IMvigor011 Trial

[Slide 1 — Title] EAU24 Paris, France (5–8 April 2024) Clinical outcomes in patients with high-risk, post-cystectomy MIBC with persistent circulating tumour DNA-negative status on serial testing: surveillance analysis from the IMvigor011 study. Authors: Thomas Powles, Joaquim Bellmunt, Jørgen Bjerggaard Jensen, Marine Gross-Goupil, Sergio Bracarda, Ariel Kann, Lydia Makaroff, Hiroyuki Nishiyama, Daniel Castellano, Shusuan Jiang, Ja Hyeon Ku, Se Hoon Park, Begoña Mellado Gonzalez, Marco Maruzzo, Ding-Wei Ye, Yuksel Urun, Rafael Morales Barrera, Consuelo Buttigliero, Erik Goluboff, Yi Shi, Zoe June Assaf, Viraj Degaonkar, Arya Tehrani, Jürgen E. Gschwend. [Slide 2 — Surveillance group analysis design] Screening: High-risk MIBC, (y)pT2–T4a N0M0 or (y)pT0–T4a N+M0 at cystectomy; received or did not receive prior NAC; eligible or not eligible for AC; cystectomy within past 6–24 weeks with no evidence of residual disease; no known PD-L1 status for adjuvant therapy; available tumour sample for PD-L1 status and WES and matched blood sample. Surveillance: Serial plasma collection and radiographic imaging q12w for up to 12 mo post-cystectomy. ctDNA+ → R 2:1 → atezolizumab × 1y vs placebo × 1y → treatment follow-up (primary analysis population; NOT included in this surveillance analysis). ctDNA– → radiographic imaging q6m for 2 y → survival follow-up q6m for 2 y (surveillance group: INCLUDED in this analysis). ctDNA– definition: disease-free status at baseline; ≥1 ctDNA– result and no ctDNA+ result; ≥1 post-baseline disease assessment; completed ≥12 mo of surveillance post-cystectomy or discontinued surveillance <12 mo with no ctDNA+ result. Primary endpoint: Investigator-assessed DFS. Key secondary endpoint: OS. ClinicalTrials.gov ID: NCT04660344. [Slide 3 — DFS in the ctDNA– population] n=171 ctDNA– patients. Median follow-up (IQR): 16.3 mo (11.6–19.3). DFS events, n (%): 17 (9.9). Median DFS (95% CI), mo: NE (NE, NE). 12-mo DFS: 92%. 18-mo DFS: 88%. [Slide 4 — OS in the ctDNA– population] n=171 ctDNA– patients. Median follow-up (IQR): 16.3 mo (11.6–19.3). OS events, n (%): 2 (1.2). Median OS (95% CI), mo: NE (NE, NE). 12-mo OS: 100%. 18-mo OS: 98%.

