ctDNA Status May Determine Adjuvant Immunotherapy Benefit in MIBC

The addition of antibody-drug conjugate (ADC) enfortumab vedotin-ejfv (Padcev) to immunotherapy regimens such as atezolizumab (Tecentriq) or pembrolizumab (Keytruda) may exhibit a more synergistic effect resulting in greater efficacy than immunotherapy alone for the treatment of patients with muscle-invasive bladder cancer (MIBC), according to Joaquim Bellmunt, MD, PhD.

Bellmunt, director of the Bladder Cancer Center at the Genitourinary Oncology Program of Dana-Farber Cancer Institute and associate professor of Medical Oncology at Harvard Medical School, spoke with CancerNetwork® about subsequent treatment regimens for patients with positive ctDNA who progressed following treatment with atezolizumab monotherapy for MIBC. This was contextualized by a presentation of data from the IMvigor-011 trial (NCT04660344)at the European Society for Medical Oncology (ESMO) Congress 2025 that were subsequently published in The New England Journal of Medicine.^1,2

He began by highlighting a benefit in patients who tested negative for ctDNA following treatment with atezolizumab, showing that for these patients, a 2-year disease-free survival rate of approximately 88% was observed. Bellmunt remarked that, based on the data, ctDNA was found to be predictive of benefit with adjuvant immunotherapy in this patient population.

Among patients who may experience progression following treatment with the monotherapy, Bellmunt explained that the addition of enfortumab vedotin to pembrolizumab to treat patients with metastatic disease displayed favorable efficacy for these patients, suggesting a similar benefit could be observed among patients with evaluable ctDNA status. Finally, he asserted that a synergistic effect of these combinations may be key to addressing recurrence following atezolizumab monotherapy.

Transcript:

The interesting thing is we have been following the patients who have sequentially tested negative for ctDNA. We have learned a lot from that because we have seen—in these patients who have had ctDNA checked every 6 weeks for a year—that if the ctDNA test is negative at [2 years], these patients have a likelihood of being disease-free in 88% of the cases. What we learned from this trial [is] that ctDNA is driving who is going to benefit receiving adjuvant immunotherapy.

The adjuvant immunotherapy with atezolizumab is monotherapy, and now, we know that for treating patients with metastatic disease, we have a more effective regimen, like the combination of enfortumab vedotin and pembrolizumab. [This] means patients who [experience progression on] immunotherapy are usually going to switch to stronger combinations. The point is that if you have been using immunotherapy, are these patients going to respond equally? People believe that there might be more than an additive effect of immunotherapy and enfortumab vedotin—there might be a synergistic effect—and maybe we are going to overcome the limitations of failing monotherapy with immunotherapy.

References

1. Powles T, Kann AG, Castellano D, et al. IMvigor011: a phase 3 trial of circulating tumour (ct)DNA-guided adjuvant atezolizumab vs placebo in muscle-invasive bladder cancer. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA8.
2. Powles T, Kann AG, Castellano D, et al. ctDNA-guided adjuvant atezolizumab in muscle-invasive bladder cancer. N Engl J Med. Published online October 20, 2025. doi:10.1056/NEJMoa2511885