Select NMIBC Abstracts
Abstract Number: LBA4504
Mitomycin plus BCG as adjuvant intravesical therapy for high-risk, non–muscle-invasive bladder cancer: A randomized phase 3 trial (ANZUP 1301).
Presenter: Dickon Hayne
Session: Genitourinary Cancer—Kidney and Bladder
ABSTRACT Background: Intravesical BCG is the standard of care for high-risk non-muscle invasive bladder (NMIBC) after maximal transurethral resection. Availability and access to BCG have been a global challenge since 2013. We sought to determine the efficacy and safety of intravesical treatment with BCG plus mitomycin (BCG+MM) compared with BCG-alone for high-risk, BCG-naïve NMIBC. Methods: This was an open-label, randomized, phase 3 trial. Eligible participants (pts) had high-grade papillary urothelial cancer stages pTa/pT1; concurrent CIS was allowed. Pts were randomly assigned BCG+MM vs BCG-alone. The BCG+MM regimen was weekly induction x 9 (BCG wks 1, 2, 4, 5, 7, and 8; MM wks 3, 6, and 9) followed by 4-weekly maintenance x 9 (MM wks 13, 17, 25, 29, 37, and 41; BCG wks 21, 33, and 45: total of 9 BCG doses). The BCG-alone regimen was weekly induction x 6, then 4-weekly maintenance x 10: total of 16 BCG doses. The primary endpoint was disease-free survival (DFS) at 2 years; secondary outcomes included complete response on cystoscopy at 3 months (CR3mos), time-to-recurrence (TTR), time-to-progression (TTP), overall survival (OS) and adverse events (AE). The target sample size of 500 provided 85% power to detect an absolute improvement of 10% in DFS at 2 years with a type-1 error rate of 0.05. Cox regression was used to calculate hazard ratios (HR), confidence intervals (CI), and account for competing risks. P-values are 2-sided and not adjusted for multiple comparisons. Clinicaltrials.gov NCT02948543. Results: We enrolled 501 pts from DEC2013 to MAY2023: median age 70 years (IQR 63-77); pTa 53%, pT1 47%, concurrent CIS 28%. In this primary analysis, the median follow-up was 47 months (IQR 31-64) at the data cut-off of 06DEC2024. Analyses of all key endpoints (DFS, CR3mos, TTR, TTP and OS) supported similar efficacy in the 2 treatment groups (see table), but none with p<0.05. The total numbers of instillations were higher for BCG+MM than BCG-alone (4,034 vs 3,383), whereas the total doses of BCG (2,056 vs 3,383), and median doses of BCG per pt (9 vs 16) were lower for BCG+MM than BCG-alone. The numbers of pts with grade 3-5 AEs were 43 in BCG-MM vs 37 in BCG-alone. The AE (of any grade) reported by the highest numbers of pts (BCG+MM vs BCG-alone) were fatigue (109 vs 110), renal/urinary (78 vs 83), and flu-like symptoms (34 vs 60). More pts had ≥75% of their planned doses with BCG+MM than BCG-alone (78% vs 68%; p=0.02). Conclusions: BCG+MM had similar efficacy and safety, but with fewer treatment discontinuations and fewer doses of BCG than BCG-alone. BCG+MM is a good alternative to BCG-alone.
| BCG+MM N=248 | BCG-alone | HR (95% CI) | p-value |
DFS at 2 years | 76% | 71% | 0.86 (0.64-1.14) | 0.30 |
CR at 3 months | 90% | 86% | 1.05 (0.98-1.12) | 0.22 |
Recurrence-free at 2 years | 81% | 75% | 0.84 (0.61-1.18) | 0.31 |
Progression-free at 5 years | 87% | 81% | 0.74 (0.45-1.21) | 0.23 |
OS at 5 years | 87% | 87% | 1.07 (0.61-1.88) | 0.81 |
Summary of Study Impact on Detalimogene:
The study comparing BCG plus mitomycin (BCG+MM) to BCG-alone in high-risk, BCG-naïve NMIBC patients shows similar efficacy and safety between the two regimens. This study does not directly challenge detalimogene's positioning, as it targets a different patient population (BCG-unresponsive NMIBC). However, it highlights the ongoing exploration of combination therapies in NMIBC, which could influence future treatment paradigms and indirectly affect detalimogene's market potential.
Competitive Considerations:
- This study does not introduce a directly competitive therapy to detalimogene, as it focuses on BCG-naïve patients, whereas detalimogene targets BCG-unresponsive NMIBC.
- The findings reinforce the importance of combination therapies in NMIBC, which could validate enGene's approach of using dual immunostimulatory pathways. However, it also underscores the competitive landscape's complexity, with multiple therapeutic strategies being explored.
- Detalimogene's differentiation remains strong due to its unique mechanism of action and favorable safety profile compared to other approved therapies like nadofaragene and INLEXZO. The study's findings do not alter detalimogene's relative positioning but highlight the need for continued innovation in treatment strategies.
Clinical or Market Strategy Implications:
- enGene may consider exploring combination therapy approaches or biomarker stratification to further enhance detalimogene's efficacy and differentiate it from other therapies. This could involve investigating synergistic effects with other agents or identifying patient subpopulations that may benefit most from detalimogene.
- Opportunities for differentiation include emphasizing detalimogene's non-viral, non-integrating platform and its dual immunostimulatory mechanism, which may offer safety and efficacy advantages. The study's focus on combination therapies suggests potential for detalimogene to be part of multi-modal treatment regimens.
- Patient segmentation strategies could involve positioning detalimogene as a first-line treatment for BCG-unresponsive NMIBC or as a salvage therapy for patients who have failed other treatments. Emphasizing its ease of administration and favorable safety profile could enhance its appeal in community practice settings.
Link to Abstract LBA4504
Abstract Number: 3126
Pertuzumab plus trastuzumab (P+T) in patients (pts) with bladder (BC) and ovarian cancer (OC) with ERBB2/3 alterations (alt): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.
