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Merck built Keytruda by moving it from late-line to early cancer
Keytruda (pembrolizumab) is the clearest example of the oncology playbook of launching in late-line patients with few options and moving up to first-line and adjuvant treatment. By September 2023, in Sleuth’s analysis, Merck’s drug had 39 FDA approvals across 16 tumor types and 2 tumor-agnostic indications, and consensus expected global sales to grow from $20.9 billion in 2022 to about $33.3 billion in 2028. That scale also set up likely the largest loss-of-exclusivity (LOE) cliff ever, from around 2028, and the Inflation Reduction Act (IRA) makes the playbook harder to repeat.
Approvals moved steadily from second-line to first-line and adjuvant use
Keytruda’s first approval, in 2014, was in second-line or later melanoma; first-line melanoma followed in 2015 and adjuvant melanoma in 2019. In non-small cell lung cancer (NSCLC), approvals moved from second-line PD-L1-positive disease in 2015 (KEYNOTE-010) to first-line monotherapy for tumors with PD-L1 of 50% or more in 2016 (KEYNOTE-024), first-line chemotherapy combinations in 2017 and 2018, and adjuvant treatment in 2023 (KEYNOTE-091).
Global sales tracked the expansion, from $55 million in 2014 to $7.2 billion in 2018 and $20.9 billion in 2022. By September 11, 2023, ClinicalTrials.gov listed 1,251 recruiting or active studies involving pembrolizumab, more than 400 of them combination trials. Actual sales later beat the September 2023 consensus, reaching $29.5 billion in 2024 and $31.7 billion in 2025 against estimates of $27.0 billion and $28.9 billion.
Each move into an earlier line of therapy opened a larger patient population, so sales kept compounding and pembrolizumab became the backbone for combinations across tumors.
Serendipity and a biomarker bet let Merck overtake BMS
Scientists at Organon found Keytruda while looking for an antibody to stimulate PD-1, not inhibit it, and the program was repeatedly deprioritized as it passed to Schering-Plough in 2007 and to Merck in 2009, because almost nothing in immuno-oncology had worked well. Merck prioritized it only after Bristol Myers Squibb (BMS) reported positive Phase 3 results for Yervoy, a CTLA-4 inhibitor, and word spread of strong early results for BMS’s PD-1 inhibitor, Opdivo.
Despite starting years behind, Merck benefited from the FDA’s then-new Breakthrough Therapy designation and from using the PD-L1 biomarker to focus on the patients most likely to respond. The biomarker was a risk, because BMS developed Opdivo without one and could pursue broader labels. It paid off in 2016, when Opdivo failed a key first-line NSCLC trial and Keytruda won first-line approval in patients with high PD-L1 expression.
Merck’s edge came less from being first than from choosing the right patients, which turned a late start into the lead in lung cancer. Keytruda and Opdivo later became one of the pairs on Sleuth’s map of biopharma duopolies.
The IRA makes the move-up playbook harder to repeat
Under the IRA, the clock for Medicare price negotiation starts at a drug’s first approval. That weakens the case for launching in metastatic disease and moving up later, because first-line and adjuvant settings are several times larger and would arrive later in the negotiation-free window.
In Sleuth’s September 2023 view, companies may run parallel studies to synchronize approvals across settings, or start earlier, which raises the evidence bar and the R&D risk up front.
A subcutaneous version was Merck’s answer to the LOE
In September 2023, Keytruda was heading toward a US LOE around 2028, the year it was then expected to become eligible for negotiated Medicare prices. Merck was developing a faster, less invasive subcutaneous formulation that might blunt some of the impact by shifting patients from IV infusion. Sleuth still expected more than 80% of Keytruda revenue to be at risk from biosimilars, given the cost and reimbursement advantages of the IV formulation. Because the subcutaneous version adds a new compound, hyaluronidase, it was assumed but not confirmed that CMS would treat it as a new drug and restart the negotiation clock.
After this analysis, the FDA approved Keytruda Qlex (pembrolizumab and berahyaluronidase alfa) on September 19, 2025. A July 2025 amendment that starts the IRA clock at a drug’s first non-orphan approval pushed Keytruda’s eligibility for selection from 2026 to 2027, so it was not among the drugs CMS selected in January 2026 for 2028 negotiated prices. In June 2026, CMS proposed grouping hyaluronidase-based subcutaneous versions with the original IV drug for negotiation.
Whether a formulation switch protects a franchise now depends on regulation as much as patient preference, which makes Keytruda a test case for how big pharma weathers major LOEs.
Approvals, active-study counts and sales consensus are as of September 2023. This page is a dated snapshot; actual 2024 and 2025 sales, Keytruda Qlex’s approval and IRA developments are current as of September 2026.
Frequently asked questions about Keytruda
How many FDA approvals did Keytruda have in 2023?
As of September 2023, Keytruda had 39 FDA approvals across 16 tumor types and 2 tumor-agnostic indications (MSI-High and TMB-High), starting with second-line melanoma in 2014.
How much does Keytruda sell?
Keytruda’s global sales grew from $55 million in 2014 to $20.9 billion in 2022, and September 2023 consensus expected about $33.3 billion in 2028. Actual sales reached $29.5 billion in 2024 and $31.7 billion in 2025.
Is there a subcutaneous version of Keytruda?
Yes. The FDA approved Keytruda Qlex (pembrolizumab and berahyaluronidase alfa) on September 19, 2025, for the solid tumor indications approved for intravenous Keytruda. Sleuth’s September 2023 view was that more than 80% of Keytruda revenue would stay at risk from biosimilars anyway.
