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Updated overall survival by circulating tumour DNA status from the phase 3 IMvigor010 trial: Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma

  • Thomas Powles,
  • Zoe June Assaf,
  • Viraj Degaonkar,
  • Petros Grivas,
  • Petros Grivas,
  • Stephane Oudard,
  • J├╝rgen E. Gschwend,
  • Peter Albers,
  • Daniel Castellano,
  • Hiroyuki Nishiyama,
  • Siamak Daneshmand,
  • Shruti Sharma,
  • Himanshu Sethi,
  • Alexey Aleshin,
  • Yi Shi,
  • Nicole Davarpanah,
  • Corey Carter,
  • Joaquim Bellmunt

Background

Interim results from IMvigor010 showed an overall survival (OS) benefit for adjuvant atezolizumab (anti–PD-L1) versus observation in patients with circulating tumor DNA (ctDNA)-positive muscle-invasive urothelial carcinoma (MIUC).

Objective

To report updated OS and safety by ctDNA status.

Design, setting, and participants

This ad hoc analysis from a global, open-label, randomized, phase 3 trial (NCT02450331) included intention-to-treat (ITT) population with evaluable cycle 1 day 1 (C1D1) ctDNA samples.

Intervention

Atezolizumab (1200 mg every 3 wk) or observation for ≤1 yr.

Outcome measurements and statistical analysis

OS, relapse rates, and safety by ctDNA status were assessed.

Results and limitations

Among 581 of 809 ITT patients included, 214 (37%) were ctDNA positive. Atezolizumab did not improve OS versus observation in ITT patients (hazard ratio [HR] 0.91 [95% confidence interval {CI} 0.73–1.13]; median follow-up 46.8 mo [interquartile range, 36.1–53.6]). In the observation arm, ctDNA positivity versus negativity was associated with shorter OS (HR 6.3 [95% CI 4.3–9.3]). The ctDNA positivity identified patients with an OS benefit favoring atezolizumab versus observation (HR 0.59 [95% CI 0.42–0.83]). A greater reduction in ctDNA levels with atezolizumab (C3D1) was associated with longer OS (100% clearance, 60.0 mo [95% CI 35.5–not estimable]; 50–99% reduction, 34.3 mo [95% CI 15.2–not estimable]; <50% reduction, 19.9 mo [95% CI 16.4–32.2]). The ctDNA positivity at C1D1 + C3D1 was associated with relapse with greater sensitivity than C1D1 alone (68% vs 57%). Adverse events were more frequent with atezolizumab than with observation, regardless of ctDNA status. A study limitation was its exploratory design.

Conclusions

Evidence suggests that ctDNA positivity in MIUC predicts a benefit with atezolizumab. An in-progress prospective study will further evaluate these findings.

Commentary by Dr. Laura Mertens

Adjuvant immune checkpoint inhibitors following radical cystectomy have demonstrated a disease-free survival (DFS) benefit over placebo in some patients. Consequently, risk-stratifying strategies are essential to identify patients who may gain an overall survival (OS) advantage from adjuvant treatment.

 

In the IMvigor010 trial, interim results indicated OS benefit for adjuvant atezolizumab (anti–PD-L1) compared to observation in patients with circulating tumour DNA (ctDNA)-positive muscle-invasive urothelial carcinoma (MIUC) after radical surgery. These interim findings suggested that ctDNA could serve as a marker to guide adjuvant treatment. Powles et al. have now published new OS data, stratifying patients based on their post-surgery ctDNA status.

 

IMvigor010 is a global, open-label, randomised, phase 3 trial (NCT02450331). Eligible patients had high risk MIUC (ypT2–T4a or ypN+ for patients treated with neoadjuvant chemotherapy; pT3–T4a or pN+ for those not treated with neoadjuvant chemotherapy). All participants had undergone radical surgery with lymph node dissection, with no radiological evidence of residual disease or metastasis. Patients were randomised 1:1 to receive atezolizumab (1200 mg every 3 wk) or observation for one year or until recurrence, unacceptable toxicity, or withdrawal of consent. The ctDNA biomarker-evaluable population included intention-to-treat patients with baseline (cycle 1 day 1) plasma samples evaluated for ctDNA status.

 

Among 581 of 809 intention-to-treat patients, 214 (37%) were ctDNA positive. Atezolizumab did not improve OS versus observation in this whole cohort (HR 0.91; 95% CI, 0.73–1.13) at a median follow-up of 46.8 months. In the observation arm, ctDNA positivity versus negativity was associated with shorter OS (HR 6.3, 95% CI 4.3–9.3). ctDNA positivity identified patients with an OS benefit favouring atezolizumab over observation (HR 0.59, 95% CI 0.42–0.83). A greater reduction in ctDNA levels with atezolizumab (measured at cycle 3 day 1) was associated with longer OS (100% clearance: 60 months, 95% CI 35.5–not estimable; 50–99% reduction: 34 months, 95% CI 15.2–not estimable; <50% reduction: 19.9 months, 95% CI 16.4-32.2). Furthermore, ctDNA positivity at C1D1 + C3D1 was more predictive of relapse than C1D1 alone.

 

Adverse events were more frequent with atezolizumab than with observation, regardless of ctDNA status. One of the main limitations of this study was its exploratory design.

 

Summary

All in all, these data suggest that ctDNA positivity in MIUC patients who underwent radical surgery predicts a benefit with atezolizumab, indicating that ctDNA is potentially a valuable biomarker for treatment stratification. However, these results must be further evaluated in ongoing prospective biomarker-driven studies. Also, further research is crucial to determine the most suitable and applicable methods for ctDNA assessment in clinical practice.