYTRUDA is not an Orange Book-listed small-molecule product; the Purple Book and BPCIA framework are the relevant regulatory references.
- Formulation, delivery, manufacturing, and method-of-use patents may delay or narrow competition but do not guarantee full franchise protection.
- Revenue exposure is potentially very large because KEYTRUDA is Merck’s largest commercial asset.
- Merck’s best defenses are continued earlier-line label expansion, lifecycle reformulation, combination development, and replacement products.
FAQs
When did KEYTRUDA first receive FDA approval?
The FDA approved KEYTRUDA in September 2014 for advanced melanoma after prior treatment with ipilimumab.[3]
Is KEYTRUDA a small-molecule drug or a biologic?
KEYTRUDA is a biologic monoclonal antibody. Its active ingredient is pembrolizumab, an anti-PD-1 antibody.
Can a KEYTRUDA biosimilar receive approval for every KEYTRUDA indication?
Not necessarily. A biosimilar may seek approval for selected indications and omit uses covered by method-of-use patents or unsupported by its regulatory application.
Will KEYTRUDA face automatic pharmacy substitution after biosimilar approval?
Not automatically. Substitution depends on the biosimilar’s FDA interchangeability designation, state law, payer policy, treatment setting, and clinical practice.
Which Merck products are intended to offset KEYTRUDA patent erosion?
Merck’s offset strategy includes Winrevair, vaccines such as Gardasil and Capvaxive, oncology combinations, and internally developed or acquired pipeline products.
References
- Merck & Co., Inc. (2023). 2022 annual report.
- Merck & Co., Inc. (2024). 2023 annual report.
- U.S. Food and Drug Administration. (2024). KEYTRUDA (pembrolizumab) prescribing information.
- U.S. Food and Drug Administration. (2024). Purple Book: Database of licensed biological products.
- U.S. Patent and Trademark Office. (n.d.). U.S. Patent No. 8,354,509, patent term and assignment records.
- U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, Orange Book.
