FDA firms up Keytruda's tumour-mutation approval and raises the cutoff

The Food and Drug Administration has done two things at once to one of its most unusual cancer approvals: made it permanent, and made it smaller. On 16 October 2026 the agency granted traditional approval to pembrolizumab — Merck's Keytruda — and to its newer under-the-skin form, pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex), for patients with solid tumours that carry an unusually high number of mutations. In the same action it raised the bar for which tumours qualify [s1]. The supplement is recorded in the agency's Drugs@FDA database under the pembrolizumab licence [s2].

A test, not a tumour type

Most cancer drugs are approved for a specific organ — lung, breast, colon. This indication is defined instead by a feature any tumour might have: tumour mutational burden, or TMB, a count of how many mutations a cancer carries per megabase of DNA. A "TMB-high" tumour is a heavily mutated one, and the theory is that such cancers produce more abnormal proteins for the immune system to recognise, which should make them more vulnerable to a drug like pembrolizumab that releases the brakes on immune cells [s1].

The approval applies to adults and children with unresectable or metastatic TMB-high solid tumours that have "progressed following prior treatment and who have no satisfactory alternative treatment options" — a last-line, tissue-agnostic use [s1]. It is identified by an FDA-authorised test rather than by where the cancer started.

From accelerated to traditional

The original TMB-high clearance was an accelerated approval, the FDA's conditional pathway: a drug reaches patients on the strength of a promising surrogate measure, on the understanding that fuller evidence must follow. The 16 October decision converts that to traditional approval, the agency's confirmation that the benefit has now been borne out [s1].

The evidence came from KEYNOTE-158, a trial of pembrolizumab across a range of advanced solid tumours [s3]. In the 220 patients whose tumours carried a burden of at least 13 mutations per megabase, the overall response rate — the share whose tumours shrank by a set amount — was 36%, with a 95% confidence interval of 30 to 43 [s1]. Responses tended to last: 58% of responders were still responding at 12 months or more [s1].

Why the cutoff moved

The narrowing is the part worth dwelling on. The earlier approval set the threshold at 10 mutations per megabase. The new one requires 13 [s1]. The reason is plain in the FDA's wording: efficacy to support traditional approval "was not confirmed in patients with TMB of 10 to <13 mut/Mb" [s1]. In other words, the drug's benefit did not hold up at the lower end of the old range, so the agency pulled the boundary in to the level where the evidence was solid.

That is how a conditional approval is supposed to work, and it rarely moves in this direction in public view. Accelerated approvals are often confirmed, sometimes withdrawn; less commonly, the confirmatory data refine the indication itself, keeping the use where it is proven and dropping the margin where it is not. Patients whose tumours fall between 10 and 13 mutations per megabase are the ones affected: a use once open to them is no longer on the label [s1].

What it means in practice

For a patient this is an uncommon but real option — reached only after standard treatments have failed, and only when a validated test shows a tumour heavily enough mutated to qualify [s1]. The dose for pembrolizumab on its own is 200 mg every three weeks or 400 mg every six weeks in adults, and 2 mg/kg (up to 200 mg) every three weeks in children, continued until the cancer progresses, toxicity becomes unacceptable, or two years have passed [s1]. The newer subcutaneous combination follows its own prescribing information [s1].

The broader significance is regulatory. A tissue-agnostic, biomarker-defined approval is a bet that a single molecular feature can predict benefit across many cancers. This decision both honours that bet and disciplines it — confirming the approach while trimming it back to the mutation level where the response data actually land [s1][s3].

Red flags: immune-checkpoint drugs such as pembrolizumab can trigger the immune system to attack healthy organs. New breathlessness, persistent diarrhoea, severe abdominal pain, yellowing of the skin or eyes, or unusual fatigue during treatment warrant prompt contact with the care team. This article describes a regulatory decision and is not medical advice. Treatment choices, including tumour mutational burden testing, are for patients and their treating oncologists.