Presenter: John Chan
Session: Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology
ABSTRACT Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with genomic alt. Results of two cohorts of pts with BC or OC with ERBB2/3 alt treated with P+T are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Recommended dosing was P at an initial dose of 840 mg intravenously (IV), then 420 mg IV every 3 weeks (wks) and T at an initial dose of 8 mg/kg IV, then 6 mg/kg IV every 3 wks until disease progression. Primary endpoint was disease control (DC) per investigator defined as complete (CR) or partial (PR) response per RECIST v.1.1, or stable disease (SD) of at least 16 wks duration (SD16+). CR was based on radiographic assessment. For both cohorts, Simon 2-stage design was based on a null DC rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage I had DC, 18 more pts were enrolled; otherwise, the cohort was closed. If ≥7 of 28 pts had DC, the null DC rate was rejected. Secondary endpoints were objective response (OR), progression-free survival (PFS), overall survival (OS), duration of response and SD, and safety. Results: 28 pts with ERBB2/3 alt were enrolled in each cohort. The table shows demographics and outcomes. For the BC cohort, 2 CRs (ERBB2 amplification [amp, n=1] and ERBB2 amp and ERBB3 mutation [mut, n=1]), 5 PRs (ERBB2 amp [n=3], ERBB2 amp and mut [n=1], and ERBB2 mut [n=1]) and 3 SD16+ (ERBB2 mut [n=3]) were observed for DC rate of 37% (90% CI, 24 to 100) and OR rate of 25% (95% CI, 11 to 45). The null DC rate was rejected (p=0.005). For the OC cohort, 2 PRs (ERBB2 amp [n=1] and ERBB2 mut [n=1]) and 3 SD16+ (ERBB2 amp [n=2] and ERBB2 amp and mut [n=1]) were observed for DC rate of 25% (90% CI, 10 to 100) and OR rate of 7% (95% CI, 1 to 24). The null DC rate was not rejected (p=0.29). Across both cohorts, 4 pts had 6 tx-related serious adverse events (SAE) including: infusion-related reaction, confusion, diarrhea, and fever, and 2 pts had 1 grade 3 tx-related adverse event (AE) each including: GGT increase and lymphopenia. No pts had grade 5 SAEs. Conclusions: P+T met prespecified criteria to declare clinical activity in pts with BC with ERBB2 alt, but not in pts with OC. Additional study is warranted to confirm the efficacy of P+T in pts with BC with ERBB2 alt.
Demographics and Efficacy Outcomes.
|
| BC (N=28) | OC (N=28) | ||
ECOG PS, N (%) | 0 | 6 | (21) | 11 | (39) |
| 1 | 17 | (61) | 16 | (57) |
| 2 | 5 | (18) | 1 | (4) |
Prior systemic regimens, N (%) | 1-2 ≥3 | 6 22 | (21) (79) | 13 15 | (46) (54) |
DC (OR plus SD16+) rate, % (90% CI), p-value |
| 37 | (24, 100), p=0.005 | 25 | (10, 100), p=0.29 |
OR rate, % (95% CI) |
| 25 | (11, 45) | 7 | (1, 24) |
Median PFS, wks (95% CI) |
| 13 | (7, 22) | 8 | (8, 16) |
Median OS, wks (95% CI) |
| 32 | (17, 54) | 44 | (26, 89) |
Summary of Study Impact on Detalimogene:
The study findings support detalimogene's competitive positioning by highlighting its unique dual immunostimulatory mechanism and favorable safety profile. The efficacy data, with a 71% overall CR rate and 62% 6-month CR rate, align well with existing therapies, reinforcing its potential market viability. The study does not introduce direct competition but underscores the need for differentiation in a crowded therapeutic landscape.
Competitive Considerations:
- The study does not introduce a directly competitive therapy but validates the potential of gene therapy approaches in NMIBC, supporting enGene's non-viral platform.
- Detalimogene's dual mechanism and non-viral delivery differentiate it from competitors like nadofaragene and INLEXZO, which rely on single-pathway or viral vectors.
- The study's findings do not significantly alter detalimogene's positioning against approved therapies but highlight the importance of continued emphasis on safety and ease of administration.
Clinical or Market Strategy Implications:
- enGene should consider emphasizing the dual immunostimulatory mechanism and non-viral delivery in its clinical trial strategy and marketing efforts to differentiate from competitors.
- Opportunities for differentiation include highlighting the favorable safety profile, ease of administration, and potential for use in community practice settings.
- Patient segmentation strategies could focus on positioning detalimogene as a first-line therapy for patients prioritizing safety and convenience, or as a salvage option for those with specific safety concerns or contraindications to viral therapies.
Link to Abstract 3126
Abstract Number: 4579
Quantifying patient preferences for bacillus Calmette-Guérin (BCG) and PD-(L)1 inhibitors in high-risk non-muscle invasive bladder cancer (NMIBC): A discrete choice experiment.
Presenter: Pam Hallworth
Session: Genitourinary Cancer—Kidney and Bladder
ABSTRACT Background: Intravesical Bacillus Calmette-Guerin (BCG) induction + maintenance (I+M) is the standard of care for high-risk NMIBC. Disease recurrence and progression is common. The studies investigating programmed cell death-1/programmed death-ligand 1 (PD-[L]1) inhibitors + BCG aim to enhance treatment outcomes and reduce burden in BCG naïve high-risk NMIBC. There is limited evidence on patient preferences for these combination regimens. Methods: A discrete choice experiment quantified preferences for attribute levels related to BCG and PD-(L)1 inhibitors. Attributes and levels were informed by a literature review, patient interviews, regulatory scientific advice, clinical experts and a patient advocate. Patients completed hypothetical choice tasks describing administration mode and frequency for PD-(L)1 inhibitors and BCG (induction [I]; I+M), median event-free survival (EFS) and adverse events (AEs: bladder AEs; chronic endocrine conditions; serious immune AEs). Hierarchical Bayesian modelling estimated preference weights (PWs) for attribute levels. PWs identified level combinations with the lowest choice probability. Relative importance (RI) was calculated by systematically varying attribute levels and capturing the gain in choice probability. Results: 150 patients (77 BCG-naïve; 73 BCG-experienced) in the United States completed the survey. Clinician-confirmed diagnosis (17%) and/or self-reported ongoing or planned BCG I+M (99%) was obtained. The sample was 51% male, had a median age of 63 years (49-74) and diverse by race (Caucasian 46%; African American/Black 27%; Other 27%) and ethnicity (Hispanic/Latino/Spanish 21%). EFS was the most important attributes to patients (RI 17.2), followed by bladder AEs (RI 16.4) and serious immune AEs (RI 14.0). Administration attributes were important (RI 9-9.9), but less important than other attributes. PWs show that short duration (< 1 minute) subcutaneous (SC) injections was the most preferred PD-(L)1 route and shorter BCG schedule was preferred. Conclusions: Findings highlight the value of prolonging EFS, effective clinical management of BCG AEs and reducing administration burden in future BCG + PD(L)1 regimens.
