Last updated: September 4, 2026
KEYTRUDA, Merck & Co.’s pembrolizumab, generated approximately $29.5 billion in global sales in 2024, up from $25.0 billion in 2023 and $21.2 billion in 2022. It is the largest product in Merck’s portfolio and one of the highest-revenue oncology medicines worldwide. Growth remains supported by new tumor types, earlier-line treatment, combination regimens, and geographic expansion, but the commercial profile changes materially as core U.S. biologic exclusivity approaches in 2028.
The primary risks are biosimilar entry, price erosion, treatment-duration limits, competitive PD-1 and PD-L1 therapies, and the eventual loss of exclusivity for the original pembrolizumab molecule. Merck is mitigating those risks through additional indications, combination products, subcutaneous delivery technology, manufacturing scale, and lifecycle management.
How much revenue does KEYTRUDA generate?
KEYTRUDA produced $29.5 billion in 2024 sales, representing about 46% of Merck’s total pharmaceutical revenue and roughly 43% of total company revenue. The product’s growth rate has remained high, although the percentage increase has moderated as the revenue base expanded.
| Fiscal year |
KEYTRUDA revenue |
Year-over-year change |
Source |
| 2022 |
$21.2 billion |
22% |
Merck 2022 Form 10-K |
| 2023 |
$25.0 billion |
19% |
Merck 2023 Form 10-K |
| 2024 |
$29.5 billion |
18% |
Merck 2024 Form 10-K |
KEYTRUDA is economically important because it combines high annual treatment value with a broad label. Revenue is distributed across non-small-cell lung cancer, melanoma, head and neck cancer, renal cell carcinoma, triple-negative breast cancer, urothelial carcinoma, endometrial carcinoma, esophageal cancer, gastric cancer, cervical cancer, and several biomarker-defined indications.
Merck’s oncology revenue is also supported by combination use with chemotherapy, axitinib, lenvatinib, enfortumab vedotin, trastuzumab, and other agents. Combination sales increase the number of treated patients but can complicate attribution, reimbursement, and competitive positioning.
What is driving KEYTRUDA market growth?
KEYTRUDA growth is primarily volume-driven rather than dependent on large price increases.
Earlier-line treatment
Clinical adoption has moved from metastatic and refractory disease into adjuvant, neoadjuvant, and perioperative settings. Earlier treatment increases the eligible patient population but can shorten the duration of treatment for some patients because therapy is administered for a defined course or discontinued after surgery.
The move into earlier disease stages creates a tradeoff:
- More patients receive therapy.
- Treatment can begin before metastatic progression.
- Some patients receive fewer total cycles.
- Payer scrutiny is greater in curative-intent settings.
- Clinical evidence must support event-free or overall-survival benefits.
New indications and biomarker expansion
Merck has used tumor-specific and biomarker-specific approvals to extend KEYTRUDA’s commercial reach. The most important biomarker strategies include PD-L1 expression, microsatellite instability-high status, mismatch-repair deficiency, and tumor mutational burden.
The label’s breadth also reduces reliance on any individual tumor type. A negative trial in one indication has less effect on total revenue when other disease areas continue to expand.
Combination regimens
Combination treatment has been central to KEYTRUDA’s commercial strategy. KEYTRUDA plus chemotherapy remains a major first-line regimen in lung cancer and other solid tumors. KEYTRUDA plus lenvatinib expanded the product’s role in renal cell carcinoma and endometrial cancer. KEYTRUDA plus enfortumab vedotin created another high-value combination in urothelial carcinoma.
Combination economics can protect market share because physicians select a regimen rather than an individual PD-1 antibody. The risk is that competing combinations may offer stronger survival data, more convenient administration, or better toxicity management.
When does KEYTRUDA lose exclusivity?
The principal U.S. composition-of-matter patent for pembrolizumab is U.S. Patent No. 8,168,757, which is commonly reported to expire in May 2028. The patent covers anti-PD-1 antibodies and includes claims relevant to pembrolizumab.
| Protection category |
Representative protection |
Expected U.S. relevance |
| Core antibody patent |
U.S. Patent No. 8,168,757 |
Principal loss-of-exclusivity date generally reported as May 2028 |
| Formulation patents |
Later patents covering antibody formulations and related compositions |
Potentially extend enforcement positions into the early-to-mid 2030s |
| Method-of-use patents |
Indication-specific and biomarker-defined claims |
May run beyond composition expiry, but do not necessarily block all biosimilar substitution |
| Manufacturing and process patents |
Cell culture, purification, formulation, and production claims |
Can increase development and manufacturing complexity |
| Regulatory exclusivity |
Biologic reference-product exclusivity |
Separate from patent term; does not replace patent protection |
The practical U.S. entry date will depend on biosimilar approvals, patent litigation, settlement agreements, injunctions, and the scope of claims that remain enforceable. A later method-of-use or formulation patent can delay a particular labeled indication or delivery presentation, but it may not prevent an approved biosimilar from entering for unpatented uses.
