Incorporating ctDNA Into Clinical Trial Design

Liquid biopsies using circulating tumor DNA (ctDNA) have become increasingly utilized in a variety of settings across the cancer continuum. Midhun Malla, MD, MS, discussed the potential applications of ctDNA and how it can be incorporated into clinical trial design.¹ ctDNA offers several advantages over tissue biopsies: it is noninvasive, can obtain repeated samples, can determine tumor heterogeneity and the surrogate of tumor burden, and can assess the emergence of resistance alterations on treatment.² One potential application of ctDNA can include assessment of minimal residual disease and recurrence monitoring.² In a study of patients with hepatocellular carcinoma (HCC) and biliary tract cancer, ctDNA levels were analyzed to determine treatment response. The researchers found that ctDNA detection was significantly associated with the stage of disease, and it may be a beneficial tool in determining which patients are at high risk for recurrence or metastasis.³ Another study evaluated ctDNA in 97 patients with liver cancer postoperatively and found that patients with positive ctDNA after surgery should receive some adjuvant treatment as soon as possible to improve survival rates.⁴ ctDNA can be incorporated into clinical trial design in this setting as seen in the DYNAMIC study. DYNAMIC was a randomized, controlled, phase 2 trial assessing if a ctDNA-guided approach could reduce the use of adjuvant chemotherapy without compromising risk. Patients were randomized 2:1 to ctDNA-guided management or standard management; ctDNA-positive patients received adjuvant chemotherapy and ctDNA-negative patients were randomized to observation. Overall, it was found that a ctDNA-guided approach reduced adjuvant chemotherapy use without compromising recurrence-free survival.⁵ Another application of ctDNA is for immunotherapy response monitoring. Standard radiologic criteria do not consistently capture the dynamics of clinical benefit, and definitive predictive biomarkers for response to determine responders versus nonresponders are lacking.¹ In a study of ctDNA evaluation in patients with HCC treated with first-line atezolizumab and bevacizumab, researchers found that ctDNA clearance at 9 weeks was associated with increased survival, and dynamic changes in ctDNA posttreatment were associated with response.^1,6 A longer progression-free survival (PFS) was found in patients with undetectable ctDNA posttreatment.⁶ Another study evaluating ctDNA as a predictive biomarker in patients with solid tumors treated with pembrolizumab found that baseline ctDNA concentration correlated with PFS, overall survival, clinical response, and clinical benefit, and the overall response rates to therapy were associated with ctDNA clearance.⁷ ctDNA as a predictive biomarker can be incorporated into clinical trial design to stratify patients to continue immunotherapy or switch therapy based on response to initial therapy using ctDNA levels.¹ ctDNA can also be used as a molecular profiling tool.² In the phase 2 study evaluating the FGFR inhibitor futibatinib in patients with intrahepatic cholangiocarcinoma, a partner-agnostic ctDNA platform used in the correlative analysis was able to identify FGFR2 fusions or rearrangements in 87% of evaluated patients.⁸ ctDNA may also be used to determine resistance in patients treated with targeted therapy, as seen in a study evaluating acquired polyclonal resistance to FGFR inhibition in patients with FGFR2 fusion CCA.¹ Finally, ctDNA can be used as a clinical trial matching tool.¹ Often biomarker-targeted clinical trial accrual can be challenging due to patient identification; trial design; cost; and patient, provider, or institution barriers.¹ A study of patients with advanced solid tumors who were treatment naïve or had disease progression after therapy used tissue or ctDNA genotyping to stratify patients based on associated genetic findings to appropriate clinical trials to identify patients who could benefit from targeted therapy.¹ Although a variety of applications for ctDNA are recognized, there are some limitations. False negatives may be seen due to low amounts of ctDNA, such as in lung cancer, increased cell-free DNA in the background, or insufficient ctDNA samples or assay sensitivity.⁹ In addition, false positives may occur due to clonal hematopoiesis of indeterminate potential or sequencing error, and ctDNA may be difficult in patients who have more than 1 cancer or a history of transplantation.⁹

Sources:

1. Malla M. Circulating tumor DNA in hepatobiliary cancers: incorporation in clinical trial design. Presented at: Cholangiocarcinoma Foundation meeting, April 12-14, 2023; Salt Lake City, UT.
2. Malla M, Loree JM, Kasi PM, Parikh AR. Using circulating tumor DNA in colorectal cancer: current and evolving practices. J Clin Oncol. 2022;40(24):2846-2857.
3. Kasi PM, Budde G, Dayyani F, et al. Tumor-informed assessment of circulating tumor DNA and its incorporation into practice for patients with hepatobiliary cancers. J Clin Oncol. 2021;39(suppl 15):4103.
4. Zhou L, Xu Y, Wang D, et al Perioperative circulating tumor DNA analysis to predict patient prognosis in liver cancer. J Clin Oncol. 2020;38(suppl 15):4593.
5. Tie J, Cohen JD, Lahouel K, et al. Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer. N Engl J Med. 2022;386(24):2261-2272.
6. Hsu CH, Lu S, Abbas A, et al. Longitudinal and personalized detection of circulating tumor DNA (CTDNA) for monitoring efficacy of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma (HCC). J Clin Oncol. 2020;38(suppl 15):3531.
7. Bratman SV, Yang SYC, Iafolla MAJ, et al. Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab. Nat Cancer. 2020;1(9):873-881.
8. Goyal L, Meric-Bernstam F, Hollebecque A, et al. Futibatinib for FGFR2-rearranged intrahepatic cholangiocarcinoma. N Engl J Med. 2023;388:228-239.
9. Bando H, Nakamura Y, Taniguchi H, et al. Effects of metastatic sites on circulating tumor DNA in patients with metastatic colorectal cancer. JCO Precis Oncol. 2022;6:e2100535.