Table 2 Clinical trial results from minimal residual disease assays based on ctDNA (numbers refer to Fig. 2)
Trial’s name [REF] Design | Target(s) tested (assay name) | Population tested | Internvention(s) tested | Responds to question No | Sample size | Study design and endpoints |
|---|---|---|---|---|---|---|
BESPOKE [225] Observational | Tumor-informed ctDNA (Signatera) | Stage II/III | Local preference | ① | 1000 | Non-randomized trial. the treating physician received the ctDNA results and, if positive, may decide to assign the patient to adjuvant therapy (escalation) or observation, based on the clinicians’ preference |
Stage I-IV | Local preference | ① | 2000 | |||
Phase III | WIF1 and NPY methylation by ddPCR | Stage II | mFOLFOX6 or CapOx for 3/6 months | ①② | 198 | Escalation. ctDNA-positive patients are randomized (2:1) to chemotherapy or observation De-escalation. ctDNA-negative patients are randomized (1:4) to follow-up within trial or follow-up outside of trial |
CIRCULATE-US [227] Phase II/III | Tumor-informed ctDNA (Signatera) | Stage II/III | FOLFOX6 or CAPEOX for 3–6 months | ①②③⑤ | N.A | De-escalation. ctDNA-negative patients are randomized to adjuvant therapy (FOLFOX6 or CAPEOX) or ctDNA-based surveillance Escalation. ctDNA-positive patients are randomized to double therapy (FOLFOX6/CAPEOX) or triplet therapy (FOLFIRINOX) Cross-over design allowed. ctDNA-negative patients who develop ctDNA positivity during surveillance may enter the escalation arm and be randomized to FOLFOX6/CAPEOX or FOLFIRINOX |
CIRCULATE-Germany/Austria [228] Phase III | Tumor-informed ctDNA (Signatera) | Stage II | Capecitabine ± oxaliplatin (investigator's choice) | ①② | 554 | Escalation. ctDNA-positive patients are randomized (2:1) to chemotherapy or follow-up De-escalation. ctDNA-negative patients are randomized (1:4) to follow-up within study or outside of study |
COBRA Escalation [229] Phase II/III | Reveal (Guardant health) * | Stage IIA (low-risk) | Oxaliplatin, capecitabine, leucovorin, leucovorin-calcium, fluorouracil | ② | 1408 (prematurely stopped) | Escalation. ctDNA positive patients are assigned to treatment, while ctDNA negative patients to observation. The phase II study assesses ctDNA clearance as an endpoint while the phase III part recurrence free survival |
CIRCULATE-Japan [230] Umbrella | Tumor-informed ctDNA (Signatera) | Stage II, III, or IV resectable | See below | ①②③ | 1039 | Ongoing umbrella trial with three sub-parts: GALAXY, ALTAIR, and VEGA (see below) |
GALAXY [231] Observational | Tumor-informed ctDNA (Signatera) | Stage II, III, or IV resectable | Observational | ① | 1039 | Observational. Part of the CIRCULATE-Japan study; ctDNA positivity at 4 weeks after surgery associated with recurrence (HR 10.0), also in stage II/III (HR 10.82), and identified patients who derived benefit from ACT (HR 6.59) |
ALTAIR [231] Phase III | Tumor-informed ctDNA (Signatera) | Stage III after completion of CapOx (3 months) | Trifluridine/tipiracil or SOC | ③ | 240 | Escalation. Part of the CIRCULATE-Japan study. Ongoing randomized phase III trial to investigate ctDNA-guided second-line adjuvant therapy management ctDNA positive patients are randomization to treatment escalation vs. surveillance. VEGA is the comparator arm |
VEGA [231] Phase III | Tumor-informed ctDNA (Signatera) | Stage II, III, or IV resectable | Observation | ② | 1240 | De-escalation. Part of the CIRCULATE-Japan study. Randomized phase III trial of treatment de-escalation for ctDNA negative patients |
CIRCULATE-IDEA Phase III | Tumor-informed ctDNA (Signatera) | Stage II high-risk Stage III low-risk | CapOx | ①②③ | 1912 | De-escalation. Sub-analysis of the CIRCULATE-Japan study, designed to create an international repository for ctDNA studies and evaluating 3-year DFS as the endpoint Patients are randomized to receive ctDNA-based treatment vs. standard of care. In the intervention arm, ctDNA negative patients receive observation while ctDNA positive patients receive CapOx. In the standard of care arm, all patients receive CapOx, regardless of ctDNA results |
DYNAMIC-III [196] Phase II/III | Tumor-informed ddPCR | Stage III | Fluoropyrimidine, or fluoropyrimidine + oxaliplatin, or FOLFOXIRI | ①② | 1000 | De-escalation and escalation. Patients are randomized to receive ctDNA-based treatment vs. standard of care. In the intervention arm, ctDNA positive patients receive escalation therapy and ctDNA negative receive de-escalation. In the comparator standard of care arm, ctDNA results are blinded |
DYNAMIC-II [196] Phase II | Tumor-informed ddPCR | Stage II | Single-agent oxaliplatin or fluoropyrimidine | ①② | 455 | De-escalation. Patients are randomized to receive ctDNA-based treatment vs. standard of care. In the intervention arm, ctDNA positive patients received adjuvant therapy and the ctDNA negative patients received observation. All patients in the standard of care arm received adjuvant therapy A lower percentage of patients in the ctDNA-guided group than in the standard-management group received adjuvant chemotherapy (15% vs. 28%; relative risk, 1.82; 95% confidence interval [CI], 1.25 to 2.65). In the evaluation of 2-year recurrence-free survival, ctDNA-guided management was noninferior to standard management (93.5% and 92.4%, respectively; absolute difference, 1.1 percentage points; 95% CI, − 4.1 to 6.2 [noninferiority margin, − 8.5 percentage points]). Three-year recurrence-free survival was 86.4% among ctDNA-positive patients who received adjuvant chemotherapy and 92.5% among ctDNA-negative patients who did not |
MEDOCC-CrEATE [224] | Tumor-informed ddPCR | Stage II | FOLFOX or CapOx for 6 months | ①② | 1320 | Escalation. Patients are randomized (1:1) to receive ctDNA-based treatment vs. standard of care. ctDNA-positive patients will receive escalation adjuvant therapy |
PEGASUS De-escalation [232] Phase II | Reveal (Guardant health) * | Stage III and high-risk stage II | CapOx, Capecitabile, Folgiri | ④ | 135 | De-escalation.This study evaluates the conversion from ctDNA negative to ctDNA positive during adjuvant therapy. ctDNA positive patients receive CapOx while ctDNA negative patients receive capecitabine alone. However, if ctDNA negative patients who convert to ctDNA positive after 1 cycle switch to CapOx |
TRACC Part C [233] | Tumor-informed ctDNA (Guardant Reveal) | Stage III and high-risk stage II | CapOx | ①② | 1620 | De-escalation. Patients are randomized to receive ctDNA-based treatment vs. standard of care. In the intervention arm, ctDNA positive patients wll receive CapOx, while ctDNA negative patients receive de-escalation therapy. For the comparator standard of care arm, patients receive CapOx |