Impact of Circulating Tumor DNA-Based Detection of Molecular Residual Disease on the Conduct and Design of Clinical Trials for Solid Tumors

Abstract

Purpose: Earlier detection of cancer recurrence using circulating tumor DNA (ctDNA) to detect molecular residual disease (MRD) has the potential to dramatically affect cancer management. We review evidence supporting the use of ctDNA as a biomarker for detection of MRD and highlight the potential impact that ctDNA testing could have on the conduct of clinical trials.

Methods: We searched the literature using MEDLINE (via PubMed) for articles from January 1, 2000, focusing on studies that assessed ctDNA as a predictor of cancer recurrence. Broadly focused searches on ctDNA and cancer were also performed to provide additional background information. www.clinialtrials.gov was searched to identify trials that incorporate ctDNA testing.

Results: Numerous studies across different cancer types indicate that ctDNA-based MRD detection predicts recurrence with high sensitivity and specificity, and with lead times that precede standard imaging by up to 12 months. Recently, ctDNA testing has started being used to enroll MRD-positive patients at high risk of recurrence into trials, promising gains in statistical power that allow clinical utility to be demonstrated with smaller cohorts. Trials where ctDNA testing based-MRD detection is used to stratify patients into low or high-risk categories for treatment assignment are also ongoing. In addition, there is increasing evidence supporting the use of ctDNA dynamics or clearance as a surrogate end point, which could significantly reduce trial duration.

Conclusion: ctDNA-based trial enrichment across many cancers seems likely to become increasingly common for cost- and time-reduction benefits. Trial efficiency could also benefit from using ctDNA as a surrogate end point, leading to accelerated approval of new therapeutics. A clear demonstration of efficacy from trials that use ctDNA-based MRD detection to assign treatment could transform clinical practice.

FIG 1.

(A) Potential reduction in sample size and costs for stage III CRC trial through enrichment with ctDNA testing. In this scenario, an 8-fold reduction in enrollment size and a 75% reduction in per patient costs after accounting for treatment and ctDNA screening can be achieved (for sample size estimates, we assumed an event rate of 0.75 in ctDNA-positive patients in the control arm and a 0.25 relative risk reduction in the treatment arm.) (B) Decrease in sample size as related to relapse rate for disease in the control group at varying drug efficiencies. Enrollment through ctDNA testing has a dramatic impact on sample size, since the event rate is greatly increased if ctDNA-positive patients are selected. The plot shows potential decreases in sample size that could have been achieved for ongoing clinical trials had ctDNA testing been used for enrichment. The PALLAS and APHINITY studies were described in the text. We also show the sample size that could have been achieved through enrichment for the IMvigor010 trial (NCT02450331), a phase III randomized trial of adjuvant atezolizumab versus observation in patients with high-risk muscle-invasive bladder cancer, which originally enrolled 800 patients. Sample size estimates were obtained from the original study (the original sample size estimates for the PALLAS and APHINITY studies were smaller than the number eventually enrolled) and the same parameters from the original estimates were used to generate hypothetical sample sizes for the enriched studies with the exception that the observation arm event rate was changed to reflect recurrence in ctDNA-positive patients (0.6 for PALLAS and APHINITY on the basis of risk reduction estimates for patients receiving endocrine therapy and 0.85 for ctDNA-positive patients with urothelial carcinoma in the IMvigor010 observation arm). Closed triangle and circle represent the original sample size estimates and open triangle and circle represent sample size estimates for enriched studies. ARR, absolute risk reduction; CRC, colorectal cancer; ctDNA, circulating tumor DNA; SOC, standard of care.

FIG 2.

(A) Marker by treatment interaction design with MRD testing after definitive treatment. ctDNA-positive patients are randomly assigned to SOC plus investigational therapy versus SOC alone. ctDNA-negative patients are assigned to the follow-up group. Noninferiority component permits comparison of ctDNA-negative patients with ctDNA-positive patients to ensure these patients have outcomes that are no worse than treatment groups. (B) Marker by treatment interaction and noninferiority designs with MRD testing after definitive treatment (GALAXY, ALTAIR, and VEGA). ctDNA-positive patients from the GALAXY study are randomly assigned in the ALTAIR study to SOC plus investigational therapy versus SOC alone. ctDNA-negative patients from GALAXY are randomly assigned to CAPOX and follow-up. Noninferiority of follow-up versus CAPOX is investigated among ctDNA-negative patients. ctDNA-negative patients from VEGA who become ctDNA-positive can crossover to ALTAIR. (C) MRD testing after definitive treatment. The results of MRD testing are used to assign ctDNA-positive patients to escalation and ctDNA-negative patients to de-escalation therapy in Arm A. Arm B has no ctDNA testing and receives SOC. ctDNA, circulating tumor DNA; FTD/TPI, trifluridine/tipiracil; MRD, molecular residual disease; SOC, standard of care.