Chemo-Free PFS Win Challenges Triplets But OS Gap Caps Disruption

KEYTRUDA Monotherapy Significantly Improves PFS in dMMR Endometrial Cancer

Merck announced positive Phase 3 KEYNOTE-C93 trial results for KEYTRUDA (pembrolizumab) monotherapy in patients with mismatch repair deficient (dMMR) advanced or recurrent endometrial cancer. The study demonstrated a statistically significant and clinically meaningful improvement in the primary endpoint of progression-free survival (PFS), reducing the risk of disease progression or death by 43% (HR=0.57; p=0.0002) compared to platinum doublet chemotherapy. Patients treated with KEYTRUDA achieved a median PFS of 38.2 months, significantly longer than the 8.4 months for chemotherapy. These findings, presented at ESMO Congress 2026 and published in The Lancet, highlight KEYTRUDA's potential as a chemotherapy-free option for this patient population.

• The KEYNOTE-C93 trial showed that KEYTRUDA monotherapy significantly reduced the risk of disease progression or death by 43% (HR=0.57; 95% CI, 0.42-0.79; p=0.0002) in dMMR advanced or recurrent endometrial cancer patients. This led to a median progression-free survival of 38.2 months for KEYTRUDA, a substantial increase compared to 8.4 months for platinum doublet chemotherapy, marking a significant advancement in treatment options.
• While the trial is ongoing for overall survival (OS), a favorable trend was observed for KEYTRUDA monotherapy (HR=0.77; p=0.1000), with 36-month OS rates of 70.7% versus 62.0% for chemotherapy. Importantly, KEYTRUDA's safety profile was consistent with previous studies, and Grade ≥3 treatment-related adverse events were significantly lower (18.1%) compared to chemotherapy (50.7%), suggesting a better tolerability profile.
• KEYTRUDA monotherapy achieved a confirmed objective response rate (ORR) of 64.1%, comparable to chemotherapy's 62.1%. However, among responders, the median duration of response (DOR) for KEYTRUDA was not reached, indicating a more durable response, in contrast to 10.2 months for chemotherapy. The 36-month DOR rate was 70.7% for KEYTRUDA versus 40.0% for chemotherapy, highlighting long-term benefit.

Why New Options are Crucial for Advanced dMMR Endometrial Cancer

Patients with advanced or recurrent endometrial cancer who progress after platinum-based chemotherapy face a poor prognosis, and treatment options have historically been limited. Patients with advanced or recurrent endometrial cancer who experience progression following platinum-based chemotherapy have limited treatment options.

• Historically limited post-platinum options have defined care, with active systemic therapy needed to prolong survival and improve disease control after failure of platinum-based chemotherapy between 2013 and 2024.

• Acquired resistance to PD-1 monotherapy can emerge, including a reported case of recurrent microsatellite instability-high endometrial cancer that acquired resistance to pembrolizumab but favorably responded to the lenvatinib and pembrolizumab combination therapy.

• For dostarlimab, its efficacy in other cancer subtypes, the development of resistance to monotherapy, and efficacy and safety in combination with other immunotherapeutic drugs have not yet been studied.

• Toxicity limits continued therapy for some patients, with treatment discontinued due to toxicity in 4.7% of patients in real-world practice, while anemia (3 of 104 [2.9%]), colitis (2 of 104 [1.9%]), and diarrhea (2 of 104 [1.9%]) were the most common grade 3 or higher treatment-related adverse events.

Unpacking the Pivotal KEYNOTE-C93 Trial Data

Key trials in mismatch repair deficient advanced or recurrent endometrial cancer span single-arm phase I/II monotherapy studies and randomized phase 3 chemoimmunotherapy combinations. Designs differ in blinding, dosing schedules, and follow-up, while endpoints consistently center on response rate, progression-free survival, overall survival, and safety per RECIST v1.1.

Reshaping First-Line Treatment for dMMR Endometrial Cancer

In Part 1 of the phase III RUBY trial (NCT03981796) in patients with primary advanced or recurrent endometrial cancer, dostarlimab plus carboplatin-paclitaxel significantly improved progression-free survival and overall survival compared with carboplatin-paclitaxel alone. In the mismatch repair deficient/microsatellite instability-high population, 118 patients were enrolled (53, dostarlimab arm; 65, placebo arm) and randomized 1:1 to dostarlimab 500 mg or placebo plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab or placebo every 6 weeks for up to 3 years. At the first interim analysis, a 72% reduction in the risk of progression or death (P < 0.0001) was seen with dostarlimab plus carboplatin-paclitaxel by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), which was consistent with blinded independent central review per RECIST v1.1. Safety results in the mismatch repair deficient/microsatellite instability-high population were similar to those previously reported for the overall population, where treatment-emergent adverse events were experienced by 100% of patients in both arms, treatment-related adverse events occurred in 97.9% of the dostarlimab arm and 98.8% of the placebo arm, immune-related adverse events occurred in 58.5% and 37.0%, respectively, and dostarlimab- or placebo-related immune-related adverse events were reported in 40.7% and 16.3%, respectively.