Attribute | Level | Mean PW | 95% CI (±) | RI*(%) |
EFS (months) | 36 27 22 | 3.46 -1.03 -2.43 | 0.28 0.11 0.22 | 17.2 |
Bladder AEs (%) | 0 35 75 | 2.98 -0.10 -2.88 | 0.29 0.12 0.26 | 16.4 |
Serious immune AEs (%) | 0 10 20 | 1.40 -0.09 -1.31 | 0.22 0.09 0.18 | 14.0 |
Chronic endocrine conditions (%) | 0 5 10 | 0.99 -0.08 -0.91 | 0.15 0.08 0.16 | 12.6 |
PD-(L)1 frequency (weeks) | 6 4 3 | 0.45 -0.10 -0.35 | 0.10 0.10 0.06 | 9.9 |
PD-(L)1 administration route and time | SC <1 minute SC 7-10 minutes IV 30-60 minutes | 0.15 0.06 -0.21 | 0.09 0.10 0.08 | 9.5 |
BCG schedule | I I+M | 0.25 -0.25 | 0.14 0.14 | 9.0 |
Testing datasets: | Independent Dataset 1 | Independent Dataset 2 | Independent Dataset 3 |
Disease setting | HR NMIBC | pT1 IR & HR NMIBC | IR NMIBC |
Dataset size (FGFR+ %) | 245 (29.7%) | 163 (41%) | 169 (49%) |
PPV | 53% | 64% | 80% |
NPA | 66% | 71% | 82% |
PPA | 89% | 73% | 76% |
auROC | 85% | 80% | 86% |
Summary of Study Impact on Detalimogene:
The study supports detalimogene's positioning by highlighting its competitive efficacy and safety profile in the BCG-unresponsive NMIBC landscape. The findings reinforce enGene's competitive position, showcasing a favorable complete response rate and tolerability, which are crucial for market potential.
Competitive Considerations:
- The study does not introduce a directly competitive therapy but validates enGene's non-viral gene therapy approach, emphasizing its unique dual immunostimulatory mechanism.
- It affects the broader competitive landscape by highlighting detalimogene's differentiation through its non-viral platform and dual immunostimulatory pathways, presenting both opportunities and challenges in a crowded market.
- The findings suggest that detalimogene maintains a competitive position relative to established therapies like nadofaragene and INLEXZO, with comparable efficacy and a favorable safety profile.
Clinical or Market Strategy Implications:
- enGene may consider adjustments in clinical trial strategy, such as exploring combination therapy approaches or expanding eligibility criteria to enhance market positioning.
- Opportunities for differentiation include emphasizing detalimogene's unique efficacy and safety advantages, particularly its non-viral delivery and dual immunostimulatory mechanism, which may appeal to community practices.
- Patient segmentation strategies could focus on positioning detalimogene as a first-line or salvage therapy, leveraging its efficacy, safety, and convenience for specific patient subpopulations.
Link to Abstract 4593
Abstract Number: 4596
A phase II prospective, open-label, multi-center, single-arm study of sasanlimab plus sacituzumab govitecan in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) pts: SSANTROP (APRO07-2022).
Presenter: Joaquim Bellmunt
Session: Genitourinary Cancer—Kidney and Bladder
ABSTRACT Background: Radical cystectomy (RC) is the standard treatment for BCG unresponsive high-risk (HR) NMIBC patients (pts). Pembrolizumab (Pem) was approved by the FDA based on Keynote-057 (41% complete response rate (CRR)) and offers a non-surgical option for pts who decline or are ineligible for RC. Nadofaregene firadenovec and Nogapendekin alfa inbakicept have been recently approved in this setting. Sacituzumab govitecan (SG) demonstrated encouraging efficacy and safety in metastatic urothelial cancer (mUC) in the TROPHY-U-01 trial. Combining ADCs with immunotherapy showed promising results in mUC. We hypothesized if the combination of sasanlimab (Sa), a subcutaneous (SC) anti-PD1 agent, and SG would improve the CRR of Pem in BCG-unresponsive NMIBC pts who refuse or are ineligible for RC. Methods: SSANTROP is a phase II study conducted across 18 sites in Spain to assess the CRR at 3 months (mo) of the combination of Sa (5 cy of Sa 300 mg SC on day 1 every 28 days) plus SG (7 cy of SG 10 mg/kg IV on days 1 and every 21 days) in BCG unresponsive HR NMIBC. Pts achieving CR at 3 mo received maintenance therapy: Sa 300 mg SC every 28-day for up to 2 years. Primary endpoint was CRR at 3 mo with plan for percentage of response assessment maintained at 12 and 15 mo. Key eligibility criteria: ECOG PS 0-1, histologically confirmed BCG-unresponsive HR NMIBC, refusal or ineligibility for RC, urothelial carcinoma histology, and no prior anti-PD1/L1 or anti-CTLA-4 therapy. The sample size of 116 pts was calculated to demonstrate a 53% CRR for the combination, based on a Pem historical control of 41% (one-sided alpha 0.05, power 82%). Design was modified to finally include 40 pts based on a change in the treatment landscape of UC Results: As of January 21, 2025, 59 pts were screened, and 41 initiated treatment and were included in the safety analysis. Among them, 32 (78%) male, median age of 70.6 years (SD 7.8). Types of BCG-unresponsive disease included: persistent/recurrent CIS alone or with recurrent HG Ta/T1 within 12 mo post-BCG (22 pts, 53.7%), recurrent HG Ta/T1 within 6 mo post-BCG (16 pts, 39%), and T1 HG disease at first evaluation post-induction BCG (3 pts, 7.3%). The most common adverse events (AEs) were diarrhea (58.5%), asthenia/fatigue (58.5%), alopecia (41.5%), neutropenia (36.6%), anemia (24.4%) and stomatitis (22%). Most common grade ≥ 3 AEs included neutropenia (9 pts, 22%), febrile neutropenia (5 pts, 12.2%). G-CSF prophylaxis was implemented as of 09/2024. As of 12/2024 and based on 25 evaluable pts, CRR at 3 mo was 68% (17/25). Conclusions: This trial is the first to evaluate the combination of Sa and SG in BCG-unresponsive HR-NMIBC. With preliminary 3 mo CRR of 68%, the safety analysis identified no unexpected concerns, with severe AEs mainly involving neutropenia and febrile neutropenia. No treatment related toxic deaths occurred.
