Exploratory Analysis From CALLA Study Highlights Potential Utility of ctDNA in Locally Advanced Cervical Cancer

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An exploratory circulating tumor DNA (ctDNA) analysis from the phase 3 CALLA trial (NCT03830866) showed that the risk of disease progression or death was reduced by at least 95% in patients with locally advanced cervical cancer treated with durvalumab (Imfinzi) plus chemoradiotherapy (CRT) or CRT plus placebo alone who had undetectable ctDNA at the start of cycle 6.

Additionally, low ctDNA at baseline was associated with improved survival outcomes in both arms compared with high ctDNA.

Findings presented at the 2025 ASCO Annual Meeting demonstrated that in the biomarker evaluable population at cycle 6, day 1, the ctDNA-positivity rates decreased to 36% in the CRT arm (n = 24/66) vs 23% in the durvalumab/CRT arm (n = 15/64). At baseline, the respective rates of ctDNA positivity were 99% (n = 92/93) and 99% (n = 91/92), respectively.

Regarding progression-free survival (PFS), undetectable ctDNA at cycle 6, day 1 was associated with reduced risk of disease progression or death vs detectable ctDNA for patients in the durvalumab arm (HR, 0.04; 95% CI, 0.01-0.16) and those in the placebo arm (HR, 0.04; 95% CI, 0.01-0.17) in the respective arms. OS was also improved in patients with undetectable ctDNA in the experimental arm (HR, 0.04; 95% CI, 0.01-0.20) and placebo arm (HR, 0.04; 95% CI, 0.01-0.19).

Additionally, low ctDNA (below the median) at baseline was associated with improved PFS compared with high ctDNA (above the median) in both the durvalumab arm (HR, 0.60; 95% CI, 0.27-1.33) and the placebo arm (HR, 0.62; 95% CI, 0.31-1.23). Notably, the durvalumab regimen was associated with improved PFS vs CRT plus placebo in patients with high ctDNA at baseline (HR, 0.75; 95% CI, 0.39-1.46) and low ctDNA at baseline (HR, 0.72; 95% CI, 0.32-1.63).

OS outcomes also favored patients with low ctDNA at baseline in the durvalumab arm (HR, 0.63; 95% CI, 0.27-1.45) and the placebo arm (HR, 0.85; 95% CI, 0.43-1.69). The durvalumab regimen was linked with improved OS in the high baseline ctDNA population (HR, 0.77; 95% CI, 0.38-1.56) and the low baseline ctDNA population (HR, 0.55; 95% CI, 0.24-1.25).

“This preplanned exploratory ctDNA analysis of a large, global locally advanced cervical cancer population from CALLA demonstrates the high sensitivity of a personalized assay for ctDNA detection,” lead study author Jyothi Mayadev, MD, a professor of Radiation Medicine and Applied Sciences at the University of California, San Diego Health, said in a presentation of the analysis.

CALLA Study Design

The randomized, double-blind, multicenter, placebo-controlled, global study evaluated the efficacy and safety of durvalumab plus CRT in female patients 18 years of age or older with locally advanced cervical cancer. Patients were required to have histologically confirmed cervical adenocarcinoma, squamous carcinoma, or adenosquamous carcinoma that was stage IB2 to IIB and node positive; or FIGO (2009) stage IIIA to IVA disease, irrespective of nodal status. Additionally, patients were required to have a WHO or ECOG performance status of 0 or 1.

Patients were stratified based on disease stage and global region, and they were randomly assigned 1:1 to receive either durvalumab/CRT or CRT alone. Of note, plasma sample collection and processing occurred on cycle 1, day 1; cycle 3, day 1; and cycle 6, day 1. The ultrasensitive, tumor-informed minimal residual disease (MRD) assay NeXT Personal was used.

The primary end point was investigator-assessed PFS per RECIST 1.1 criteria; the secondary end point was OS. The key exploratory end point was the ctDNA analysis.

Baseline Patient Characteristics

Notably, the baseline patient characteristics in the biomarker-evaluable population were similar to those of the intention-to-treat population. In the biomarker evaluable population at cycle 3, day 1, the majority of patients were younger than 65 years old in the placebo (88%) vs durvalumab (85%) arms. The majority identified as non-Asian (placebo, 98%; durvalumab, 95%). Disease statuses included FIGO less than III and node-positive disease (32%; 40%), FIGO III or greater and node-negative (34%; 37%), and FIGO III or greater and node-positive (33%; 24%). Moreover, lymph node sites included pelvic (69%; 54%), no pelvic (31%; 46%), para-aortic (9%; 10%), and no para-aortic (91%; 90%). A PD-L1 tumor area positivity (TAP) of 20% or greater was observed in 44% vs 47% of patients in the respective arms.

Additional Efficacy and ctDNA Detection Data

Of note, in the PD-L1 defined subgroups, a higher reduction in ctDNA positivity rates in the durvalumab/CRT vs placebo/CRT arms was demonstrated in the subgroup with PD-L1 TAP of 20% or greater. At cycle 6, day 1, patients with PD-L1 TAP of 20% or greater had a ctDNA positivity rate of 19% vs 41% in the durvalumab vs placebo arms, respectively, indicating a 22% difference in detection rate. Those with PD-L1 TAP of less than 20% at cycle 6, day 1, the ctDNA positivity rate was 30% vs 32% in the respective arms, revealing a 2% difference in detection rate.

After CRT at cycle 3, day 1, ctDNA was a negative prognostic factor for both PFS and OS. Undetectable ctDNA was associated with improved PFS in the durvalumab arm (HR, 0.23; 95% CI, 0.11-0.50) and the placebo arm (HR, 0.15; 95% CI, 0.07-0.33. Undetectable ctDNA at cycle 3, day 1, was also linked with improved OS in the experimental arm (HR, 0.20; 95% CI, 0.09-0.47) vs and control arm (HR, 0.18; 95% CI, 0.08-0.38).

In patients who had ctDNA detected at cycle 3, day 1, 68% of patients experienced subsequent disease progression before data cutoff. By the time of data cutoff, 83% of patients with no ctDNA detection had not experienced disease progression. The median lead time between cycle 3, day 1, ctDNA detection and disease progression was 164 days (range, 46-497).

Disclosures: Mayadev reported receiving honoraria from AstraZeneca; holds consulting or advisory roles with Agenus, AstraZeneca/MedImmune, Merck, Primmune Therapeutics, and Varian Medical Systems; receives institutional research funding from Varian Medical Systems; and travel expenses from Merck.

Reference

Mayadev J, Limón JCV, Godinez FJR, et al. 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. J Clin Oncol. 2025; 43(suppl 16):5502. doi: doi.org/10.1200/JCO.2025.43.16_suppl.5502