[Slide 1 — IMvigor011 study design] Screening: MIBC within 6–24 weeks of radical cystectomy; histologically confirmed (y)pT2–T4aN0M0 or (y)pT0–T4aN+M0 urothelial cancer; no evidence of radiographic disease; prior neoadjuvant chemotherapy permitted; ECOG PS 0–2. Surveillance ctDNA monitoring until 1y post-cystectomy: 6-weekly ctDNA testing, 12-weekly radiographic imaging. Repeat testing if ctDNA–. ctDNA+ any time → confirm no evidence of radiographic disease → R 2:1 → Atezolizumab 1680 mg IV q4w for up to 1 y vs Placebo IV q4w for up to 1 y → Treatment follow-up. ctDNA– until 1y → No treatment → Surveillance follow-up. Primary endpoint: INV-assessed DFS. Key secondary endpoint: OS. [Slide 2 — INV-assessed DFS in patients who tested ctDNA+] Atezolizumab n=167 · Placebo n=83. Events, n (%): Atezo 112 (67.1) vs Placebo 66 (79.5). DFS, median (95% CI), mo: 9.9 (7.2, 12.7) vs 4.8 (4.1, 8.3). Stratified HR (95% CI): 0.64 (0.47, 0.87). Stratified P value: 0.0047. Median follow-up: 16.1 mo from randomisation. Landmark DFS: 12-mo 44.7% (atezo) vs 30.0% (placebo); 24-mo 28.0% vs 12.1%. Consistent benefit in relevant secondary endpoints: DFS per IRF: HR 0.66 (95% CI 0.48, 0.91). Distant-metastasis free survival: HR 0.66 (95% CI 0.47, 0.94). [Slide 3 — OS in patients who tested ctDNA+] Atezolizumab n=167 · Placebo n=83. Events, n (%): Atezo 60 (35.9) vs Placebo 36 (43.4). OS, median (95% CI), mo: 32.8 (27.7, NE) vs 21.1 (14.7, NE). Stratified HR (95% CI): 0.59 (0.39, 0.90). Stratified P value: 0.0131. Median follow-up: 16.1 mo from randomisation. Landmark OS: 12-mo 85.1% (atezo) vs 70.0% (placebo); 24-mo 62.8% vs 46.9%. Consistent benefit: Disease-specific survival HR 0.64 (95% CI 0.40, 1.05). [Slide 4 — NEJM publication masthead] The New England Journal of Medicine — Original Article. ctDNA-Guided Adjuvant Atezolizumab in Muscle-Invasive Bladder Cancer. Authors: Thomas Powles, Ariel G. Kann, Daniel Castellano, Marine Gross-Goupil, Hiroyuki Nishiyama, Sergio Bracarda, Jørgen Bjerggaard Jensen, Lydia Makaroff, Shusuan Jiang, Ja Hyeon Ku, Se Hoon Park, Marco Maruzzo, Andrea Necchi, Rafael Morales-Barrera, Emilio Francesco Giunta, Jae Lyun Lee, Giampaolo Tortora, Yüksel Ürün, Lukasz Dolowy, Dilek Erdem, Alvaro Pinto, Fabricio Grando, Wei Zou, Zoe June Assaf, Jacqueline Vuky, Viraj Degaonkar, Elizabeth E. Steinberg, Joaquim Bellmunt, Jürgen E. Gschwend, for the IMvigor011 Investigators. Published October 20, 2025. N Engl J Med 2025;393:2395-2408. DOI: 10.1056/NEJMoa2511885.

[Slide 1 — Natera press release, May 15, 2026] Signatera™ CDx Approved by the FDA as a Companion Diagnostic in Muscle-Invasive Bladder Cancer (MIBC). Marks the first FDA-approved use of personalized molecular residual disease (MRD) testing to guide treatment decisions. Solidifies Natera's Treatment on MRD (TOMR) approach as the new standard of care in MIBC, enabling precision interventions for MRD-positive patients while sparing MRD-negative patients from potentially unnecessary treatment.

[Slide 1 — IMvigor011 schema] Adjuvant Atezolizumab vs Placebo in High-Risk Muscle-Invasive Bladder Cancer Who Are ctDNA Positive Following Cystectomy (IMvigor011). Post-cystectomy for high-risk urothelial cancer → serial ctDNA testing → +ve (ctDNA positive) → randomize 2:1 → atezolizumab vs placebo. ctDNA -ve → continued surveillance (no treatment) — testing window: 20 weeks. Primary endpoint: PFS (later updated to DFS). Secondary endpoint: OS.

[Slide 1 — NEJM publication masthead] The New England Journal of Medicine — Original Article. ctDNA-Guided Adjuvant Atezolizumab in Muscle-Invasive Bladder Cancer. Authors: T. Powles, A.G. Kann, D. Castellano, M. Gross-Goupil, H. Nishiyama, S. Bracarda, J. Bjerggaard Jensen, L. Makaroff, S. Jiang, J.H. Ku, S.H. Park, O. Reig Torras, D. Ye, M. Maruzzo, A. Necchi, R. Morales-Barrera, E.F. Giunta, J.L. Lee, G. Tortora, Y. Ürün, L. Dolowy, D. Erdem, A. Pinto, F. Grando, W. Zou, Z.J. Assaf, J. Vuky, V. Degaonkar, E.E. Steinberg, J. Bellmunt, and J.E. Gschwend, for the IMvigor011 Investigators.