What is the Orange Book status of KEYTRUDA?
KEYTRUDA is a biologic, so its primary regulatory reference is the FDA’s Purple Book rather than the Orange Book. The Orange Book lists approved drug products, including many small-molecule drugs. The Purple Book identifies licensed biological products and reference products relevant to biosimilar competition.
Paragraph IV certification is therefore not the standard pathway for challenging KEYTRUDA patents. A pembrolizumab biosimilar applicant would use the abbreviated biologics license application pathway under section 351(k) of the Public Health Service Act and may participate in the statutory patent-information exchange known as the “patent dance.”
The regulatory distinction matters:
- Small-molecule generics commonly file ANDAs.
- Generic applicants can use Paragraph IV certifications.
- Biosimilar applicants file 351(k) applications.
- Biosimilar applicants address patents through the Biologics Price Competition and Innovation Act framework.
- Interchangeability is a separate FDA designation and is not automatic upon biosimilar approval.
How strong is the KEYTRUDA patent estate?
KEYTRUDA’s patent estate is commercially strong but not uniformly blocking.
The core antibody patent is the most important protection because it covers the active biologic itself. Once that protection expires, a biosimilar developer can seek approval for pembrolizumab subject to remaining patent disputes.
Later patents can strengthen Merck’s position in specific areas:
Formulation patents
Formulation claims may cover concentration, excipients, stability, storage, or administration conditions. These patents can make it harder for competitors to copy a particular presentation, but they do not always block a biosimilar using a different formulation that satisfies FDA comparability requirements.
Method-of-use patents
Method patents can cover use in a specific cancer, biomarker-defined population, line of therapy, or combination. Their commercial value depends on prescribing behavior and the ability to prevent or deter use for the patented indication.
A biosimilar may be approved with “skinny labeling” that omits patented indications. In oncology, that strategy is complex because treatment decisions, clinical guidelines, electronic ordering systems, and combination regimens can create indirect substitution pressure.
Manufacturing patents
Manufacturing patents can target cell lines, culture conditions, purification methods, analytical controls, and formulation processes. They may increase litigation risk and development cost, but manufacturing patents generally do not provide the same market-wide exclusion as a valid composition patent.
Are there KEYTRUDA biosimilars or Paragraph IV challengers?
No FDA-approved pembrolizumab biosimilar had entered the U.S. market by the end of 2024. The relevant competitive threat is therefore future 351(k) development rather than an existing generic launch.
Several factors may delay entry:
- The complexity of demonstrating analytical and clinical similarity for a monoclonal antibody.
- The need to establish manufacturing capacity at commercial scale.
- Patent litigation over the core antibody, formulation, and use claims.
- The need to develop a viable pricing and contracting strategy against Merck.
- The difficulty of gaining rapid adoption in oncology practices without interchangeability.
- The risk that Merck’s contracting and combination strategies reduce the economic value of a biosimilar.
The absence of a current biosimilar does not eliminate post-2028 erosion risk. Pembrolizumab is an attractive target because its sales base is large, the molecule is clinically validated, and many indications create multiple opportunities for biosimilar utilization.
Which companies are likely to challenge KEYTRUDA?
Potential competitors include large biosimilar manufacturers with experience in monoclonal antibodies, including Amgen, Biocon Biologics, Celltrion, Samsung Bioepis, Sandoz, and Fresenius Kabi. Publicly reported development programs and commercial intentions can change, and not every developer will progress to filing or launch.
The strongest potential challengers are companies with:
- Existing oncology biosimilar infrastructure.
- U.S. and European regulatory experience.
- Commercial relationships with hospitals and specialty distributors.
- Manufacturing capacity for high-volume antibody products.
- The ability to support multiple indications and payer contracts.
