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Molecular Residual Disease Using ctDNA May Predict Benefit From Consolidation Immunotherapy in NSCLC

NEW YORK − A retrospective study published in Nature Cancer last week found that circulating tumor DNA can be used to identify non-small cell lung cancer patients who might benefit from consolidation therapy with immune checkpoint inhibitors (ICI) after chemoradiation and to monitor their responses. 

The study, led by Everett Moding, Ash Alizadeh and Maximilian Diehn from Stanford University and Steven Lin from the University of Texas MD Anderson Cancer Center, found that patients with circulating tumor DNA detected after chemoradiation who then received consolidation immune checkpoint inhibitors had better progression-free survival compared to patients with circulating tumor DNA detected post-chemoradiation who did not receive consolidation immunotherapy afterwards. The results suggest that ctDNA analysis may be useful in determining which patients would benefit from follow-up consolidation immunotherapy.

Consolidation therapy is given after a tumor has disappeared after initial treatment as a measure to kill any cancer cells remaining in the body. Studies have shown that while consolidation immunotherapy after chemoradiation improves progression-free survival and overall survival in NSCLC, tumors eventually recur.

Previously, the team knew that testing for the presence of ctDNA to detect molecular residual disease (MRD) after chemoradiation can accurately detect which NSCLC patients will experience recurrence. In this study, they sought to investigate whether consolidation ICI can improve clinical outcomes in these patients at risk of recurrence.

By using Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq), 218 blood and tissue samples that had been prospectively collected for the purpose of ctDNA analysis from two cohorts of patients with localized chemoradiation-treated NSCLC with or without consolidation ICI were analyzed.

In the consolidation ICI cohort, 79 percent of patients received durvalumab (Medimmune/AstraZeneca's Imfinzi), the rest received atezolizumab (Genentech's Tecentriq) as part of the DETERRED trial. All patients had unresectable stage IIB-IIIB NSCLC.

In the cohort receiving no consolidation immunotherapy and in those receiving such therapy, 78 percent and 75 percent, respectively, had detectable ctDNA levels before receiving chemoradiation. All patients with detectable ctDNA had progression 24 months after starting chemoradiation compared to all those with undetectable ctDNA who did not experience progression, confirming to researchers that MRD is prognostic for risk of disease progression post-chemoradiation.

In the eight patients who progressed, ctDNA was detected before or at the time of disease progression in all patients. Detection of ctDNA before patients received consolidation ICI or early in the treatment process was a strong predictor of risk of disease progression, as 86 percent of patients with detectable ctDNA early in the course of receiving immunotherapy developed progressive disease. A year after starting chemoradiation, none of the patients with detectable ctDNA in the early-on consolidation ICI group had freedom from progression, while 87.5 percent of patients with undetectable ctDNA had freedom from progression.

Next, the researchers wanted to see if ctDNA detection after chemoradiation could identify the patients who would benefit from consolidation ICI. The majority of patients in the consolidation ICI cohort had undetectable ctDNA after chemoradiation and good outcomes, with 80 percent having freedom from progression at one-year post-treatment. The study showed that in those with undetectable ctDNA, patients had good outcomes post chemoradiation regardless of whether they received ICI, which suggests that the addition of consolidation immunotherapy doesn't boost benefit in a population that is already predisposed to do well.

Comparatively, patients with detectable ctDNA after chemoradiation in the consolidation ICI cohort had significantly better freedom from progression than patients who received no consolidation ICI afterwards.

"To the best of our knowledge, our results provide the first evidence that systemic therapy (in this case immunotherapy) can potentially improve the clinical outcomes of patients with detectable MRD," Moding and colleagues wrote in the paper. "Furthermore, our findings suggest that ctDNA analysis could potentially guide the decision to administer consolidation ICI after [chemoradiation] and distinguish responders and nonresponders early during consolidation ICI."

Further, the researchers found that the patterns of ctDNA levels may be used to predict which patients benefit more from consolidation ICI. Rising ctDNA levels early on during consolidation ICI correlated with poor outcomes, and patients with increasing ctDNA through the course of treatment developed progressive disease within 4.5 months of starting consolidation ICI, suggesting resistance to immunotherapy.

Patients with decreasing ctDNA during consolidation ICI had good outcomes, with 100 percent of those analyzed having freedom from progression one-year post-treatment. This data suggests that ctDNA monitoring after chemoradiation and early during consolidation ICI could further stratify the subset of patients who would benefit most from consolidation ICI.

"[Circulating tumor] DNA kinetics early during consolidation ICI further clarified which patients benefited from consolidation therapy, with patients whose ctDNA concentration decreased during consolidation ICI having superior outcomes compared to patients with a rising ctDNA concentration," the authors wrote, noting the need for additional studies to determine if ctDNA analysis can determine the optimal duration of immunotherapy in responding patients.