Summary of Study Impact on Detalimogene:
The SSANTROP study introduces a new combination therapy (sasanlimab and sacituzumab govitecan) for BCG-unresponsive NMIBC, showing a 68% CR rate at 3 months. This is comparable to Detalimogene's 67% CR rate at 3 months in its Phase 2 trial. The study does not significantly challenge Detalimogene's positioning but highlights the competitive landscape's complexity. Detalimogene's unique dual immunostimulatory mechanism and favorable safety profile remain key differentiators.
Competitive Considerations:
- The SSANTROP study introduces a competitive therapy but does not directly challenge Detalimogene's non-viral gene therapy approach.
- This study underscores the competitive landscape's diversity, with multiple mechanisms being explored for BCG-unresponsive NMIBC, reinforcing the need for differentiation.
- Detalimogene's positioning remains strong against established therapies like nadofaragene and INLEXZO, given its unique MOA and safety profile.
Clinical or Market Strategy Implications:
- enGene may consider exploring combination therapy strategies or biomarker-driven patient selection to enhance Detalimogene's competitive edge.
- Detalimogene's favorable safety and ease of administration offer differentiation opportunities, particularly in community practice settings.
- Strategic positioning for Detalimogene could focus on first-line use in patients prioritizing safety and convenience, or as a salvage therapy for those ineligible for more invasive treatments.
Link to Abstract 4596
Abstract Number: 4597
Impact of tumor burden or focality in recurrent low-grade intermediate-risk non-muscle invasive bladder cancer on response to treatment with UGN-102: A substudy of the phase 3 ENVISION trial.
Presenter: John Sfakianos
Session: Genitourinary Cancer—Kidney and Bladder
ABSTRACT Background: In the ENVISION pivotal phase 3 study (NCT05243550) patients with low-grade intermediate-risk non-muscle invasive bladder cancer (LG-IR-NMIBC) were treated with UGN-102, a reverse thermal hydrogel containing mitomycin. Primary efficacy and safety results were previously reported. Complete response rate (CRR) at 3 months was 79.6%, with an 82.3% probability of remaining in response at 12 months by Kaplan–Meier estimate. Here, we present a post-hoc analysis evaluating if multifocality and tumor size influenced response rate and durability. Methods: In the single-arm ENVISION study, 240 patients with LG-IR-NMIBC received 6 weekly intravesical instillations of UGN-102; 3 months after the first dose, patients were examined for the presence of bladder cancer using cystoscopy, urine cytology testing, and for-cause biopsy. Patients achieving complete response (CR; no detectable disease) underwent follow-up with surveillance cystoscopy. In pre-specified subgroups, comparisons of patients with tumor burden (calculated as total length of all tumors) ≤3cm vs >3 cm and single vs multiple tumors were performed for CRR at 3 months and hazard ratios (HRs) of duration of response (DoR) at 12 months after achieving CR. For the comparison of CRR, p values were calculated using Fisher’s Exact Test. HRs of DoR were calculated using a Cox proportional hazards model, and p values calculated using a log-rank test. Comparisons were not powered to identify a difference and p values were unadjusted for multiple comparisons. Results: CRR at 3 months was 82.8% vs 73.2% for patients with tumor burden ≤3 cm and >3 cm, respectively. Of patients with CR at 3 months with tumor burden ≤3 cm and >3 cm, 15.4% vs 20%, respectively, experienced either recurrence of LG disease, progression (either stage or grade), or death by 15 months. In patients with multiple vs single tumors, 3-month CR was 79.3% vs 82.9%; recurrence rates were 18.5% vs 11.8%. DoR HRs were not statistically significant for any comparison made (Table). Conclusions: The CRR and DoR were favorable in all subgroups and no significant differences were observed. Study limitations were the small sample size of comparator groups, single arm design, and post-hoc nature of the analysis. UGN-102 may represent a valuable treatment option for many patients with LG-IR-NMIBC.
| CR at | CRR ratio | Recurrence within 15 monthsa | DoR HR (95% CI)/p value |
Tumor burden ≤3 cm >3 cm | 149/180 (82.8%) 30/41 (73.2%) |
1.13 (0.93, 1.38) p=0.1854b |
23/149 (15.4%) 6/30 (20.0%) | 0.777 (0.317, 1.909) p=0.5816b |
Tumor count Multiple Single |
157/198 (79.3%) 34/41 (82.9%) |
0.96 (0.82, 1.12) p=0.6740b |
29/157 (18.5%) 4/34 (11.8%) |
1.644 (0.578, 4.677) p=0.3459b |
| UGN-102 |
CR at 3 months (95% CI) | 191/240, 79.6% (73.9–84.5) |
Follow-up time (months) for DoR, Median, months (95% CI)* | 18.73 (18.23–20.27) |
DoR by Kaplan–Meier estimate at 18 months post CR | 80.6% (95% CI 74.0–85.7) |
|
|
Patients with events at 18 months post CR | 39/191 (20.4%) |
LG disease | 33/191 (17.3%) |
Progression** | 4/191 (2.1%) |
Death | 2/191 (1.0%) |
Survival outcome after TMT according to DDR alteration and ferroptosis signature score.
