ENERGIZE Key Takeaways
Design
Phase III, randomized 1:1: neoadjuvant nivolumab 360 mg plus gemcitabine-cisplatin every 3 weeks for 4 cycles, radical cystectomy, then adjuvant nivolumab 480 mg every 4 weeks for 9 cycles (n=325), versus gemcitabine-cisplatin for 4 cycles and radical cystectomy with no further treatment (n=328). Co-primary endpoints: pCR and EFS per blinded independent central review. A third arm adding linrodostat (BMS-986205) was terminated in December 2021 and excluded from formal testing. (ESMO 2026 4736O, Necchi; median follow-up 54.5 mo; data cutoff not shown on slides)
Efficacy
EFS HR 0.94 (95% CI 0.72–1.24; 95.74% CI 0.71–1.25), two-sided P=0.6697 against a significance threshold of 0.0426; median EFS not reached vs 67.6 months. pCR 39.1% vs 29.6% (difference 9.5%; 99.91% CI −2.6 to 21.6) did not meet its multiplicity-adjusted threshold. OS HR 0.88 (95% CI 0.64–1.21), analyzed descriptively. (ESMO 2026 4736O, Necchi; median follow-up 54.5 mo; data cutoff not shown on slides)
ctDNA (exploratory)
Neoadjuvant ctDNA clearance (Signatera, cycle 1 to cycle 4) 81.3% (87/107) vs 71.7% (66/92), Fisher exact P=0.130. In a pooled analysis of both arms, detectable pretreatment ctDNA was associated with shorter EFS and OS. (ESMO 2026 4736O, Necchi; median follow-up 54.5 mo; data cutoff not shown on slides)
Regulatory status
⚠️ Perioperative nivolumab plus neoadjuvant gemcitabine-cisplatin is not approved for MIBC; ENERGIZE did not support it. ✅ Nivolumab (Opdivo) is FDA-approved as adjuvant therapy for urothelial carcinoma at high risk of recurrence after radical resection (CheckMate-274, August 19, 2021). Linrodostat is investigational. (FDA)
KOL pulse
Physicians posting from the session reported a negative trial and turned to one question: why NIAGARA, with perioperative durvalumab plus gemcitabine-cisplatin, was positive while ENERGIZE and KEYNOTE-866 were not. Several pointed to ctDNA as prognostic but not predictive of nivolumab benefit.
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Top KOLs Discussing ENERGIZE
ENERGIZE Key Slides & Visuals
ENERGIZE Top Tweets
𝕏It hard to explain why 1 trial with gem/cis +/-PD(L)1 (NIAGARA) is +ve for EFS/OS and 2 very similar trials (presented today) are negative in MIBC. Potentially NIAGARA has the highest risk population, not all respond to IO and the maintenance phase the most effect- but the OS of gem/cis pembro HR of 1 is concerning. This reflects what we saw in metastatic disease with contradictory results for the big combination trials. Overall EVP looks better and more consistent #ESMO26 @myESMO @Annals_Oncology @OncoAlert
𝕏🚨 New ESMO 2026 data challenge our understanding of perioperative therapy in MIBC! KEYNOTE-866 (phase III, n=707), ENERGIZE (phase III, n=653): Adding perioperative pembro or nivolumab to neoadjuvant gemcitabine/cisplatin did not significantly improve EFS and OS, despite numerically higher pCR! Yet NIAGARA demonstrated significant EFS (HR 0.68) and OS (HR 0.75) benefits with perioperative durvalumab. Why does one chemoimmunotherapy strategy succeed while others fails? Different patient populations, trial designs, or underlying biology? We urgently need predictive biomarkers—not just another checkpoint inhibitor. Meanwhile, new KEYNOTE-905 data in cisplatin-ineligible MIBC (ad hoc, n=255) show: • Pembrolizumab alone: pCR 25.3%; EFS HR 0.71 vs surgery alone. • EV+pembrolizumab: pCR 58.8%; EFS HR 0.40 vs surgery alone. The key question is no longer simply whether to add immunotherapy—but which patients need chemotherapy, ADC-based therapy, or both. Histology, NECTIN4/HER2 biology, and longitudinal ctDNA deserve prospective evaluation as treatment-selection tools. Exciting times for MIBC—but precision must catch up with therapeutic progress. @OncoAlert Faculty @DrChoueiri , @tompowles1 , @apolo_andrea , @neerajaiims , @montypal , @Silke_Gillessen , @AOmlin , @brian_rini , @PGrivasMDPhD , @TiansterZhang , @amerseburger , @DrDanielHeng , @HHammersMD , @scocmem , @AndreaNecchi , @AmandaNizamMD , @drenriquegrande , @nataliagandur , @AlbigesL , @cdanicas , @declangmurphy , @seanmmcbride , @shilpaonc , @DrRanaMcKay , @scserendipity1 , @DrYukselUrun , @ravikanesvaran , @BraunMDPhD , @EfstathiouEleni , @mzugman , @crisbergerot
