ctDNA dynamics and prognostic value during first-line treatment of metastatic colorectal cancer: Analysis from the phase 3 PARADIGM study.

3573 Background: The phase 3 PARADIGM trial showed overall survival (OS) and tumor response advantages of anti-EGFR (panitumumab, PAN) over anti-VEGF (bevacizumab, BEV) therapy with FOLFOX6 in first-line metastatic colorectal cancer (mCRC) despite similar progression-free survival (PFS), highlighting limitations of imaging-based PFS as a surrogate for clinical benefit. We investigated whether ctDNA dynamics provide more refined prognostic information complementary to baseline (BL) ctDNA. Methods: Plasma samples collected from 556 patients (pts) with mCRC paired at pre-treatment (BL) and post-treatment (after treatment discontinuation) were profiled for ctDNA. Distribution of the highest variant allele fraction was modeled using a Gaussian mixture model. At pre- and post-treatment, pts were classified into 3 groups—High, Mid, and Low—according to ctDNA levels. OS, post-treatment survival (PTS), and PFS were compared across 9 ctDNA dynamic categories (eg, High→Low, High→Mid, High→High) based on changes from pre- to post-treatment. Results: Lower BL ctDNA was significantly associated with longer OS (median OS [95% CI]: Low, n = 97, 50.7 mo [44.0–65.2]; Mid, n = 159, 34.1 mo [26.9–37.1]; High, n = 300, 27.8 mo [26.2–31.3]). BL ctDNA level also correlated with tumor volume and mutation burden. Pts with lower ctDNA at treatment discontinuation had longer PTS. Incorporating ctDNA dynamics provided additional prognostic value. Regardless of BL ctDNA level, pts whose post-treatment ctDNA decreased to Low had the best survival (eg, High→Low: 50.9 mo [35.8–61.0]), while pts with persistently high ctDNA showed the poorest survival (High→High: 23.3 mo [18.2–27.8]). The prognostic value of ctDNA dynamics was consistent across treatment arms. Among pts with High BL ctDNA (PAN, n = 152; BEV, n = 148), a greater proportion achieved Low ctDNA at post-treatment with PAN vs BEV (29 [19.1%] vs 16 [10.8%], p = 0.053), whereas the proportions achieving Mid ctDNA were similar (52 [34.2%] vs 58 [39.2%], p = 0.40). In the High→Low/Mid ctDNA subsets, treatment discontinuation following curative resection was more frequent with PAN vs BEV (High→Low: 18/29 [62.1%] vs 7/16 [43.8%]; High→Mid: 11/52 [21.2%] vs 5/58 [8.6%]). OS and PTS trends were favorable with PAN vs BEV (OS; High→Low: 61.0 vs 43.1 mo, HR 0.49, 95% CI 0.23–1.04; High→Mid: 33.6 vs 26.8 mo, HR 0.74, 95% CI 0.50–1.11, PTS; High→Low: 55.1 vs 39.0 mo, HR 0.48, 95% CI 0.22–1.03; High→Mid: 20.6 vs 19.4 mo, HR 0.72, 95% CI 0.48–1.07). Conclusions: ctDNA dynamics add prognostic value beyond BL ctDNA level. In pts with high BL ctDNA, PAN yielded more conversions into low ctDNA levels and discontinuations following curative resection, with OS/PTS trends favoring PAN. These findings suggest that ctDNA dynamics may better reflect long-term clinical benefit than PFS, although standardized thresholds and prospective validation are needed. Clinical trial information: NCT02394834 ; NCT02394795 .