ctDNA can be used as a marker of MRD after definitive surgery and after (neo)adjuvant therapy to enrich a trial for patients with higher-risk disease and increased events of disease recurrence or death. Since the recurrence rate drives statistical power, much smaller sample sizes are possible for ctDNA-positive cohorts. There is substantial evidence that ctDNA-based MRD detection can stratify patients into high-risk and low-risk groups, which allows for more efficient trials by targeting high-risk patients for enrollment. Numerous retrospective studies across multiple cancer types have reported that ctDNA-based MRD detection is sensitive and specific for recurrence in both postoperative and serial testing scenarios. For some cancers, the latter can improve the sensitivity of ctDNA testing relative to the postoperative setting.
A hypothetical clinical trial enrolling of ctDNA-positive stage III patients with CRC in the adjuvant setting is shown in Figure 3. The example assumes 19% of patients are ctDNA-positive, of which 75% will experience recurrence, compared to patients enrolled irrespective of ctDNA status, with a recurrence rate of 27%. Since the recurrence rate drives statistical power, smaller sample sizes are possible for ctDNA-positive cohorts. This results in an 8-fold reduction in enrollment and a 75% reduction in per-patient costs after accounting for treatment and ctDNA screening 1.
Figure. ctDNA enrichment reduces clinical trial cost using a hypothetical colorectal cancer trial adapted from Kasi et al.1.
Recent phase III adjuvant clinical trials that have enrolled thousands of patients further highlight the benefit of enriching trials with high-risk patients. For example, the PALLAS study enrolled 5,760 patients with early-stage breast cancer with a planned ten years of follow-up to determine whether a CDK4/6 inhibitor added to endocrine therapy improves disease-free survival (DFS). Similarly, the APHINITY study randomly assigned 4,805 patients with breast cancer to investigate the combination of pertuzumab with chemotherapy and trastuzumab. Both trials only showed modest results and could have substantially reduced sample size and costs if reliable biomarkers to identify patients at high risk for recurrence were available at enrollment 7 (Above figure).
References
*1 Kasi, P. M. et al. Impact of Circulating Tumor DNA–Based Detection of Molecular Residual Disease on the Conduct and Design of Clinical Trials for Solid Tumors. JCO Precis Oncol e2100181 (2022) http://doi.org/10.1200/PO.21.00181
The PEMDAC phase 2 study of pembrolizumab and entinostat in patients with metastatic uveal melanoma
https://www.nature.com/articles/s41467-021-25332-w
Design:
A phase 2, randomized, controlled noninferiority trial assessed whether ctDNA-guided management, as compared with standard management, could reduce the use of adjuvant therapy without compromising the risk of recurrence after surgery for stage II colon cancer.
Intervention:
455 patients were randomly assigned in a 2:1 ratio to have treatment decisions guided by either ctDNA results or standard clinicopathological criteria. For ctDNA-guided management, patients with positive ctDNA tests at week 4 or 7 after surgery received fluoropyrimidine or oxaliplatin-based chemotherapy, and those with negative tests at both weeks received no chemotherapy. The primary efficacy end point was recurrence-free survival at 2 years. A key secondary end point was adjuvant chemotherapy use.
Results:
Management guided by ctDNA was noninferior to standard management with respect to 2-year recurrence-free survival and resulted in less use of adjuvant chemotherapy.
Conclusions:
Among patients with stage II colon cancer, ctDNA-guided management was noninferior to standard management with respect to 2-year recurrence-free survival and resulted in reduced use of adjuvant chemotherapy.
Significant cost savings can be achieved through reduced chemotherapy use, also leading to fewer associated costly side effects.
References:
Ny, L., Jespersen, H., Karlsson, J. et al. The PEMDAC phase 2 study of pembrolizumab and entinostat in patients with metastatic uveal melanoma. Nat Commun 12, 5155 (2021). https://doi.org/10.1038/s41467-021-25332-w