𝕏🎯 #ESMO26 ENERGIZE ph3 trial presenting by @AndreaNecchi other periop of IO therapy in MIBC! Cis-Gem + Nivo vs Cis-Gem! Other negative study of IO + cisplatin-based chemo!🧐 Reinforce the value of ADC + Pembro in this setting! @OncoAlert @myESMO @GuardConsortium @PGrivasMDPhD @apolo_andrea
𝕏🚨⭐🟠 #ESMO26 | Abstract 4736O | ENERGIZE (CA017-078) Phase III trial of neoadjuvant chemotherapy ± nivolumab followed by adjuvant nivolumab in muscle-invasive bladder cancer (MIBC) 🎤 Presented by @AndreaNecchi 🇮🇹 @OncoAlert @urologysummit 🔬 Can perioperative nivolumab improve outcomes in patients with cisplatin-eligible MIBC? 📊 STUDY DESIGN Phase III randomized trial | N=653 🔹 Nivolumab + gemcitabine/cisplatin → radical cystectomy → adjuvant nivolumab (n=325) 🔹 Gemcitabine/cisplatin → radical cystectomy → observation (n=328) 📊 KEY RESULTS ❌ Event-free survival (co-primary endpoint) • Median EFS: NR vs 67.6 months • HR 0.94 (95% CI 0.72–1.24) • p=0.6697 ➡️ No statistically significant improvement. 📈 Pathological complete response (co-primary endpoint) • pCR: 39.1% vs 29.6% • Absolute difference: +9.5 percentage points ❌ Did not meet the prespecified multiplicity-adjusted significance threshold. 🔬 Combined pathological response (≤ypT1N0) • 51.7% vs 41.8% 🧬 ctDNA EXPLORATORY ANALYSIS ✅ Neoadjuvant ctDNA clearance: • 81.3% vs 71.7% 📌 Pretreatment ctDNA positivity was associated with shorter EFS and OS. However, no clear differential treatment benefit was observed according to baseline ctDNA status. 📊 Overall survival • OS data remain immature. • No established survival advantage. ⚠️ Safety was consistent with the known profiles of the individual agents. 🔬 CONCLUSION Adding perioperative nivolumab to neoadjuvant gemcitabine/cisplatin did not significantly improve the co-primary endpoints of pCR or EFS in patients with MIBC. ⭐ MY POINT OF VIEW | CLINICAL PEARL Improving pathological response does not necessarily translate into better long-term outcomes. ENERGIZE reinforces an essential principle in perioperative oncology: pCR signals must be interpreted alongside EFS, OS, toxicity and statistical robustness. 🧬 ctDNA is emerging as a powerful prognostic biomarker, but its ability to guide treatment intensification or de-escalation still requires prospective validation. 💡 The future of perioperative MIBC treatment is not simply adding more immunotherapy. It is identifying who truly benefits—and who can safely avoid unnecessary treatment. 🌍 GU Oncology Community @gbanna74 @ravikanesvaran @tompowles1 @PGrivasMDPhD @apolo_andrea @sonpavde @montypal @TiansterZhang @DrYukselUrun @drenriquegrande @cdanicas @ecancer @UrologyTimes @urotoday @wearemedsir @OpenMedicineHQ @UCSFCancer #BladderCancer #MIBC #GUOncology #ClinicalTrials #OncoAlert
𝕏Another negative Ph.III perioperative IO trial by @AndreaNecchi : CA017-078 evaluates Nivo + Gem/Cis -> surgery -> adjuvant Nivo vs Gem/Cis alone in MIBC. EFS HR 0.94 (95.74% CI 0.71-1.25), p=0.67. pCR 39.1% vs 29.6% (NS). OS HR 0.88. Important implications for perioperative IO strategies. #ESMO26 #BladderCancer @myESMO @OncoAlert
