Ultrasensitive detection and tracking of circulating tumor DNA (ctDNA) and association with relapse and survival in locally advanced cervical cancer (LACC): Phase 3 CALLA trial analyses.

5502 Background: In LACC, there is an unmet need for prognostic biomarkers as about 1/3 of patients (pts) relapse after chemoradiotherapy (CRT). The global randomized CALLA trial (NCT03830866) of durvalumab (D) in combination with CRT followed by D (D+CRT arm) vs CRT (CRT arm) did not significantly improve progression-free survival (PFS) in a biomarker unselected intent-to-treat (ITT) population. We analyzed the association of ultrasensitive ctDNA detection with relapse and survival in the largest ctDNA data set in LACC to date. Methods: Adult women with Stage IB2-IIB node positive (N+) or IIIA-IVA any N LACC (ITT) were randomized 1:1 to D+CRT or CRT alone. NeXT Personal (Personalis, Fremont, CA), an ultrasensitive tumor-informed MRD assay with up to 1,800 patient-specific variants from WGS, was used for ctDNA analysis from Cycle 1 Day 1 (C1D1; baseline [BL]), C3D1, and 6 mo post treatment initiation. Correlations were analyzed between ctDNA detection and outcomes (PFS, overall survival [OS]). Results: Of 770 pts randomized, the biomarker-evaluable population (BEP) comprised 185, 186, and 130 pts at BL, C3D1, and 6 mo, respectively. BL pt characteristics, PD-L1, PFS, and OS between BEP and ITT populations were generally similar. ctDNA was detected in 99% of pts at BL and decreased after treatment, reaching 23% in the D+CRT and 36% in the CRT arm at 6 mo. The lower detection rate in the D+CRT arm was associated with the PD-L1 tumor area positivity (TAP) ≥20% subpopulation. At BL, pts with low (<BL median [5268.2 ppm]) ctDNA levels had a reduced risk of progression vs pts with high (≥median) ctDNA levels (PFS hazard ratio [HR] D+CRT 0.57 [95% CI, 0.26-1.26]; CRT 0.62 [0.31-1.23]). Pts with detectable ctDNA at C3D1 or 6 mo had a higher risk of progression independent of treatment arm (Table). No differences in risk of progression between the D+CRT vs CRT arms were observed based on ctDNA detection. Correlations between ctDNA and OS will be presented. Conclusions: This pre-planned analysis of a large, global LACC population from CALLA demonstrates the high sensitivity of a personalized ctDNA assay. High ctDNA levels at BL were associated with higher risk of progression or death. Lower ctDNA detection rates after treatment with D+CRT and CRT correlated with improved survival and highlight increased tumor control by D, especially in the PD-L1 TAP ≥20% subpopulation. This analysis supports the potential utility of ultrasensitive ctDNA analysis to guide treatment decisions in LACC. Clinical trial information: NCT03830866 . D+CRT CRT Not detected Detected Not detected Detected C3D1 n=60 n=33 n=56 n=37 Median PFS (95% CI), mo NC (NC-NC) 14.03 (7.49-NC) NC (NC-NC) 10.68 (7.39-NC) HR (95% CI) 0.23 (0.11-0.50) 0.15 (0.07-0.33) 6 mo n=49 n=15 n=42 n=24 Median PFS(95% CI), mo NC (NC-NC) 10.35 (7.49-NC) NC (NC-NC) 12.98 (10.38-NC) HR (95% CI) 0.04 (0.01-0.16) 0.04 (0.01-0.17) NC, not computed/not reached.