Pembrolizumab alone outperformed chemotherapy first-line in mismatch-repair-deficient endometrial cancer

Design

Phase 3, randomised, open-label, active-comparator; interim analysis

Population

299 adults with advanced or recurrent dMMR endometrial cancer, 24 countries

Primary outcome

Progression-free survival and overall survival

Effect

Median PFS 38.2 vs 8.4 months, HR 0.57 (0.42–0.79); OS HR 0.77 (0.52–1.15), not significant

KEYNOTE-C93 was an open-label phase 3 trial at 122 centres in 24 countries. It randomised 299 adults with inoperable stage III–IV or recurrent endometrial cancer that was mismatch-repair deficient (dMMR) to pembrolizumab every six weeks for up to 18 cycles, or six cycles of carboplatin plus paclitaxel. This is a prespecified interim analysis, published in The Lancet on 26 October.

Median progression-free survival was 38.2 months with pembrolizumab against 8.4 months with chemotherapy (HR 0.57, 95% CI 0.42–0.79). The curves only separated after six months: at 6 months about three-quarters of each group were progression-free, at 12 months 67% against 40%. Overall survival did not yet meet the significance threshold (HR 0.77, 0.52–1.15). Grade 3 or worse treatment-related events occurred in 18% on pembrolizumab and 51% on chemotherapy, with far less hair loss, anaemia and neuropathy. Two treatment-related deaths occurred on pembrolizumab and one on chemotherapy.

The important limitation is the comparator. Current first-line standard for dMMR disease in many guidelines is immunotherapy combined with chemotherapy, and this trial did not test against that. What it shows is that chemotherapy can be avoided first-line for some patients without losing disease control, which matters to women who cannot tolerate it. The trial was industry funded.

For every clinician, the lesson is upstream: the treatment now depends on a tumour test, so MMR status needs to be known.

• Every endometrial cancer should have mismatch repair status tested; treatment choices now depend on it.
• dMMR endometrial cancer also raises the question of Lynch syndrome; check that genetic counselling has been offered.
• Immunotherapy can cause endocrine, liver, lung and bowel toxicity months later; new symptoms in a patient on it need the oncology team informed.
• Pembrolizumab is marketed in India, but its approval status for this use there is unclear and cost limits access; chemotherapy remains a valid standard.

Why it matters

A single tumour test now decides whether a woman with advanced endometrial cancer may avoid first-line chemotherapy.

Don't overread it

This interim analysis has not shown longer survival, and it did not compare against immunotherapy plus chemotherapy.

The statistics, in plain English

A hazard ratio of 0.57 means the rate of progression was about 43% lower with pembrolizumab over the follow-up. The overall survival interval (0.52–1.15) crosses 1.0, so a survival benefit is not yet shown — it may emerge with longer follow-up, or may not.

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