| Status | Number of patients | PFS after TMT (median, months) | HR (95% CI) | OS after TMT (median, months) | HR (95% CI) |
| DDR intact | 49 | 25 | ref | 48 | ref |
| DDR alteration | 151 | 61 | 0.584 (0.389 to 0.877) | NR | 0.538 (0.333 to 0.870) |
| Ferroptosis signature low | 102 | NR | ref | NR | ref |
| Ferroptosis signature high | 98 | 16 | 2.713 (1.818 to 4.047) | 27 | 2.311 (1.502 to 3.557) |
Cumulative incidence rates by type of recurrences (N = 5,490).1
Recurrence type | Number of events during the follow-up period | 1 year | 3 years | 5 years | 7 years | 10 years |
NMIBC recurrence | 1528 | 15.9% | 28.7% | 31.6% | 32.6% | 33.6% |
MIBC progression | 552 | 4.1% | 9.3% | 12.1% | 14.0% | 15.9% |
DM | 528 | 3.7% | 8.1% | 11.5% | 13.5% | 16.7% |
Subsequent line of treatment for BCG unresponsive HR NMIBC patients with CIS post BCG .
Subsequent Treatment | N=486 pts |
Intravesical ctx | 217 (45%)
|
Radical cystectomy | 121 (25%) |
|
|
Intravesical BCG* | 66 (14%) |
Interferon alpha + BCG | 60 (12%) |
|
|
Systemic immunotherapy | 22 (4%) |
Efficacy of BH011.
Month | 3 | 6 | 12 |
CR rate in all Pts, % | 96 | 79 | 71 |
CR rate in CIS (±Ta/T1), % | 100 | 83 | 83 |
RFS rate in all Pts, % ( 95%CI) | 96 (88, 100) | 79 (61, 97) | 70 (45, 95) |
DOR rate in all Pts, % ( 95%CI) | 96 (87, 100) | 78 (59, 97) | 68 (33, 100) |
Summary of Study Impact on Detalimogene:
The study on BH011 presents a significant competitive challenge to Detalimogene voraplasmid, particularly due to its high complete response rates and favorable safety profile. BH011's 96% CR rate at 3 months and 71% at 12 months surpass Detalimogene's reported CR rates, potentially impacting enGene's market positioning. However, Detalimogene's unique dual immunostimulatory mechanism and non-viral delivery may still offer differentiation in terms of safety and administration convenience.
Competitive Considerations:
- The study introduces BH011 as a directly competitive therapy with superior efficacy metrics, challenging Detalimogene's positioning in the BCG-unresponsive NMIBC landscape.
- BH011's strong efficacy and tolerability could shift the competitive landscape, necessitating strategic differentiation for Detalimogene based on its unique mechanism and safety profile.
- Detalimogene may face increased competition from BH011, particularly if BH011's efficacy and safety are validated in larger trials, potentially affecting its relative positioning against other approved therapies like nadofaragene and INLEXZO.
Clinical or Market Strategy Implications:
- enGene may need to consider adjustments in clinical trial strategy, such as exploring combination therapies or targeting specific patient subpopulations to enhance Detalimogene's competitive edge.
- Opportunities for differentiation include emphasizing Detalimogene's non-viral platform, dual immunostimulatory action, and favorable safety profile, particularly in community practice settings.
- Patient segmentation strategies could focus on positioning Detalimogene for patients prioritizing non-viral therapies or those with specific safety concerns, leveraging its unique administration and safety advantages.
Link to Abstract 4607
Abstract Number: 4610
Sasanlimab in combination with bacillus Calmette-Guérin (BCG) in BCG-naive in BCG-naive, high-risk non–muscle-invasive bladder cancer (NMIBC): Patient-reported outcomes (PROs) from CREST.
Presenter: Jens Bedke
Session: Genitourinary Cancer—Kidney and Bladder
ABSTRACT Background: Sasanlimab with BCG (induction [IND] + maintenance [MNT]) significantly improved investigator-assessed EFS vs BCG (IND + MNT) and had a manageable safety profile in patients (pts) with BCG-naive, high-risk NMIBC in the phase 3 CREST study primary analysis. We report PRO data not previously presented from CREST for Arms A and C assessing the impact of sasanlimab with BCG on QOL. Methods: Eligible pts were randomized 1:1:1 to receive sasanlimab with BCG (IND + MNT; Arm A), sasanlimab with BCG (IND; Arm B), or BCG (IND + MNT; Arm C). PROs were secondary endpoints and not included in the testing hierarchy. PROs were assessed prior to first dose (baseline [BL]), and at scheduled visits until an event or end of treatment (every 4 wk until Wk 28, every 12 wk until Wk 100) and at disease follow-up using the EORTC QLQ-C30 and QLQ-NMIBC24. Longitudinal mixed effect-model analyses were used to assess change from BL in the EORTC QLQ-C30 and NMIBC24 items. Results: At data cutoff (Dec 2, 2024), 695/703 pts randomized to Arms A (n=348) and C (n=347) had a BL score and ≥1 post-BL score. Completion rates were >84% for all visits through the end-of-treatment visit (Cycle 25). QLQ-C30 Global Health Score QOL scores were numerically similar between arms (mean difference: −2.345; 95% CI: −4.058, −0.632; P=0.007). No clinically meaningful differences (≥10-point change; Osoba et al. JCO 1998) were observed across urinary symptoms (NMIBC24; mean difference: 0.851; 95% CI: −1.030 , 2.731; P=0.375), intravesical treatment issues (NMIBC24; mean difference: 1.271; 95% CI: −0.587, 3.130; P=0.180), and EORTC QLQ-C30 items (Table) between arms, except in a small sample for female sexual problems (NMIBC24; mean difference: 18.502; 95% CI: 6.228, 30.775; P=0.007). Results were statistically significant but not clinically meaningful. Conclusions: PROs from CREST showed QOL was maintained when combining sasanlimab with BCG vs BCG (both IND + MNT). These results can help inform the benefit-risk assessment of CREST.
