🚨⭐🟠 #ESMO26 | Abstract 4734O | KEYNOTE-B15 / EV-304
ctDNA Analysis of the Phase III KEYNOTE-B15 Trial: Neoadjuvant and Adjuvant Enfortumab Vedotin + Pembrolizumab in Cisplatin-Eligible Muscle-Invasive Bladder Cancer
🎤 Presented by Jonathan Chatzkel 🇺🇸 | Moffitt Cancer Center
@OncoAlert @urologysummit

🧬 Can molecular response help redefine perioperative treatment in MIBC?

🔬 STUDY DESIGN
Phase III KEYNOTE-B15/EV-304 | N=808
🟢 Perioperative EV + pembrolizumab (n=405)
🔴 Neoadjuvant gemcitabine/cisplatin followed by observation (n=403)

All patients underwent planned radical cystectomy + PLND.

Exploratory ctDNA analysis using the tumor-informed Signatera assay at baseline, presurgery, postsurgery and during adjuvant treatment.

📊 KEY RESULTS
🧬 1️⃣ Baseline ctDNA: a powerful prognostic marker

ctDNA positivity was associated with worse EFS.
EV + pembrolizumab vs chemotherapy:

✅ Baseline ctDNA-positive:
HR 0.54 (95% CI 0.37–0.80)

✅ Baseline ctDNA-negative:
HR 0.68 (95% CI 0.37–1.26)

📌 EFS estimates favored EV + pembrolizumab in both subgroups, although the CI crossed 1 in ctDNA-negative patients.

🧬 2️⃣ ctDNA CLEARANCE BEFORE SURGERY

✅ EV + pembrolizumab: 82.1%
🔴 Gemcitabine/cisplatin: 66.7%

📈 Absolute difference: +15.4 percentage points.

Molecular clearance was associated with more favorable EFS and pathological response.
🔬 3️⃣ pCR BY PRESURGICAL ctDNA STATUS

Among patients who were ctDNA-negative before surgery:
✅ EV + pembrolizumab: 72.4%
🔴 Gemcitabine/cisplatin: 43.7%

Among those remaining ctDNA-positive:
• EV + pembrolizumab: 3.7%
• Chemotherapy: 2.2%

📌 Persistent ctDNA positivity identified patients with a very low probability of pCR.

🧬 4️⃣ POSTSURGICAL ctDNA AND EFS
EV + pembrolizumab vs chemotherapy:

✅ ctDNA-negative:
HR 0.48 (95% CI 0.29–0.81)

🔹 ctDNA-positive:
HR 0.63 (95% CI 0.30–1.35)

Postoperative ctDNA positivity was associated with particularly poor EFS.

⚠️ Interpretation requires caution: the postsurgical ctDNA-positive subgroup was small, and sample availability decreased over time.

🔬 CONCLUSIONS
✅ ctDNA positivity identifies patients with poorer prognosis.

✅ ctDNA clearance was higher with EV + pembrolizumab than with cisplatin-based chemotherapy.
✅ Molecular clearance correlated with improved pathological response and EFS.
✅ EFS estimates favored EV + pembrolizumab across ctDNA-defined groups.

⭐ MY POINT OF VIEW | CLINICAL PEARL

We are moving beyond pathological response toward molecular assessment of treatment effectiveness.

🧬 ctDNA could become an essential tool for perioperative risk stratification in MIBC.

But an important distinction remains:
Prognostic ≠ Predictive.

These findings do not yet establish ctDNA as a biomarker for selecting EV + pembrolizumab, omitting cystectomy or safely de-escalating adjuvant therapy.
💡 The next breakthrough may not be another treatment combination, but learning how to personalize treatment intensity according to molecular response.

📌 Prospective ctDNA-guided trials will be essential to translate molecular clearance into clinical decisions.

🌍⭐ GU ONCOLOGY COMMUNITY

@brian_rini @tompowles1 @declangmurphy @KidneyCancer @salvolarosa @RenuEapen @seanmcbride @DrJaVallejo @crisbergerot @DrDanielHeng @apolo_andrea @DrChoueiri @PGrivasMDPhD @TiansterZhang @HHammersMD @neerajaiims @amerseburger @sonpavde @drenriquegrande @scserendipity1 @Silke_Gillessen @EfstathiouEleni @BraunMDPhD @cdanicas @AOmlin @montypal

@gbanna74 @ravikanesvaran @Uromigos @gu_onc
@ecancer @UrologyTimes @urotoday @wearemedsir @OpenMedicineHQ @UCSFCancer

#BladderCancer #MIBC #ctDNA #GUOncology #PrecisionOncology #OncoAlertAF