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Clinical Trial
. 2025 May 15;16(1):4514.
doi: 10.1038/s41467-025-59615-3.

Long-Term Efficacy of Pembrolizumab and the Clinical Utility of ctDNA in Locally Advanced dMMR/MSI-H Solid Tumors

Michael LaPelusa  1 , Wei Qiao  2 , Bryan Iorgulescu  3 , Francis San Lucas  3 , Keyur Patel  3 , Deepak Bhamidipati  4 , Jane Varkey Thomas  5 , Nancy You  6 , Wai Chin Foo  7 , Dipen Maru  7 , Selvi Thirumurthi  8 , Van Morris  5 , Scott Kopetz  5 , Michael Overman  5 , Kaysia Ludford  5
Affiliations
Clinical Trial

Long-Term Efficacy of Pembrolizumab and the Clinical Utility of ctDNA in Locally Advanced dMMR/MSI-H Solid Tumors

Michael LaPelusa et al. Nat Commun. .

Abstract

Neoadjuvant immunotherapy can induce pathologic complete response (pCR) in patients with localized deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) tumors. The long-term outcomes of these patients are unknown, as is the clinical utility of measuring circulating tumor DNA (ctDNA). Follow-up was evaluated in patients enrolled in a phase II trial (NCT04082572) that evaluated the efficacy and safety of pembrolizumab in patients with localized dMMR/MSI-H tumors. The primary outcomes of this trial have previously been reported. 3-year EFS and OS rates were 80% (95% CI: 66% - 93%) and 94% (95% CI: 86% - 100%). Patients without detectable ctDNA after pembrolizumab had higher 3-year EFS and OS rates than patients with detectable ctDNA after pembrolizumab (3-year EFS 92% vs 20%; p < 0.001, 3-year OS 100% vs 80%; p < 0.001). Patients with colorectal cancer (CRC) who had undetectable ctDNA after pembrolizumab were more likely to have pCR compared to those with detectable ctDNA after pembrolizumab (91% vs 0%; p = 0.03). Patients with CRC who were managed non-operatively and had undetectable ctDNA after pembrolizumab had a higher 2-year EFS rate than patients with detectable ctDNA after pembrolizumab (100% vs 33%; p = 0.03). Pembrolizumab demonstrates long-term efficacy in patients with localized dMMR/MSI-H tumors.

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Conflict of interest statement

Competing interests: Scott Kopetz has ownership interest in Lutris, Frontier Medicines, Navire and is a consultant for Genentech, Merck, Boehringer Ingelheim, Bayer Health, Pfizer, Mirati Therapeutics, Flame Biosciences, Carina Biotech, Frontier Medicines, Replimune, Bristol-Myers Squibb-Medarex, Amgen, Tempus, Harbinger Oncology, Zentalis, AVEO, Tachyon Therapeutics, Agenus, Revolution Medicines, Kestrel Therapeutics, Roche, Arcus Biosciences, AstraZeneca Pharmaceuticals, BeiGene, Clasp Therapeutics, Cytovation, Dewpoint Therapeutics, Marengo Therapeutics, SageMedic, Servier, Sibylla, T-Cypher Bio, XAIRA, AmMax Bio, Ikena, and receives research funding from, Guardant Health, Genentech/Roche, EMD Serono, Amgen, Lilly, Daiichi Sankyo, Pfizer, Boehringer Ingelheim, BridgeBio, Zentalis, BioMed Valley, Johnson & Johnson, BMS, Cardiff, Jazz Pharmaceuticals, Frontier Medicines. Michael Overman is a consultant for Merck, Roche, BMS, Astrazeneca, Janssen, Pfizer, Summit, Nouscom, and Amgen. The other authors have no relevant competing interests to disclose.

Figures

Fig. 1
Fig. 1. 3-year EFS and 3-year OS among all patients.
A – 3-year event-free survival (EFS) rate among all patients. Kaplan–Meier for EFS for the full study cohort (n =  35). The 3‑year EFS rate was 80 % (95 % CI, 66–93). Tick marks denote censored observations, and the shaded band represents the 95% CI. B 3-year overall survival (OS) rate among all patients. Kaplan–Meier curve for OS for the full study cohort (n =  35). The 3-year OS rate was 94% (95% CI, 86–100). Tick marks denote censored observations, and the shaded band represents the 95% CI.
Fig. 2
Fig. 2. 3-year EFS and 3-year OS stratified by ctDNA status after pembrolizumab.
A – 3-year event-free survival (EFS) rate by circulating tumor DNA (ctDNA) status after pembrolizumab. Kaplan–Meier curves for EFS according to ctDNA status after completion of pembrolizumab. Patients who were ctDNA-negative after pembrolizumab (n =  27) experienced a significantly higher 3-year EFS rate than those who were ctDNA-positive after pembrolizumab (n =  5) (92% vs 20%; log-rank P  <  0.001). Tick marks indicate censored observations, and shaded areas represent 95 % CI. Red curve = patients who were ctDNA-negative after pembrolizumab. Blue curve = patients who were ctDNA-positive after pembrolizumab. B 3-year overall survival (OS) rate by circulating tumor DNA (ctDNA) status after pembrolizumab. Kaplan–Meier curves for OS according to ctDNA status after completion of pembrolizumab. Patients who were ctDNA-negative after pembrolizumab (n = 27) experienced a significantly higher 3-year OS rate than those who were ctDNA-positive after pembrolizumab (n = 5) (100% vs 80%; log-rank P  <  0.001). Tick marks indicate censored observations, and shaded areas represent 95 % CIs. Red curve = patients who were ctDNA-negative after pembrolizumab. Blue curve = patients who were ctDNA-positive after pembrolizumab.
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References

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