Competition will also come from branded immuno-oncology products rather than only biosimilars.
| Product |
Company |
Class |
Competitive position |
| OPDIVO |
Bristol Myers Squibb |
PD-1 inhibitor |
Major branded competitor across lung, melanoma, renal, gastrointestinal, and other cancers |
| TECENTRIQ |
Roche |
PD-L1 inhibitor |
Strong position in lung, hepatocellular, urothelial, and other cancers |
| IMFINZI |
AstraZeneca |
PD-L1 inhibitor |
Strong lung and biliary tract presence |
| LIBTAYO |
Regeneron/Sanofi |
PD-1 inhibitor |
Concentrated presence in selected solid tumors |
| JEMPERLI |
GSK |
PD-1 inhibitor |
Important in mismatch-repair-deficient and endometrial cancer |
| ZYNYZ |
Incyte |
PD-1 inhibitor |
Narrower dermatologic oncology positioning |
The most important competitor is OPDIVO, especially where nivolumab is used with YERVOY, chemotherapy, or other agents. TECENTRIQ and IMFINZI are more significant in specific tumor types and treatment settings.
What licensing deals support KEYTRUDA’s lifecycle?
Merck has pursued lifecycle management beyond the original intravenous product.
In 2024, Merck entered into an agreement with Alteogen related to ALT-B4, a recombinant human hyaluronidase technology intended to enable subcutaneous delivery of biologic medicines. The commercial objective is to develop a subcutaneous version of pembrolizumab that could reduce infusion time and improve treatment convenience.
A subcutaneous presentation could support:
- Faster administration.
- Lower infusion-center burden.
- Greater outpatient flexibility.
- New formulation and device patents.
- Potential differentiation after the intravenous product faces biosimilar competition.
The strategy does not automatically preserve all KEYTRUDA revenue. A new presentation would require regulatory approval, manufacturing validation, payer acceptance, and sufficient clinical and commercial differentiation. It could, however, shift part of the franchise from a directly substitutable intravenous product into a differentiated delivery system.
What is the FDA regulatory status of KEYTRUDA?
KEYTRUDA received its first FDA approval in 2014 for advanced melanoma. It has since received numerous regular and accelerated approvals across solid tumors and hematologic disease settings.
The FDA label includes indications based on disease type, prior therapy, biomarker status, and combination partner. Accelerated approvals carry confirmatory-trial obligations. If required studies fail to verify benefit, the FDA can narrow or withdraw an indication.
Regulatory growth has followed four major paths:
- Expansion into additional tumor types.
- Movement from later-line to first-line treatment.
- Expansion into adjuvant and perioperative therapy.
- Combination approvals with chemotherapy and targeted agents.
The commercial value of a new approval depends on eligible-patient volume, treatment duration, reimbursement, competitive standards of care, and whether the indication expands use before or after biosimilar entry.
What is the likely KEYTRUDA financial trajectory through 2030?
KEYTRUDA can continue growing before loss of exclusivity, but the growth rate is likely to decelerate as the product reaches a large base and faces treatment-duration limits.
A scenario framework using 2024 revenue of $29.5 billion illustrates the exposure:
| Scenario |
2028 revenue pattern |
2030 revenue pattern |
Main assumptions |
| Resilient franchise |
Continued growth into 2028, limited erosion after entry |
Revenue remains near pre-LOE levels |
Delayed biosimilar uptake, strong new indications, successful subcutaneous conversion |
| Base case |
Growth slows before 2028, moderate erosion after entry |
Material decline from peak |
One or more biosimilars launch, contracting pressure increases, core indications remain durable |
| Aggressive erosion |
Growth stalls before 2028, rapid post-entry decline |
Large reduction from peak |
Multiple biosimilars, price competition, interchangeability, and loss of hospital share |
A 20% decline from the 2024 base would reduce annual revenue by approximately $5.9 billion. A 40% decline would reduce revenue by approximately $11.8 billion. These are sensitivity calculations, not Merck guidance.
The actual erosion curve will depend on:
- Number of approved biosimilars.
- Timing of first launch.
- FDA interchangeability designations.
- Medicare and commercial payer policies.
- Hospital group purchasing contracts.
- Physician willingness to switch stable patients.
- Availability of subcutaneous KEYTRUDA.
- Merck’s rebates and contracting strategy.
- Remaining indication-specific patents.
What generic launch risks exist for KEYTRUDA?
The primary risk is a staggered biosimilar launch rather than an immediate collapse.
A likely launch sequence would begin with one or more biosimilars entering selected high-volume indications, followed by broader payer coverage and increasing use in treatment-naive patients. Stable-patient switching could occur more slowly, particularly where physicians associate a branded product with extensive survival data and established support services.
Merck may protect revenue through:
- Contracting and rebates.
- Patient-support programs.
- Subcutaneous delivery.
- Combination regimens.
- New perioperative indications.
- Geographic expansion.