𝕏🚨⭐🟠 #ESMO26 GU Oncology Invited Discussion 🎤 Prof. Robert Jones 🇬🇧 @OncoAlert 🔬 Why did NIAGARA succeed while KEYNOTE-866 and ENERGIZE failed to meet their primary efficacy endpoints? 📊 EFS HR: ✅ NIAGARA: 0.68 ❌ KEYNOTE-866: 0.88 ❌ ENERGIZE: 0.94 🧩 Different populations, baseline risks, eligibility criteria and trial designs complicate comparisons. ⭐ MY POINT OF VIEW Different outcomes across trials do not establish superiority of PD-L1 over PD-1 blockade. 💡 In curative-intent MIBC, patient selection, endpoint definitions and absolute clinical benefit matter as much as the HR. Cross-trial comparisons generate hypotheses, not definitive conclusions. 🌍 GU Oncology Community @gbanna74 @ravikanesvaran @urologysummit @tompowles1 @PGrivasMDPhD @apolo_andrea @sonpavde @AndreaNecchi @drenriquegrande @DrYukselUrun @yekeduz_emre @cdanicas @ecancer @UrologyTimes @urotoday @wearemedsir @OpenMedicineHQ @UCSFCancer #BladderCancer #UrothelialCancer #GUOncology #ADC #ClinicalTrials
𝕏5 phase III perioperative MIBC trials, with differing results. EV-303, EV-304 and NIAGARA improved EFS/OS, while ENERGIZE and KEYNOTE-866 did not meet their EFS endpoints. Important differences in patient populations, regimens and trial design. Cross-trial comparisons require caution. #ESMO26 @OncoAlert
𝕏#ESMO26 Day 1 has arrived! Follow along with @OncoAlert for full coverage! Highlights from the GU Renal & Urothelial Proffered Paper Session today: 🔴 Ph 3 KEYNOTE-866 (GC +/- perioperative pembro in MIBC) 🔴 Ph 3 ENERGIZE (GC +/- perioperative nivo in MIBC) 🔴 Ph 1 TROPHYU-01 Cohort 7 (SG + EV + Zim in 1L La/mUC) 🔴 ctDNA analyses from Ph 3 KEYNOTE-B15 (EV+P vs GC in cis-eligible MIBC) Key❓: Why were KN-866 and ENERGIZE negative while NIAGARA was positive? @scocmem @nataliagandur @DrKarineTawagi @niklas_kluemper @OncoAlert
𝕏#ESMO2026 🚨 Three phase III trials with perioperative chemoimmunotherapy. Different outcomes in MIBC. NIAGARA: durvalumab + GC → EFS HR 0.68, OS HR 0.75 ✅ KEYNOTE-866: pembrolizumab + GC → EFS HR 0.88, OS HR 1.00 CA017-078: nivolumab + GC → EFS HR 0.94 Interestingly, all three showed numerically higher pCR rates, but only NIAGARA demonstrated statistically significant survival benefits in the reported analyses. Why? Differences in trial populations, treatment schedules, statistical design—or tumor biology? These are cross-trial observations, not head-to-head comparisons. We should resist attributing the differences simply to PD-1 versus PD-L1 inhibition. The key challenge: identifying which MIBC patients truly benefit from adding immunotherapy to chemotherapy. We urgently need predictive biomarkers and molecularly informed perioperative treatment selection. 🔬 @OncoAlert Faculty @DrChoueiri , @tompowles1 , @apolo_andrea , @neerajaiims , @montypal , @Silke_Gillessen , @AOmlin , @brian_rini , @PGrivasMDPhD , @TiansterZhang , @amerseburger , @DrDanielHeng , @HHammersMD , @scocmem , @AndreaNecchi , @AmandaNizamMD , @drenriquegrande , @nataliagandur , @AlbigesL , @cdanicas , @declangmurphy , @seanmmcbride , @shilpaonc , @DrRanaMcKay , @scserendipity1 , @DrYukselUrun , @ravikanesvaran , @BraunMDPhD , @EfstathiouEleni , @mzugman , @crisbergerot @Markuseckstein3
𝕏@AndreaNecchi with phase 3 #ENERGIZE trial results — cis gem nivo vs cis gem in muscle invasive #bladdercancer. 10% path CR rate diff but no diff on EFS or OS. ctDNA (+) at baseline has poor prognosis. @oncoalert #ESMO26 @myESMO https://t.co/HTP7Fwmx6p
About the ENERGIZE Trial
ENERGIZE tested whether adding the PD-1 inhibitor nivolumab before and after radical cystectomy improves outcomes over neoadjuvant gemcitabine-cisplatin in previously untreated muscle-invasive bladder cancer. Patients were randomized from September 17, 2019, to November 7, 2022. Most patients (76.6% vs 77.4%) had cT2 disease at study entry, and about half had tumor PD-L1 expression of 1% or higher. Eligibility required a calculated GFR of at least 50 mL/min.
