Table 1.
Representative MRD-directed adjuvant therapy trials in solid cancers
| Study name (registration No.) | Cancer type | Stage | No. of patients | Phase | MRD assaya) | Intervention | Primary endpoint |
|---|---|---|---|---|---|---|---|
| COBRA: NRG-GI005 (NCT04068103) | Colon | IIA | 1,408 | II/III | Guardant REVEAL | ctDNA (+): FOLFOX/CAPOX vs. SoC ctDNA (−): Surveillance vs. SoC |
RFS, ctDNA clearance |
| CIRCULATE-US: NRG-GI008 (NCT05174169) | Colon | II–III | 1,750–1,912 | III | Signatera | ctDNA (+): FOLFOXIRI vs. FOLFOX/CAPOX ctDNA (−): FOLFOX/CAPOX vs. surveillance |
3-yr DFS |
| ACT3 (NCT03803553) | Colon | III | 500 | III with phase II trials | Guardant REVEAL | ctDNA (+) & MSS: FOLFIRI vs. surveillance ctDNA (+) & BRAF/MSS: encorafenib/binimetinib/cetuximab ctDNA (+) & MSI: nivolumab |
5-yr DFS, ctDNA clearance |
| DYNAMIC III (ACTRN-12617001566325) | Colon | III | 1,000 | II/III | Safe-SeqS | SoC vs. ctDNA informed treatment strategy | 2-yr RFS |
| TRACC (NCT04050345) | Colon | II–III | 1,621 | III | NGS-based 22-gene panel | SoC vs. ctDNA informed treatment strategy | 3-yr DFS |
| PEGASUS (NCT04259944) | Colon | II–III | 140 | II | Guardant REVEAL | ctDNA-guided therapy (both de-escalation & escalation) | Feasibility of ctDNA-guided treatment |
| CIRCULATE AIO-KRK-0217 (NCT04089631) | Colon | II | 4,812 | III | Tumor-informed NGS | ctDNA (+): capecitabine±oxaliplatin vs. no chemotherapy ctDNA (−): study follow-up vs. standard follow-up |
3-yr DFS |
| CIRCULATE PRODIGE 70 (NCT04120701) | Colon | II | 1,980 | III | ddPCR (2 methylated markers WIF1, NPY) | ctDNA (+): FOLFOX vs. surveillance | 3-yr DFS |
| CLAUDIA Colon Cancer: KCSG CO22-12 (NCT05534087) | Colon | II–III | 236 | III | IMBdx AlphaLiquid DETECT | ctDNA (+): FOLFOX/CAPOX 3M+ mFOLFIRINOX 3M (total 6M) vs. FOLFOX/CAPOX 6M | 3-yr DFS |
| VEGA (jRCT1031200006) | Colon | II (high -risk)/III (low-risk) | 1,240 | III | Signatera | ctDNA (−): CAPOX 3M vs. surveillance | 3-yr DFS |
| ALTAIR (NCT04457297) | Colon | II–IV | 240 | III | Signatera | ctDNA (+): TAS-102 vs. placebo | DFS |
| IMPROVE-IT 2 (NCT04084249) | Colon | II–III | 254 | III | ddPCR | SoC follow-up vs. ctDNA-guided surveillance | Fraction of pts. recurrence receiving curative treatment |
| MEDOCC-CrEATE (NL6281/NTR6455) | Colon | II | 1,320 | II | PGDx elio | SoC (surveillance) vs. ctDNA informed treatment strategy | Proportion of patients starting adjuvant chemotherapy after ctDNA (+) |
| MERMAID-1 (NCT04385368) | NSCLC | II–III | 332 | III | ArcherDX PCM | ctDNA (+): durvalumab+SoC chemotherapy vs. placebo+SoC chemotherapy | DFS in MRD+ analysis set |
| MERMAID-2 (NCT04642469) | NSCLC | II–III | 284 | III | ArcherDX PCM | ctDNA (+): durvalumab vs. placebo | DFS in the PD-L1 TC ≥ 1% analysis set |
| NCT04585477 | NSCLC | II–III | 80 | II | Avenio (CAPP-Seq) | ctDNA (+): durvalumab×12 ctDNA (−): surveillance (no therapy) |
ctDNA MRD response in ctDNA (+) cohort |
| NCT04585490 | NSCLC | III | 48 | II | Avenio (CAPP-Seq) | ctDNA (+): platinum doublet ×4+ durvalumab for 1 yr ctDNA (−): durvalumab for 1 yr |
ctDNA MRD response in ctDNA (+) cohort |
| c-TRAK TNb) (NCT03145961) | TNBC | II/III | 208 | II | ddPCR | ctDNA(+): pembrolizumab vs. observation | ctDNA detection rate and sustained ctDNA clearance rate on pembrolizumab |
| ZEST (NCT04915755) | TNBC or HR+/HER2− | I–III | 800 | III | Signatera | ctDNA (+) [cohort 2]: niraparib vs. placebo | DFS |
| PERSEVERE (NCT04849364) | TNBC | I–III | 197 | II | ParadigmDx | ctDNA (+) & genomic target: capecitabine or talazoparib or atezolizumab or inavolisib ctDNA (+) & genomic target: treatment of choice ctDNA (−): treatment of choice |
2-yr DFS in ctDNA (+) & genomic target |
CAPOX, capecitabine and oxaliplatin; CAPP-Seq, cancer personalized profiling by deep sequencing; ctDNA, circulating tumor DNA; ddPCR, droplet digital polymerase chain reaction; DFS, disease-free survival; FOLFIRI, 5-fluorouracil, leucovorin, and irinotecan; FOLFOX, folinic acid, 5-fluorouracil and oxaliplatin; FOLFOXIRI, oxaliplatin, irinotecan, leucovorin, and 5-fluorouracil; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; MRD, minimal residual disease; MSI, microsatellite instability; MSS, microsatellite stable; NGS, next-generation sequencing; NSCLC, non–small cell lung cancer; PD-L1, programmed death-ligand 1; RFS, relapse-free survival; SoC, standard of care; TC, tumor cells; TNBC, triple-negative breast cancer.
MRD detection methods can be classified into two categories: tumor-agnostic and tumor-informed methods. Tumor-agnostic methods identify de novo mutations from plasma using a fixed panel, while tumor-informed methods first detect mutations in tumor tissue and then track them in plasma using a customized panel based on the mutations found in the tumor tissue. Tumor-agnostic assays are generally fast and simple because it does not require tumor tissue and uses a fixed panel. This approach is more cost-effective and scalable, but it may have lower sensitivity as it can only detect common mutations. In contrast, tumor-informed panels generally have a higher sensitivity by targeting a larger number of mutations. However, these methods are more expensive and take longer to generate results compared to tumor-agnostic panels [83,84],
The recently published c-TRAK TN study reported a ctDNA detection rate of 27.3% (44/161) among patients with high-risk early-stage triple-negative breast cancer after 12 months [85]. However, the study also found that 72% (23/32) of the patients who received intervention based on ctDNA results had already developed metastases at the time of ctDNA staging. These results suggest that ctDNA MRD detection may not be sensitive and early enough to guide treatment decisions in patients with breast cancer.