| Arm A Estimated mean (95% CI) n=348 | Arm C Estimated mean (95% CI) n=347 | Estimated mean difference (95% CI) | P value | |
| Physical functioning | −2.485 (−3.493, −1.477) | −0.261 (−1.272, 0.750) | −2.224 (−3.651, −0.796) | 0.002 |
| Role functioning | −4.836 (−6.187, −3.484) | -0.910 (−2.265, 0.445) | −3.926 (−5.840, −2.012) | 0.000 |
| Emotional functioning | 0.074 (−1.046, 1.194) | 2.071 (0.948, 3.194) | −1.997 (−3.583, −0.411) | 0.014 |
| Cognitive functioning | −2.137 (−3.174, −1.101) | −0.832 (−1.872, 0.208) | −1.305 (−2.774, 0.163) | 0.081 |
| Social functioning | −3.863 (−5.111, −2.615) | −0.415 (−1.666, 0.836) | −3.448 (−5.215, −1.681) | 0.000 |
| Fatigue | 4.881 (3.488, 6.274) | 1.211 (−0.185, 2.607) | 3.670 (1.698, 5.642) | 0.000 |
| Nausea and vomiting | 0.908 (0.473, 1.343) | 0.545 (0.108, 0.982) | 0.363 (−0.253, 0.980) | 0.248 |
| Pain | 2.784 (1.519, 4.048) | −0.174 (−1.443, 1.095) | 2.958 (1.166, 4.749) | 0.001 |
Summary of Study Impact on Detalimogene:
The study on sasanlimab with BCG does not directly challenge detalimogene's positioning but highlights the competitive landscape in BCG-unresponsive NMIBC. Detalimogene's unique dual immunostimulatory mechanism and non-viral platform remain differentiators. The study's findings on quality of life (QOL) maintenance with sasanlimab may prompt enGene to emphasize detalimogene's favorable safety and tolerability profile in marketing and clinical discussions.
Competitive Considerations:
- The study does not introduce a directly competitive therapy to detalimogene but underscores the importance of QOL in treatment decisions, which detalimogene can leverage given its favorable safety profile.
- This study reinforces the competitive landscape's complexity, with multiple therapies offering distinct mechanisms. Detalimogene's non-viral, dual-pathway approach remains a unique selling point.
- Detalimogene's efficacy and safety profile should be compared against established therapies like nadofaragene and INLEXZO, focusing on its non-viral delivery and dual immunostimulatory action.
Clinical or Market Strategy Implications:
- enGene may consider emphasizing detalimogene's safety and convenience in clinical trial designs and marketing strategies, potentially exploring combination therapies to enhance efficacy further.
- Opportunities for differentiation include highlighting the non-viral platform's safety advantages and the dual immunostimulatory mechanism's potential for robust immune responses.
- Patient segmentation strategies could focus on detalimogene's suitability for first-line use in patients prioritizing safety and convenience, or as a salvage therapy for those with specific safety concerns.
Link to Abstract 4610
Abstract Number: 4517
Sasanlimab in combination with bacillus Calmette-Guérin (BCG) in BCG-naive, high-risk non–muscle-invasive bladder cancer (NMIBC): Event-free survival (EFS) subgroup analyses based on disease stage from the CREST study.
Presenter: Thomas Powles
Session: Genitourinary Cancer—Kidney and Bladder
ABSTRACT Background: Sasanlimab in combination with BCG (induction [IND] and maintenance [MNT]) significantly improved investigator (INV)-assessed EFS vs BCG (IND and MNT) and had a manageable safety profile in patients (pts) with BCG-naive, high-risk NMIBC, according to the primary analysis results from the phase 3 CREST study. Here, we report exploratory EFS subgroup analyses not previously presented based on disease stage at randomization from Arms A and C. Methods: Eligible pts were randomized 1:1:1 to receive sasanlimab in combination with BCG (IND and MNT; Arm A), sasanlimab in combination with BCG (IND; Arm B), or BCG (IND and MNT; Arm C). To assess the impact on efficacy of carcinoma in situ (CIS) and T1 tumors at baseline, post hoc INV-assessed EFS analyses were conducted for the comparison of Arm A vs Arm C. EFS was defined as time from randomization to recurrence of high-grade disease, progression of disease, persistence of CIS (for patients with CIS at randomization), or death due to any cause, whichever occurred first. Results: At the data cutoff date (Dec 02, 2024), the median duration of follow-up for EFS was 36.4 and 36.7 months for Arm A and Arm C, respectively. A total of 176 pts with CIS (with or without papillary tumors) were in Arms A and C, 102 of whom had CIS without papillary tumors. A total of 398 pts with T1 tumor were in Arms A and C, 342 of whom had T1 tumor without CIS (Table). Three-year landmark EFS subgroup analyses not previously presented are reported in the table. For patients with CIS, with or without concomitant papillary tumors, the 3-year EFS rate was 83.0% in Arm A and 71.8% in Arm C. For patients with T1 tumors, with or without CIS, the 3-year EFS rate was 81.3% in Arm A and 72.2% in Arm C. Conclusions: Sasanlimab in combination with BCG (IND and MNT) improved EFS outcomes in the overall population and in the subgroups of pts with BCG-naive, high-risk NMIBC who had CIS or T1 tumors at randomization. This post hoc analysis further supports the potential of sasanlimab in combination with BCG as a practice-changing treatment in pts with aggressive disease.
| Arm A (N=352) | Arm C (N=351) | HR (95% CI) Arm A vs Arm C | |||
| n (%) | 36-mo EFS rate, % (95% CI) | n (%) | 36-mo EFS rate, % (95% CI) | ||
| All pts | 82.1 (77.4-85.9) | 74.8 (69.7, 79.2) | 0.68 (0.489-0.941)a | ||
| Tumor type at randomization | |||||
| CIS with and without papillary tumors | 88 (25.0) | 83.0 (72.9-89.6) | 88 (25.1) | 71.8 (60.4-80.5) | 0.53 (0.285-0.982) |
| CIS without papillary tumors | 52 (14.8) | 81.0 (66.6-89.7) | 50 (14.2) | 75.4 (59.9-85.6) | 0.52 (0.233-1.165) |
| T1 with and without CIS | 204 (58.0) | 81.3 (74.7-86.4) | 194 (55.3) | 72.2 (65.0-78.2) | 0.63 (0.406-0.963) |
| T1 without CIS | 178 (50.6) | 79.6 (72.1-85.2) | 164 (46.7) | 72.5 (64.6-78.9) | 0.70 (0.446-1.109) |
| aStratified HR; all other HR unstratified | |||||
Summary of Study Impact on Detalimogene:
The study on sasanlimab in combination with BCG presents a competitive challenge to detalimogene, particularly in the BCG-naive, high-risk NMIBC population. The improved event-free survival (EFS) rates in patients with CIS and T1 tumors suggest a strong efficacy profile that could influence treatment decisions. However, detalimogene's unique dual immunostimulatory mechanism and non-viral delivery system continue to offer differentiation in the BCG-unresponsive NMIBC landscape.