Andrea Necchi presented the final EFS analysis and exploratory ctDNA data at ESMO 2026 (Abstract 4736O) in the same session as KEYNOTE-866, with a concurrent paper in Annals of Oncology. The discussion that followed centered on the contrast with NIAGARA, which is FDA-approved for MIBC, and on cross-trial differences in disease stage, chemotherapy dosing and control-arm outcomes.
Trial Methodology & Results
Study Design
Phase III, randomized 1:1, open-label comparison of NIVO+GC vs GC; stratified by clinical stage (T2 vs T3/T4a), GFR (50 to <60 vs ≥60 mL/min) and PD-L1 status. Third arm (NIVO + linrodostat + GC) terminated December 2021. (Study design slide; ClinicalTrials.gov NCT03661320)
Population
Previously untreated MIBC with a predominant urothelial component, cT2–T4a N0 M0, GFR ≥50 mL/min, ECOG PS 0–1. cT2 at entry 76.6% vs 77.4%. (Study design and baseline slides)
Interventions
Nivolumab 360 mg Q3W x4 + gemcitabine-cisplatin Q3W x4 → radical cystectomy → nivolumab 480 mg Q4W x9, vs gemcitabine-cisplatin Q3W x4 → radical cystectomy → no further treatment.
Endpoints
Co-primary: pCR and EFS per BICR. Secondary: OS, safety. Exploratory: ctDNA (Signatera tumor-informed MRD assay).
Presenter
Andrea Necchi (Milan, Italy) — ESMO 2026 Proffered paper session, Genitourinary tumours, renal and urothelial, October 23, 2026, Abstract 4736O.
Sponsor
Bristol Myers Squibb; Ono Pharmaceutical is listed as collaborator on ClinicalTrials.gov.
Survival and response, ENERGIZE (ESMO 2026 4736O, Necchi; median follow-up 54.5 mo; data cutoff not shown on slides)
| Measure | NIVO+GC (n=325) | GC (n=328) |
|---|---|---|
| EFS events | 104 (32.0%) | 104 (31.7%) |
| Median EFS | Not reached | 67.6 mo (95% CI 63.0–NE) |
| 12-month EFS | 82.6% | 78.6% |
| 24-month EFS | 72.3% | 71.6% |
| 36-month EFS | 68.1% | 68.5% |
| OS events | 71 (21.8%) | 81 (24.7%) |
| Median OS | Not reached | Not reached |
| 12-month OS | 91.6% | 92.8% |
| 24-month OS | 84.8% | 85.2% |
| 36-month OS | 79.8% | 80.5% |
| pCR | 39.1% | 29.6% |
| Combined response (≤ypT1N0) | 51.7% | 41.8% |
EFS HR 0.94 (95% CI 0.72–1.24; 95.74% CI 0.71–1.25), two-sided P=0.6697 (threshold 0.0426). OS HR 0.88 (95% CI 0.64–1.21), descriptive. pCR difference 9.5% (95% CI 2.3–16.7; 99.91% CI −2.6 to 21.6), descriptive update at the EFS final analysis. Landmark values as labeled on the presented Kaplan-Meier slides.
