KEYNOTE-C93 Shows PFS Benefit With First-Line Pembrolizumab Monotherapy in dMMR Endometrial Cancer

First-line pembrolizumab (Keytruda) monotherapy improved progression-free survival (PFS) compared with carboplatin plus paclitaxel in patients with mismatch repair–deficient (dMMR) advanced or recurrent endometrial cancer, according to findings from the phase 3 KEYNOTE-C93/GOG-3064/ENGOT-en15 trial (NCT05173987) presented at the 2026 ESMO Congress and simultaneously published in The Lancet.^1,2 Overall survival (OS), the dual primary end point, numerically favored pembrolizumab but did not meet the prespecified criterion for statistical significance at this interim analysis.

At a median follow-up of 36.7 months (range, 28.4-50.0), the median PFS per blinded independent central review (BICR) was 38.2 months (95% CI, 17.9-not reached [NR]) with pembrolizumab (n = 149) vs 8.4 months (95% CI, 6.8-10.4) with carboplatin plus paclitaxel (n = 150; HR, 0.57; 95% CI, 0.42-0.79; P = .0002).¹ The 24-month PFS rates were 55.4% vs 31.0%, respectively, and the 36-month PFS rates were 52.8% vs 30.0%.

The HR for OS was 0.77 (95% CI, 0.52-1.15; P = .1000), which did not cross the prespecified 1-sided boundary of .0189 at an information fraction of 95%. The median OS was NR in either arm, and the 36-month OS rates were 70.7% with pembrolizumab vs 62.0% with chemotherapy.

Chemotherapy combined with immune checkpoint inhibition has become the preferred first-line treatment for advanced or recurrent endometrial cancer, and approximately 25% to 30% of patients with endometrial cancer in this setting have dMMR tumors, which are highly immunogenic.

"There is a strong desire among health care providers and patients and their families for a first-line chemotherapy-free option for patients with advanced or recurrent endometrial cancer," said lead study author Brian M. Slomovitz, MD, director of gynecologic oncology and deputy director of the Braman Comprehensive Cancer Center at Mount Sinai Medical Center in Miami Beach, Florida.

How was the phase 3 KEYNOTE-C93 trial of pembrolizumab in dMMR endometrial cancer designed?

The randomized, open-label trial enrolled patients aged 18 years or older with histologically confirmed inoperable, advanced or recurrent endometrial carcinoma or carcinosarcoma; centrally confirmed dMMR status; radiographically evaluable disease per RECIST v1.1; no prior systemic therapy for advanced disease; and an ECOG performance status of 0 or 1. Prior (neo)adjuvant chemotherapy was permitted if recurrence occurred at least 6 months after the last dose.

Patients were randomly assigned 1:1 to receive pembrolizumab at 400 mg intravenously every 6 weeks for up to 18 cycles, or carboplatin at an area under the curve of 5 or 6 plus paclitaxel at 175 mg/m² intravenously every 3 weeks for 6 cycles. The control arm received no maintenance therapy, and patients with BICR-confirmed progressive disease on chemotherapy could cross over to receive up to 18 cycles of pembrolizumab. The dual primary end points were PFS per RECIST v1.1 by BICR and OS; objective response rate (ORR) per BICR was the key secondary end point, and the 3 were tested hierarchically.

Topline results announced in July 2026 showed that the trial met its PFS primary end point.³ At the data cutoff of April 24, 2026, a total of 299 patients had been randomly assigned at 122 sites in 24 countries.¹ Recurrent disease was present in 55.7% and 53.3% of patients in the pembrolizumab and chemotherapy arms, respectively, and 91.3% of patients in each arm had endometrioid histology. The median duration of treatment was 23.4 months with pembrolizumab (n = 149) vs 3.5 months with chemotherapy (n = 144), and 50.3% and 75.7% of treated patients, respectively, completed planned treatment.

How durable were responses and PFS with pembrolizumab vs chemotherapy in dMMR endometrial cancer?

The PFS curves crossed at approximately 6 months, reflecting early disease control with chemotherapy and longer-term durable disease control with pembrolizumab. In a post hoc restricted mean survival time analysis, the difference between arms favored pembrolizumab by 4.03 months (95% CI, 1.92-6.14) at 24 months and 6.82 months (95% CI, 3.44-10.20) at 36 months. The PFS HR was 0.45 (95% CI, 0.29-0.70) among patients with recurrent disease (n = 163) and 0.77 (95% CI, 0.49-1.21) among those with newly diagnosed advanced disease (n = 136).