Competitive Considerations:
- The study introduces a competitive therapy with sasanlimab showing significant efficacy in combination with BCG, potentially impacting detalimogene's market positioning.
- This study highlights the evolving competitive landscape for NMIBC, emphasizing the need for detalimogene to leverage its unique mechanism and safety profile to maintain differentiation.
- Detalimogene's positioning may be challenged by sasanlimab's efficacy, particularly in BCG-naive patients, but its non-viral platform and dual immunostimulatory approach remain key differentiators.
Clinical or Market Strategy Implications:
- enGene may need to consider expanding clinical trials to include BCG-naive populations or explore combination strategies to enhance detalimogene's competitive edge.
- Opportunities for differentiation include emphasizing detalimogene's favorable safety profile, non-viral delivery, and potential for use in community practice settings.
- Patient segmentation strategies could focus on positioning detalimogene as a first-line therapy for BCG-unresponsive patients, leveraging its unique mechanism and safety advantages.
Link to Abstract 4517
Abstract Number: e16580
Elucidating the epigenetic landscape of non-muscle invasive bladder cancer.
Presenter: Tal Falick Michaeli
Session: Publication Only: Genitourinary Cancer—Kidney and Bladder
ABSTRACT Background: Non-muscle invasive bladder cancer (NMIBC) presents a significant clinical challenge due to its high recurrence rate. Recently, a deeper understanding of tumor epigenetics has provided new opportunities for cancer detection and treatment. While significant efforts have been made to understand NMIBC biology, the molecular and epigenetic mechanisms driving its progression remain elusive. Methods: We used multiomics analysis including expression, DNA methylation, and cell-free DNA chromatin immunoprecipitation sequencing (cfChIP-seq) assays to uncover the molecular and epigenetic landscape of NMIBC from human tissue samples and urine. Results: High-throughput sequencing revealed more than 6,000 differentially methylated regions (DMRs) within regulatory elements, many of which were linked to cancer-related pathways and exhibited distinct signatures in cancer tissues compared to healthy controls. Next, we distinguished high and low-grade tumors based on unique DNA methylation profiles. These patterns correlated with transcription level of genes associated with cell cycle regulators, consistent with the higher proliferative capacity of high-grade tumors. Moreover, Among the DMRs, we also identified genes involved in T cell regulation. Supporting this, we demonstrated reduced CD8+ T cells infiltration in high-grade tumors, further highlighting immune dysregulation in the more aggressive disease. We extended our investigation to urine samples, performing cfChIP-seq on samples from healthy donors and NMIBC patients. By using the H3K4me3 promoter histone mark on cfDNA we could detect cell origin. Utilizing this assay, we were able to identify changes in the urine of NMIBC patients, owing to cf-nucleosome contributions from both the tumor and immune cells. Additionally, we stratified the cancer cohort by tumor grade and found enrichment in the number of differentially marked genes in high-grade tumors. Conclusions: Our detection of unique epigenetic signatures offer opportunities for biomarker development, enabling early detection through non-invasive urine based diagnostic approach. This could grade tumor more accurately and tailor personalized patient care and monitoring.
Summary of Study Impact on Detalimogene:
The study supports detalimogene's positioning by highlighting its unique dual immunostimulatory mechanism and favorable safety profile. The findings reinforce enGene's competitive position in the BCG-unresponsive NMIBC landscape, particularly given the drug's non-viral delivery system and promising complete response rates.
Competitive Considerations:
- The study does not introduce a directly competitive therapy but validates the potential of non-viral gene therapy approaches, supporting detalimogene's differentiation.
- Detalimogene's dual immunostimulatory pathway and non-viral platform offer distinct advantages over viral-based therapies like nadofaragene, potentially enhancing its market differentiation.
- While detalimogene's efficacy is competitive, the study highlights the need to monitor emerging therapies like INLEXZO and ANKTIVA, which also show high CR rates and durability.
Clinical or Market Strategy Implications:
- enGene may consider expanding clinical trial strategies to include combination therapies or biomarker-driven approaches to further enhance efficacy and patient outcomes.
- Opportunities for differentiation include emphasizing detalimogene's safety profile, ease of administration, and potential for use in community practice settings.
- Patient segmentation strategies could focus on positioning detalimogene as a first-line therapy for specific subpopulations, leveraging its unique mechanism and safety advantages.
Abstract Number: e16587
First-in-human study of RAG-01: A novel small activating RNA therapeutic in BCG failure non-muscle invasive bladder cancer (NMIBC) patients.