Event-free survival (co-primary)
104 EFS events in each arm (32.0% vs 31.7%). Median EFS was not reached with NIVO+GC and was 67.6 months (95% CI 63.0–NE) with GC. HR 0.94 (95% CI 0.72–1.24; 95.74% CI 0.71–1.25); two-sided P=0.6697 against a significance threshold of 0.0426. The EFS co-primary endpoint did not meet the significance criterion of the prespecified testing procedure. (ESMO 2026 4736O, Necchi; median follow-up 54.5 mo; data cutoff not shown on slides)
EFS HR 0.94 · P=0.6697 · not metSource: ClinicalTrials.gov NCT03661320 · presented slides (KOL capture) ↗
Pathological complete response (co-primary)
pCR 39.1% vs 29.6%, difference 9.5% (95% CI 2.3–16.7; multiplicity-adjusted 99.91% CI −2.6 to 21.6). The multiplicity-adjusted analysis did not establish a significant difference. Combined pathological response (≤ypT1N0) 51.7% vs 41.8%. The figures shown are a descriptive pCR update at the EFS final-analysis cutoff; the prespecified pCR analysis had already been completed and was not retested. (ESMO 2026 4736O, Necchi; median follow-up 54.5 mo; data cutoff not shown on slides)
pCR 39.1% vs 29.6% · not significantSource: presented pCR slide (posted by @TiansterZhang) ↗
Overall survival and safety
OS events 71 (21.8%) vs 81 (24.7%); median OS not reached in either arm; HR 0.88 (95% CI 0.64–1.21). OS was analyzed descriptively because the EFS testing condition was not met; the presented summary describes OS data as immature with no clear treatment difference. The presented summary describes the safety profile of NIVO+GC as consistent with that of the individual agents. (ESMO 2026 4736O, Necchi; median follow-up 54.5 mo; data cutoff not shown on slides)
OS HR 0.88 · descriptive, immatureSource: presented OS slide (posted by @Dr_Aggen) ↗
Exploratory ctDNA analyses
ctDNA testing used the Signatera tumor-informed MRD assay; 53.0% (346/653) of patients were ctDNA-evaluable. Neoadjuvant ctDNA clearance from cycle 1 to cycle 4 was 81.3% (87/107) with NIVO+GC vs 71.7% (66/92) with GC (Fisher exact P=0.130). In a pooled analysis across arms, pretreatment ctDNA detection was associated with shorter EFS and OS. These analyses are exploratory. (ESMO 2026 4736O, Necchi; median follow-up 54.5 mo; data cutoff not shown on slides)
ctDNA clearance 81.3% vs 71.7% · exploratorySource: presented ctDNA slides (KOL capture) ↗
ENERGIZE in the News
ENERGIZE FAQ
What is the ENERGIZE trial?
ENERGIZE (CA017-078, NCT03661320) is a Bristol Myers Squibb phase III randomized trial in previously untreated muscle-invasive bladder cancer. It compared neoadjuvant nivolumab plus gemcitabine-cisplatin, radical cystectomy and adjuvant nivolumab (n=325) with neoadjuvant gemcitabine-cisplatin and radical cystectomy alone (n=328). A third arm adding linrodostat (BMS-986205) was terminated in December 2021.
What did ENERGIZE show at ESMO 2026?
Neither co-primary endpoint was met. EFS HR was 0.94 (95% CI 0.72-1.24), two-sided P=0.6697; median EFS was not reached vs 67.6 months. pCR was 39.1% vs 29.6% (difference 9.5%), which did not meet the multiplicity-adjusted threshold. OS HR was 0.88 (95% CI 0.64-1.21), analyzed descriptively, with median follow-up of 54.5 months.
Is perioperative nivolumab approved for muscle-invasive bladder cancer?
No. Perioperative nivolumab with neoadjuvant gemcitabine-cisplatin is not approved for MIBC, and ENERGIZE did not support it. Nivolumab (Opdivo) is FDA-approved, based on CheckMate-274, as adjuvant treatment for adults with urothelial carcinoma at high risk of recurrence after radical resection (August 19, 2021).
How does ENERGIZE compare with NIAGARA and KEYNOTE-866?
All three added a PD-1 or PD-L1 antibody to neoadjuvant gemcitabine-cisplatin with continued therapy after cystectomy. NIAGARA (durvalumab) improved EFS (HR 0.68) and OS (HR 0.75) and is FDA-approved; ENERGIZE (EFS HR 0.94) and KEYNOTE-866 (EFS HR 0.88) were negative. The trials differ in population, disease stage, design and endpoints, so these are cross-trial observations, not head-to-head comparisons.
What did the ctDNA analysis show?
In exploratory analyses with the Signatera assay, neoadjuvant ctDNA clearance was 81.3% with nivolumab plus chemotherapy vs 71.7% with chemotherapy (P=0.130), and detectable pretreatment ctDNA was associated with shorter EFS and OS across both arms. The analyses did not establish ctDNA as a predictor of benefit from nivolumab.
Key KOL Sentiments - ENERGIZE
Compiled and reviewed by the KOL Pulse research team, led by Brian Shields, Founder, KOL Pulse. Last updated October 23, 2026. Statistics carry their source and data-cut label in place; every quote is verbatim from the physician’s own post.