AACR 2025: ctDNA-Guided Adjuvant PD-1 Blockade Shows Promise for Patients With Resected dMMR Solid Tumors

In a phase 2 clinical trial (NCT03832569), adjuvant pembrolizumab (Keytruda; Merck & Co), a PD-1 immune checkpoint inhibitor, demonstrated the ability to clear minimal residual disease (MRD) and reduce recurrence rates in patients with detectable circulating tumor DNA (ctDNA) following resection of advanced mismatch repair-deficient (dMMR) solid tumors. Lead investigator Yelena Y. Janjigian, MD, chief attending on gastrointestinal oncology service in the Department of Medicine at Memorial Sloan Kettering (MSK) Cancer Center, presented these data at the 2025 American Association for Cancer Research (AACR) Annual Meeting in Chicago, Illinois.

These findings highlight the emerging paradigm of using ctDNA as a real-time biomarker to guide adjuvant immunotherapy.

“While previous studies have established that patients with MRD 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,” Janjigian said in an AACR statement.

Microscopic view of malignant tumor cells. Image Credit: © imtde.sign - stock.adobe.com

Immune checkpoint inhibitors targeting PD-1/PD-L1 pathways are already well established in the treatment of advanced dMMR solid tumors, and in selected perioperative settings, particularly for colorectal cancers. However, early-stage dMMR tumors are frequently cured with surgery alone, creating a dilemma regarding how to selectively offer adjuvant immunotherapy to those who need it without exposing patients to unnecessary toxicity, cost, and potential immune-related adverse events.

“As immunotherapy has started to enter the treatment landscape of early-stage solid tumors, it’s critical to understand which patients derive the most benefit from these therapies. Many biomarkers have been investigated to identify these patients, however, most of the ones currently used in clinical practice are static measures obtained at time of diagnosis (eg, PD-L1 tumor proportion score/combined positive score),” said Kevin Chen, PharmD, MS, BCOP, CPP, clinical pharmacy practitioner, Thoracic Oncology & Sarcoma, University of North Carolina (UNC) Medical Center and assistant professor of clinical education, UNC Eshelman School of Pharmacy in Chapel Hill, to Pharmacy Times. “There remains an emerging need to identify dynamic biomarkers of immunotherapy efficacy, such as MRD assessed via ctDNA.”

The study prospectively screened 174 patients with resected dMMR solid tumors for ctDNA positivity 6 to 10 weeks post-surgery. Of these, 20 patients had detectable ctDNA, indicative of MRD. Thirteen patients ultimately received 6 months of pembrolizumab therapy. The cohort included patients with gastroesophageal, colorectal, and endometrial cancers, demonstrating the potential of this approach across multiple tumor types. Six patients who were ctDNA positive but did not receive immunotherapy experienced disease progression before treatment initiation, emphasizing the aggressive nature of molecularly persistent disease. A separate observational arm followed 152 ctDNA-negative patients without additional therapy.

Results from the interventional arm showed ctDNA clearance at 6 months was achieved in 11 of the 13 patients treated with pembrolizumab (85%), and 8 of these patients remained recurrence-free at a median follow-up of 32.1 months. Importantly, the median time to recurrence was not reached. In contrast, ctDNA-positive patients who did not receive pembrolizumab had a median time to recurrence of 0.8 months. Moreover, 2-year overall survival (OS) rates were 92.3% in the pembrolizumab-treated ctDNA-positive group compared to 66.7% in ctDNA-positive patients who did not receive immunotherapy. In the observational cohort of ctDNA-negative patients, 2-year OS was 98.5% with a recurrence rate of 5.9%.

These findings carry important implications for oncology pharmacists and the multidisciplinary teams they support. First, ctDNA appears poised to become a critical tool for risk stratification in early-stage dMMR cancers, allowing for precision in adjuvant therapy decisions. Second, pembrolizumab, traditionally reserved for metastatic or unresectable disease, shows potential value in the adjuvant setting based on MRD as a biomarker.

However, Janjigian noted there are study limitations. The sample size of the interventional arm was relatively small (13 treated patients), and although follow-up approaching 3 years is notable, longer surveillance is necessary to fully confirm durable disease control and survival advantages.

“Although the sample size of the current study is small, it does provide a proof-of-concept of using a ctDNA MRD assay to identify patients who may benefit from additional adjuvant pembrolizumab,” Chen said to Pharmacy Times. “Importantly, more data needs to be generated to further characterize this strategy, as well as specific attention focused on different types of solid tumors, as the sensitivity of ctDNA MRD assays vary greatly based on malignancy.”

Additionally, some patients who were ctDNA-negative still experienced recurrence, which underscores the need for ongoing assay refinement and potential integration of additional modalities to improve sensitivity.

“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,” Janjigian said in an AACR statement.

REFERENCE

Janjigian YY. Adjuvant PD-1 Blockade for Mismatch Repair-deficient Solid Cancers Directed by ctDNA Status Delivers Clinical Benefit. April 27, 2025. Accessed April 28, 2025. https://aacr.ent.box.com/s/7kqh7a2rzj0bqdu5k2c164hfvs1akgv6