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Pembrolizumab (Keytruda), an anti-PD-1 antibody, cleared minimal residual illness and guarded in opposition to recurrence in sufferers with DNA mismatch repair-deficient (dMMR) early-stage strong cancers who had detectable circulating tumor DNA (ctDNA) after resection, in response to preliminary outcomes from a section II trial offered on the American Affiliation for Most cancers Analysis (AACR) Annual Assembly 2025, held April 25–30.
PD-1/PD-L1 immune checkpoint inhibitors are efficient in dMMR cancers, and are permitted in superior strong cancers characterised by dMMR no matter their tissue of origin, as a first-line remedy in dMMR colorectal most cancers, and in sure perioperative settings.
Nevertheless, given that the majority early-stage dMMR tumors are cured with surgical procedure alone, remedy should be rigorously utilized to these on the highest threat of recurrence and spare these at low threat from the associated fee and potential problems related to remedy, defined Yelena Y. Janjigian, MD, research presenter and chief attending on gastrointestinal oncology service within the Division of Medication at Memorial Sloan Kettering (MSK) Most cancers Middle.
This MSK trial evaluated whether or not ctDNA—a identified biomarker of recurrence and poor prognosis—could possibly be used to information post-surgical immunotherapy in sufferers at highest threat.
“With my MSK colleague Michael Foote, MD, and Melissa Lumish, MD, from University Hospitals Seidman Cancer Center, we hypothesized that early intervention with immunotherapy in ctDNA-positive patients could prevent clinical recurrence,” mentioned Janjigian.
On this investigator-initiated research, Janjigian and colleagues screened 174 sufferers with resected dMMR tumors and recognized 20 sufferers with detectable ctDNA six to 10 weeks after surgical procedure.
13 of those sufferers—six with gastroesophageal most cancers, 5 with colorectal most cancers, and two with endometrial most cancers—acquired pembrolizumab. Six ctDNA-positive sufferers have been monitored however skilled medical illness development earlier than beginning remedy, and weren’t included within the interventional research cohort. One further affected person was not evaluable. The trial additionally included an observational arm that monitored 152 sufferers with dMMR illness who have been ctDNA-negative at post-resection analysis.
The investigators noticed ctDNA clearance at six months in 11 of 13 sufferers who acquired pembrolizumab, and eight remained freed from recurrence at a median follow-up of 32.1 months. As compared, the median time to recurrence within the ctDNA-positive sufferers who recurred previous to receiving pembrolizumab was 0.8 months. Within the observational arm, 5.9% of the sufferers (9/152) skilled recurrence. The median time to recurrence was not reached within the pembrolizumab-treated sufferers or the observational arm.
At two-year follow-up, general survival charges have been 92.3% within the investigational arm of ctDNA-positive sufferers handled with pembrolizumab, 98.5% within the observational arm of ctDNA-negative sufferers, and 66.7% in sufferers who have been ctDNA-positive however didn’t obtain pembrolizumab.
“The study suggests that ctDNA-guided treatment strategies may help prevent relapse in patients whose tumors would otherwise recur,” mentioned Janjigian.
This research represents an essential step towards integrating ctDNA detection into routine medical decision-making for sufferers with dMMR cancers, in response to Janjigian, and highlights ctDNA’s transformative potential as a dynamic biomarker, each as a prognostic software and a way to actively information and optimize remedy selections in actual time.
“While previous studies have established that patients with minimal residual disease are at high risk of recurrence, our study demonstrates that treating these patients with a ctDNA-guided adjuvant immunotherapy approach can effectively eliminate residual disease before macroscopic recurrence occurs,” she mentioned. Nevertheless, this must be confirmed in a bigger, randomized trial with longer follow-up, she famous.
Past dMMR cancers, which represent solely a small fraction of general most cancers circumstances, Janjigian believes this strategy could possibly be expanded to a broader vary of cancers and should redefine how we use immunotherapy in early-stage illness.
“Our findings lay the groundwork for future trials to validate ctDNA as a predictive biomarker and ultimately improve outcomes for patients with curable malignancies, ensuring that high-risk patients receive timely intervention while avoiding overtreatment in those who are unlikely to benefit,” mentioned Janjigian.
Limitations of the research embody small pattern measurement and comparatively quick follow-up to guage long-term survival. Moreover, the discovering that some sufferers who have been ctDNA-negative nonetheless skilled recurrence means that additional assay refinement is required to seize all at-risk people.
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Adjuvant PD-1 blockade for mismatch repair-deficient strong cancers directed by ctDNA standing delivers medical profit (2025, April 29)
retrieved 30 April 2025
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