Early identification and treatment of occult metastatic disease in stage III colon cancer (SU2C ACT3 clinical trial).
Authors: Leon Pappas, Rona Yaeger, Pashtoon Murtaza Kasi, Manish A. Shah, Nilofer Saba Azad, Nora K. Horick, Ryan Bruce Corcoran, Luis A. Diaz, Aparna Raj Parikh
Journal: Journal of Clinical Oncology (2024)

148 Background: Despite adjuvant chemotherapy, nearly 30% of patients with Stage III colon cancer (CC) will recur. We are performing a randomized clinical trial using a plasma-only circulating tumor DNA (ctDNA) platform after adjuvant therapy for patients with ctDNA-positive Stage III CC. Methods: Patients (pts) with Stage III CC are eligible for prescreening, including tumor tissue profiling by next-generation sequencing. Pts are screened 3-6 weeks after adjuvant chemotherapy. At screening blood is collected for ctDNA analysis with a CLIA-certified sequencing panel (Reveal, Guardant Health). A baseline CT scan is required to confirm lack of metastases. Pts with undetectable ctDNA (-) at screening undergo surveillance with imaging, labs and ctDNA testing every 3 months (Arm 3). ctDNA-detectable (+) pts who are biomarker-negative are randomized to 1:1 to FOLFIRI (Arm 1) or active surveillance (Arm 2). ctDNA+ pts with an actionable biomarker (biomarker-positive) are given 6 months biomarker-directed therapy as follows: V600E/MSS- encorafenib, binimetinib and cetuximab (Arm 5), HER2 amplified trastuzumab/pertuzumab (arm 6), and MSI-H nivolumab (Arm 4). Primary outcome is ctDNA clearance in Arms 1 and 2, 1-month after completion of additional adjuvant therapy or surveillance. Secondary outcomes include RFS and OS in Arms 1 and 2, ctDNA clearance and RFS/OS in the other arms. An interim analysis is planned after 13 patients are enrolled in Arm 1 and primary outcome will be assessed after 50 patients’ complete treatment/surveillance in Arms 1 and 2. Results: From 4/16/2020 through 9/8/2023, 147 patients were screened, 66 screen failed. Pre-screening as well as active ongoing enrollment is underway. To date, 73 patients have enrolled (46 male and 27 female). 53 (72.6%) were white. 10 (13.7%) patients were noted to be ctDNA+ within 6 weeks of completion of adjuvant therapy: 4 in Arm 1; 5 in Arm 2; 1 in Arm 4. 63 pts were ctDNA- and in Arm 3. Conclusions: In this ctDNA guided trial, with single time-point testing, only 13.7% of pts were ctDNA+ after adjuvant chemotherapy. 90% of ctDNA+ patients did not have an actionable biomarker. Strict windows for eligibility and enrollment initially restricted eligibility but these were adjusted to increase eligibility. To mitigate the low positivity rate and allow us to meet our accrual goals in arm 1 and 2, the protocol was amended to allow for entry into the ctDNA+ arms at any time during the first 3 years after completion of adjuvant therapy as opposed to within 6 weeks of completion of adjuvant therapy. The lessons learnt would have implications for other ctDNA-driven clinical trials. Clinical trial information: NCT03803553. Patient distribution in the SU2C ACT3 study. Total Screened Pre-Screening Screen Fail Enrolled Off Study ctDNA Treatment Arm + - Arm 1 Arm 2 Arm 3 Arm 4 Arm 5 Arm 6 147 8 66 73 10 10 63 4 5 63 1 0 0