For previously treated mismatch repair deficient/microsatellite instability-high advanced/recurrent disease, single-agent programmed death-1 inhibitors showed durable activity. In the phase 2 KEYNOTE-158 study (NCT02628067), patients received pembrolizumab 200 mg Q3W for ≥35 cycles, and as of January 12, 2022, median (range) follow-up in the MSI-H/dMMR (n = 94) group was 54.5 (14.7-71.4) months, with objective response rate (95% CI) of 50% (40%-61%), 15 patients (16%) with complete response and 32 (34%) with partial response, median progression-free survival of 13.1 (95% CI, 4.3-25.7) months, and median overall survival of 65.4 (95% CI, 29.5-not reached) months. In GARNET Cohort A1, patients received dostarlimab 500 mg every 3 weeks for 4 cycles, then dostarlimab 1000 mg every 6 weeks until disease progression, with objective response rate of 43.5% (95% CI 34.0% to 53.4%) with 11 complete responses and 36 partial responses. An indirect treatment comparison of GARNET Cohort A1 versus doxorubicin from ZoptEC (NCT01767155) reported median (95% CI) overall survival of not reached (NR; 18.0 months--NR) for dostarlimab (n = 92) versus 11.2 (10.0-13.1) months for doxorubicin (n = 233; HR: 0.41 [95% CI: 0.28-0.61]), median progression-free survival of 12.2 (3.3-NR) and 4.9 (4.1-6.6) months, respectively, and Grade ≥3 adverse events in 48.1% vs 78.3%, respectively.

A Bayesian network meta-analysis of four phase III randomized controlled trials involving 2577 patients found that dostarlimab plus chemotherapy or durvalumab plus chemotherapy with olaparib was associated with more survival benefits than other immunotherapy regimens and chemotherapy in the mismatch repair-deficient microsatellite instability-high (dMMR/MSI-H) and mismatch repair-proficient microsatellite-stable (pMMR/MSS) population, respectively. In that analysis, pembrolizumab plus chemotherapy versus chemotherapy increased efficacy (cost) by 3.76 QALYs and US$540 817, which yielded incremental cost-effectiveness ratios of US$143 894/QALY in the dMMR/MSI-H population. Real-world data were consistent with trial results, with a disease control rate of 56% (n=24/43) and overall response rate of 35% (n=15/43) in France, and an objective response rate of 53.6% (95% CI 44.4 to 62.5) with complete response in 27 patients (21.6%) and partial response in 40 (32%) in the GEICO 120-R/DORA study of 129 patients with a median follow-up of 11.6 months (range; 0.8-30.1).

First-Line KEYTRUDA Monotherapy: Reshaping dMMR Endometrial Cancer Care

The recent announcement regarding KEYTRUDA's positive Phase 3 KEYNOTE-C93 trial results marks a significant milestone in the treatment of mismatch repair deficient (dMMR) advanced or recurrent endometrial cancer. For years, patients facing this aggressive disease have primarily relied on platinum-based chemotherapy, often with limited long-term success and considerable side effects. While pembrolizumab has already been established as an effective option for previously treated dMMR endometrial cancer, these new data propel it into the first-line setting as a monotherapy, offering a compelling chemotherapy-free alternative.

The observed median progression-free survival of 38.2 months with KEYTRUDA, dramatically surpassing the 8.4 months seen with chemotherapy, underscores a profound clinical benefit. This magnitude of improvement is transformative, suggesting a potential for extended disease control and improved quality of life for patients who can avoid the immediate toxicities associated with traditional chemotherapy regimens. This shift necessitates robust and accurate dMMR biomarker testing to ensure appropriate patient selection, as the efficacy of immune checkpoint inhibitors is largely confined to this molecular subtype.

However, the introduction of any new therapy comes with considerations. While avoiding chemotherapy, patients on pembrolizumab may experience immune-related adverse events (irAEs), which, though distinct from chemotherapy side effects, can be serious and require careful management. Furthermore, despite the impressive response rates, not all dMMR patients will respond to immunotherapy, and some may eventually develop resistance. For these patients, combination strategies, such as pembrolizumab with lenvatinib, which has shown efficacy in dMMR patients who failed monotherapy, may become crucial subsequent options. This evolving landscape highlights the ongoing need for personalized treatment approaches and continued research into predictive biomarkers and combination therapies to address primary resistance and disease progression.