Evidence continues to accumulate that detection of residual circulating tumor DNA (ctDNA) after curative-intent therapy foretells very poor outcomes across a variety of solid cancers. Over 20 studies have now demonstrated the prognostic importance of ctDNA molecular residual disease (MRD) in diverse histologies, including lung, colon, breast, bladder, and pancreatic cancer. Given the high risk of relapse with ctDNA MRD, the natural inclination would be to add additional treatment in hopes of improving outcomes. However, whether additional treatment can actually improve outcomes in ctDNA MRD positive solid cancers has been an ongoing area of debate.
Those choosing to view the glass half full point to the data from hematologic malignancies that escalating therapy can improve outcomes in patient with minimal residual disease detected by PCR or flow cytometry. Furthermore, a handful of studies have shown that chemotherapy can decrease and sometimes eliminate (at least temporarily) ctDNA MRD in patients with solid tumors. However, no studies have shown that outcomes are improved in ctDNA MRD positive patients who receive additional systemic therapy. As a result, there has been no evidence to argue against the glass half empty view that patients with ctDNA MRD may have levels of residual disease too high to benefit from additional therapy. In this view, it is the patients who are missed by ctDNA MRD assays (i.e. false negatives) who are potentially the ones who benefit from adjuvant/consolidation therapy. Indeed, we have encountered this argument in discussions to design prospective clinical trials that would personalize treatment based on ctDNA MRD.
With this motivation in mind, we saw a recent change in the standard of care for patients with locoregionally advanced non-small cell lung cancer (NSCLC) as an opportunity to address this controversy using an “in silico clinical trial”. In February 2018, the United States Food and Drug Administration approved consolidation immunotherapy with durvalumab (an anti-PD-L1 antibody) after chemoradiation therapy for NSCLC. As a result, we were able to retrospectively assemble two groups of patients for ctDNA analysis: 1) patients who did not receive consolidation immunotherapy (i.e. patients treated before regulatory approval) and 2) patients who did receive consolidation immunotherapy. By performing ctDNA analysis using CAPP-Seq in these two groups, we were able to ask if outcomes differed between patients who had detectable ctDNA MRD after chemoradiation based on whether or not they received consolidation immunotherapy. We found that such patients had significantly improved freedom from progression if they received further treatment, suggesting that effective systemic therapy can improve outcomes in ctDNA MRD-positive patients. Furthermore, patients whose ctDNA levels decreased early during immunotherapy had significantly better outcomes than patients with rising ctDNA concentrations. In our study, patients without ctDNA MRD had excellent outcomes regardless of whether they received consolidation immunotherapy, suggesting the benefit from additional therapy in these patients is likely small.
Ultimately, we need prospective clinical trials to verify that ctDNA analysis should be used to personalize adjuvant or consolidation therapy in patients with solid cancers. However, our findings suggest that such studies are likely to be positive if an effective systemic therapy is used and provide insight into how ctDNA analysis might be incorporated into NSCLC treatment in the future (Figure 1). We envision that in the future, locally advanced NSCLC patients could routinely undergo ctDNA testing after completing chemoradiation. Patients with negative ctDNA MRD could continue on surveillance ctDNA analysis with plans to start salvage immunotherapy if ctDNA becomes positive in the future. Patients with positive ctDNA MRD would start immunotherapy, and response could be assessed early using ctDNA kinetics so that treatment could be changed or escalated in patients with rising ctDNA. Furthermore, if ctDNA changes during adjuvant or consolidation therapy are further validated to strongly correlate with patient outcomes in larger prospective trials, change in ctDNA (or ctDNA clearance) during adjuvant/consolidation therapy could potentially become a surrogate endpoint for regulatory approval. If so, this could dramatically increase the pace at which new therapies are tested and approved in the early stage setting. Although considerable work lies ahead, we believe the glass is half full for use of ctDNA MRD analysis to personalize therapy in early stage cancer patients.
Figure 1: Possible personalized treatment schema based on ctDNA kinetics for patients with locoregionally advanced non-small cell lung cancer. The schematic was produced using Servier Medical Art (https://smart.servier.com). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/).
Written by Everett Moding & Maximilian Diehn.