Among patients with measurable disease per BICR at baseline (n = 145 per arm), the ORR was 64.1% (95% CI, 55.8%-71.9%) with pembrolizumab vs 62.1% (95% CI, 53.6%-70.0%) with chemotherapy. The complete response rates were 33.8% vs 26.2%, respectively, and the disease control rates were 70.3% vs 69.0%. The median duration of response (DOR) was NR (range, 2.0+ to 40.7+) among pembrolizumab responders (n = 93) vs 10.2 months (range, 1.9+ to 43.8+) among chemotherapy responders (n = 90). The rates of DOR of 36 months or longer were 70.7% vs 40.0%, respectively.

How did crossover to immunotherapy affect the KEYNOTE-C93 OS analysis in dMMR endometrial cancer?

Among patients in the chemotherapy arm with BICR-confirmed progression (n = 88), 85.2% received subsequent immunotherapy, including on-study crossover to pembrolizumab. Among patients in the pembrolizumab arm with progression (n = 63), 46.0% received subsequent platinum-based chemotherapy. In 3 supplementary analyses adjusting for subsequent immunotherapy in the control arm, the OS HRs ranged from 0.55 (95% CI, 0.38-0.85) to 0.66 (95% CI, 0.35-1.25).

Investigator-assessed PFS on next-line therapy also favored pembrolizumab (HR, 0.63; 95% CI, 0.43-0.91), with the median NR in the pembrolizumab arm and NR (95% CI, 32.8-NR) in the chemotherapy arm.

What were the safety and quality-of-life outcomes with pembrolizumab monotherapy in KEYNOTE-C93?

In the safety population, treatment-related adverse effects (TRAEs) occurred in 71.1% of patients in the pembrolizumab arm (n = 149) vs 97.9% of patients in the chemotherapy arm (n = 144). The rates of grade 3 or higher TRAEs were 18.1% vs 50.7%, respectively; serious TRAEs occurred in 14.1% vs 16.0%; and TRAEs led to discontinuation of any treatment in 9.4% vs 14.6%. Two treatment-related deaths occurred with pembrolizumab, 1 each due to hepatic failure and bacterial meningitis, and 1 treatment-related death due to pulmonary embolism occurred with chemotherapy.

The most common TRAEs were hypothyroidism and fatigue with pembrolizumab and alopecia, anemia, and nausea with chemotherapy. Immune-mediated adverse effects and infusion reactions occurred in 41.6% vs 17.4% of patients, respectively, and were grade 3 or higher in 7.4% vs 3.5%. No new safety signals were identified.

At week 12, the primary time point for patient-reported outcomes, global health status/quality of life scores improved with pembrolizumab (n = 142) and declined with chemotherapy (n = 133), for a between-arm difference of 7 points, according to Slomovitz. Physical, role, cognitive, and social functioning also favored pembrolizumab, whereas patients receiving chemotherapy reported worsening fatigue, tingling or numbness, muscular pain, and body image.

The investigators noted that the trial did not compare pembrolizumab with chemotherapy plus immunotherapy, the current first-line standard of care, and concluded that pembrolizumab monotherapy may broaden first-line treatment choice for certain patients with dMMR advanced or recurrent endometrial cancer.

Disclosures: Slomovitz reported receiving personal consulting fees from MSD, AstraZeneca, Daiichi Sankyo, Incyte, Seagen, Novocure, Karyopharm, Genmab, Aadi, Regeneron, Immunocure, Gilead, Eisai, Beigene, and GSK.

References

1. Slomovitz BM, Backes F, Maćkowiak-Matejczyk B, et al. KEYNOTE-C93/GOG-3064/ENGOT-en15: phase 3, randomized, open-label study of first-line pembrolizumab vs carboplatin + paclitaxel in mismatch repair-deficient (dMMR) advanced or recurrent endometrial cancer. Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA12.
2. Slomovitz BM, et al. First-line pembrolizumab versus carboplatin plus paclitaxel in participants with mismatch repair-deficient advanced or recurrent endometrial cancer (KEYNOTE-C93/GOG-3064/ENGOT-en15): interim analysis of a multicentre, open-label, randomised, active-comparator controlled, phase 3 trial. Lancet. Published online October 26, 2026. doi:10.1016/S0140-6736(26)02095-7
3. Pembrolizumab monotherapy improves PFS vs chemotherapy in frontline dMMR endometrial cancer. OncLive. Published July 15, 2026. Accessed October 26, 2026. https://www.onclive.com/view/pembrolizumab-monotherapy-improves-pfs-vs-chemotherapy-in-frontline-dmmr-endometrial-cancer