Analysis Links ctDNA Clearance to Improved Outcomes in Advanced Cervical Cancer

Jyoti S. Mayadev, MD

Findings from an ultrasensitive circulating tumor DNA (ctDNA) analysis from the phase 3 CALLA trial (NCT03830866) highlighted ctDNA clearance as a key predictor of prognosis in patients with locally advanced cervical cancer, with potential to guide future personalized treatment strategies beyond standard chemoradiation, according to Jyoti S. Mayadev, MD.

The CALLA study evaluated chemoradiation with or without durvalumab (Imfinzi) in patients with locally advanced cervical cancer.1 At a median follow-up of 18.5 months (interquartile range [IQR], 13.2-21.5) for the durvalumab arm and 18.4 months (IQR, 13.2-23.7) for the placebo arm, the median progression-free survival (PFS) was not reached (NR; 95% CI, NR-NR) for either group, indicating no statistically significant PFS improvement with the addition of durvalumab to chemoradiotherapy in the biomarker-unselected population (HR, 0.84; 95% CI, 0.65-1.08; P = .17).

At the 2025 ASCO Annual Meeting, Mayadev presented findings from a ctDNA analysis of a biomarker-evaluable population from CALLA (n = 186).2 This analysis showed that low baseline ctDNA levels were associated with reduced risks of progression and death regardless of treatment arm. Additionally, ctDNA positivity following chemoradiation was a negative prognostic factor for PFS and overall survival (OS) across both arms.

“ctDNA using this ultrasensitive assay was both predictive and prognostic for locally advanced cervical cancer in patients who had positive ctDNA [levels] after their treatment cycle of chemoradiation and durvalumab or placebo,” Mayadev said in an interview with OncLive® during ASCO 2025.

In the interview, Mayadev discussed background information about CALLA, the potential clinical implications of the ctDNA analysis outcomes, the benefits of the ctDNA assay used in the study, and what the future may hold regarding the further development of personalized medicine in cervical cancer.

Mayadev is a radiation oncologist and a professor of radiation medicine and applied sciences at the University of California, San Diego Moores Cancer Center.

OncLive: What was the design of the CALLA study, and what prior findings influenced this ctDNA analysis?

Mayadev: We were excited, on behalf of the CALLA study team, to discuss at ASCO 2025 our interesting findings [from an analysis of] ctDNA as a biomarker in patients with locally advanced cervical cancer. [Data from] the CALLA trial were published [in 2023]. It was a large, global, randomized trial for patients with high-risk and node-positive locally advanced cervical cancer. Patients were [randomly assigned to receive] chemoradiation and placebo vs chemoradiation and durvalumab.

Although there was no difference in the primary end point of PFS, we had a preplanned exploratory analysis evaluating ultrasensitive DNA at key time points. These time points were taken at baseline before chemoradiation and durvalumab or placebo, after chemoradiation, and 3 months post-chemoradiation plus durvalumab or placebo. ctDNA was [measured using] an ultrasensitive assay by Personalis that used whole genome sequencing, which allowed for a tumor-specific panel that examined ctDNA down to [approximately] 1 to 3 parts per million.

What were the key findings from this analysis?

Of the 770 patients [enrolled in CALLA], 186 comprised our biomarker-eligible population. From these patients, we had 2 key takeaways. One, we found that baseline ctDNA levels, by this ultrasensitive assay, were 99% in both arms.

Another key takeaway was that patients with high baseline ctDNA levels had worse [treatment outcomes] despite chemoradiation [plus either] durvalumab or placebo. There was no difference between the arms regarding the prognostic and predictive nature that [the assay] provided. Another key takeaway was that if patients had normalized ctDNA levels after chemoradiation plus durvalumab or in the placebo arm, they did well regarding PFS and OS.

[As part of] CALLA, there was an unplanned subset analysis in patients who had PD-L1–high disease, [meaning they had a] tumor area positivity [TAP] score greater than 20%. Those patients had even more benefit [with either treatment], and this was shown by a decreased amount of detectable ctDNA after chemoradiation and durvalumab [or placebo]. This persisted at the 3-month mark when we collected the data again for ctDNA. If patients had positive, persistent ctDNA levels, they did worse in terms of PFS and OS. [Among] patients who were ctDNA positive, 68% went on to progress and have relapsed cervical cancer. On the flip side, if patients normalized and had negative ctDNA levels after chemoradiation [plus durvalumab] or placebo after 3 months, they had an excellent PFS and OS, regardless of treatment arm.

How does this ctDNA assay improve upon previously established disease detection and monitoring strategies for patients in this population?

This ctDNA ultrasensitive assay could detect recurrences with a median lead time of [approximately] 5 months and a maximum [lead time of approximately] 16 months. Therefore, it was much more sensitive than clinical exams or imaging.

In combination with ctDNA levels, how might PD-L1 TAP influence treatment decision-making for patients with cervical cancer?

Patients with high TAP scores—greater than or equal to 20%—had a significant benefit with the addition of durvalumab to chemoradiation. This was further shown by a risk reduction [based on ctDNA clearance]. If patients had a TAP score greater than or equal to 20%, they were more able to normalize their ctDNA levels and have responses that were better than in patients with a TAP score less than 20%.

What are the potential clinical implications of this study’s findings?

We continue to evolve the paradigm in locally advanced cervical cancer. Now, with our data investigating an ultrasensitive ctDNA assay, we're starting to find blood-based biomarkers that will help oncologists and patients determine further therapy strategies, or potentially [determine whether] they need therapy after chemoradiation. We continue to personalize medicine in locally advanced cervical cancer.

References

1. Monk BJ, Toita T, Wu X, et al. Durvalumab versus placebo with chemoradiotherapy for locally advanced cervical cancer (CALLA): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24(12):1334-1348. doi:10.1016/S1470-2045(23)00479-5
2. Mayadev J, Vázquez Limón JC, Ramirez Godinez FJ, 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:10.1200/JCO.2025.43.16_suppl.5502