- Manufacturing efficiencies.
- Patent settlements that establish controlled entry dates.
How does KEYTRUDA compare with OPDIVO’s patent and commercial position?
KEYTRUDA and OPDIVO compete directly in several tumor types, but their market profiles differ.
| Factor |
KEYTRUDA |
OPDIVO |
| Sponsor |
Merck |
Bristol Myers Squibb |
| Mechanism |
PD-1 inhibitor |
PD-1 inhibitor |
| Commercial scale |
Larger global oncology franchise |
Major global oncology franchise |
| Key advantage |
Broad label, strong first-line use, extensive combinations |
Deep combination use, including YERVOY-based regimens |
| Main risk |
Pembrolizumab biosimilar entry around the late 2020s |
Nivolumab and combination-product loss of exclusivity over time |
| Lifecycle strategy |
Additional indications and subcutaneous development |
Combination products and subcutaneous nivolumab development |
The competitive outcome will vary by tumor type. KEYTRUDA has a strong position in lung cancer and several earlier-line settings. OPDIVO remains influential where dual checkpoint blockade or specific combination evidence drives treatment selection.
What patent litigation and settlement issues affect KEYTRUDA?
The principal legal risk is future biosimilar litigation under the BPCIA rather than traditional ANDA Paragraph IV litigation. Disputes may involve:
- Core antibody patents.
- Formulation patents.
- Manufacturing patents.
- Method-of-use patents.
- Patent-listing and disclosure issues.
- The timing of commercial launch.
- Interchangeability and substitution.
A settlement could establish a launch date before the expiration of every asserted patent. The commercial result would depend on the agreed date, royalty structure, scope of licensed indications, and whether multiple biosimilar developers receive similar rights.
No single patent date should be treated as the complete commercial loss-of-exclusivity date. The core patent, regulatory exclusivity, formulation claims, use patents, and settlement terms can produce different entry dates for different products and indications.
Key Takeaways
- KEYTRUDA generated $29.5 billion in 2024 sales and is Merck’s dominant product.
- Revenue grew 18% in 2024, but percentage growth is likely to slow as the base expands.
- U.S. core composition protection is generally reported to expire in May 2028.
- KEYTRUDA is regulated as a biologic and is tracked through the Purple Book, not primarily the Orange Book.
- Paragraph IV challenges are not the standard pathway; future competitors will file 351(k) biosimilar applications.
- No FDA-approved pembrolizumab biosimilar had launched in the U.S. by the end of 2024.
- Merck’s main defenses are label expansion, combination therapy, contracting, manufacturing scale, and subcutaneous delivery.
- A 20% decline from 2024 sales would equal about $5.9 billion in annual revenue; a 40% decline would equal about $11.8 billion.
- OPDIVO is the principal branded PD-1 competitor, while TECENTRIQ and IMFINZI remain important in selected tumor types.
- The most likely commercial outcome is a gradual, indication-by-indication erosion rather than an immediate revenue collapse.
FAQs
When will the first KEYTRUDA biosimilar launch in the United States?
The commercial window is generally associated with the expiration of core U.S. pembrolizumab patent protection in 2028, subject to FDA approval, litigation, and settlement terms.
Is KEYTRUDA interchangeable with a future pembrolizumab biosimilar?
Not automatically. A biosimilar would need a separate FDA determination for interchangeability. Without that designation, substitution practices would depend on state law, payer policy, and prescriber decisions.
Can a KEYTRUDA biosimilar be approved for every cancer indication?
Not necessarily. A biosimilar applicant may seek all reference-product indications or omit indications protected by method-of-use patents and submit a narrower label.
Will subcutaneous KEYTRUDA prevent biosimilar erosion?
It may reduce erosion for patients and providers who value faster administration, but it will not necessarily protect the intravenous product or all franchise revenue.
How exposed is Merck’s total business to KEYTRUDA loss of exclusivity?
Highly exposed. KEYTRUDA accounted for approximately 46% of Merck’s pharmaceutical revenue in 2024, making successful replacement growth critical to the company’s post-2028 financial trajectory.
References
- Merck & Co., Inc. (2023). 2022 annual report.
- Merck & Co., Inc. (2024). 2023 annual report.
- Merck & Co., Inc. (2025). 2024 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. (2008). U.S. Patent No. 8,168,757: Anti-PD-1 antibodies.
- U.S. Food and Drug Administration. (2024). Biosimilar and interchangeable biosimilar products.
- Merck & Co., Inc. (2024). Merck and Alteogen collaboration announcement regarding subcutaneous delivery technology.