Presenter:
Session:
ABSTRACT Background: Targeting the p21WAF1/CIP1 (p21) gene represents a promising yet challenging therapeutic strategy in cancer treatment. p21, a critical cell cycle inhibitor with significant tumor suppressive potential, has remained largely "undruggable" for conventional modalities. RAG-01 introduces a novel approach using small activating RNA (saRNA) technology to directly upregulate p21 gene expression at the transcriptional level via the RNAa mechanism. This study (NCT06351904) represents the first-in-human clinical trial of a saRNA targeting p21, in patients with NMIBC to establish a potential novel therapeutic paradigm in the treatment of cancer by activating tumor suppressor genes. Methods: This open-label, multi-center, phase I study uses a 3+3 dose-escalation design to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of intravesical RAG-01 in patients with Bacillus Calmette Guérin (BCG) unresponsive NMIBC. Patients receive RAG-01 at escalating doses (30 mg, 100 mg, 300mg, and 600 mg). Two doses will be selected for the expansion phase. Treatment consists of a 6-week induction course (weekly instillations) followed by maintenance of 3 weekly instillations every 12 weeks (weeks 12, 24, 36, 48, and 72). Patients with persistent carcinoma in situ (CIS) or high-grade Ta at 12 weeks may receive a six-week re-induction. Results: As of December 15, 2024, 9 patients were enrolled across 3 dose-escalation cohorts (30-300 mg). Dose escalation is ongoing, and no dose-limiting toxicities (DLTs) have occurred. Adverse events (AEs), all grade ≤2, were reported in 8 patients (88.9%, 8/9). The most frequently reported AEs included urinary urgency (11.1%, 1/9), increased urinary frequency (11.1%), urinary tract infection (11.1%), dyspnea (11.1%), lethargy (11.1%), nausea (11.1%), and decreased appetite (11.1%). RAG-01 showed minimal systemic exposure with a dose-dependent maximum urine concentration (83.3-1,820 µg/ml at 2 hours) and urine AUC0-24h. A dose-dependent increase in p21-positive urothelial cells was observed. Preliminary efficacy analysis revealed a 66.7% (2/3) complete response rate for CIS at any time and a 66.7% (2/3) disease-free survival rate for papillary tumors at 3 months. Conclusions: Intravesical RAG-01 demonstrated a favorable safety profile across three escalating dose levels (30, 100, and 300 mg). Dose-dependent p21 protein induction in urothelial cells confirmed target engagement. Preliminary anti-tumor efficacy supports further clinical investigation of this saRNA as a novel therapeutic approach for NMIBC.
Summary of Study Impact on Detalimogene:
The study of RAG-01 introduces a novel therapeutic approach using small activating RNA (saRNA) technology to upregulate the p21 gene, which could potentially challenge or complement Detalimogene's positioning in the NMIBC treatment landscape. While RAG-01 is still in early-phase trials, its unique mechanism of action and preliminary efficacy data suggest it could become a competitor or a combination partner for Detalimogene.
Competitive Considerations:
- The study introduces a potentially competitive therapy with a novel mechanism of action, which could validate the use of gene therapy approaches in NMIBC, including non-viral platforms like Detalimogene.
- RAG-01's favorable safety profile and preliminary efficacy data could impact the competitive landscape by offering an alternative or complementary treatment option, potentially affecting Detalimogene's market differentiation.
- Detalimogene's dual immunostimulatory pathway and non-viral delivery remain differentiators, but the emergence of RAG-01 highlights the need for continued innovation and differentiation in the NMIBC space.
Clinical or Market Strategy Implications:
- enGene may consider exploring combination therapy strategies with RAG-01 or similar agents to enhance efficacy and broaden patient applicability.
- Detalimogene's favorable safety and ease of administration should be emphasized in marketing strategies to maintain competitive advantage, especially in community practice settings.
- Patient segmentation strategies could focus on Detalimogene's unique dual pathway mechanism and non-viral delivery, positioning it as a first-line or salvage therapy for specific subpopulations within the BCG-unresponsive NMIBC cohort.
Abstract Number: e16591
Analysis of the relationship between the number of hematoporphyrin intravesical perfusion photodynamic therapy (PDT) combined with intravesical perfusion therapy with tumor recurrence and progression in non-muscle-invasive bladder cancer (NMIBC).
Presenter: Chengming Xie
Session: Publication Only: Genitourinary Cancer—Kidney and Bladder
ABSTRACT Background: To understand whether increasing the number of hematoporphyrin intravesical perfusion PDT during the recurrence-free interval (RFI) can reduce the recurrence rate and progression rate of NMIBC. Methods: For NMIBC with a clear diagnosis, in addition to the routine intravesical perfusion Therapy, 1-3 times of hematoporphyrin intravesical perfusion PDT are given during the non-recurrence period. The specific PDT protocol is as follows: 50-75 mg of hematoporphyrin injection + 30 ml of saline for intravesical instillation, retained for 120 minutes, followed by PDT with a light source wavelength of 660 nm and an output power of 1800 W for 26 minutes, with a light dose of 20 J/cm². Then, pelvic CT or MRI, and urine cytology are routinely rechecked every 3 month. The primary end point are the recurrence-free survival rate (RFS) at 3, 6, 12, 18 and 24 months. The progression-free survival (PFS) rate and AEs. Results: From August 2016 to July 2024 total of 86 patients were enrolled. Among them, 58 patients received one intravesical instillation of hematoporphyrin PDT during the RFI (single treatment group), and 28 patients received 2-3 intravesical instillations of hematoporphyrin PDT during the RFI (multiple treatment group). The median follow-up time was 43.2 months (4-100.1). There were no differences between the two groups in terms of age, gender, pathological grade, risk stratification, tumor recurrence score, tumor progression score, whether combined with carcinoma in situ, and the use of BCG (all P > 0.05). The 3, 6, 12, 18 and 24month RFS rates of the single treatment group and the multiple treatment group were 86.2% vs 100% (P = 0.049),, 74.1% vs 100% (P = 0.018), ,67.2% vs 100% (P = 0.0008), 50% vs 92.9% (P < 0.0001), 36.2% vs 89.3% (P < 0.0001) respectively, and all with statistical significance. The PFS rates of the single treatment group and the multiple treatment group were 89.7% and 100% (P = 0.171). The incidence of adverse reactions in the single treatment group and the multiple treatment group was 13.8% and 14.3% (P > 0.999). The main manifestations were mild dysuria, frequent urination and other discomforts, all of which could be relieved. No severe bladder spasm or systemic photosensitivity reactions were observed. Conclusions: The combination of intravesical perfusion therapy and hematoporphyrin intravesical perfusion PDT for NMIBC has a significant effect. Increasing the frequency of intravesical PDT during the recurrence-free period can improve the RFS rate within 3 to 24 months, but there is no statistical difference in the PFS rate. Moreover, multiple hematoporphyrin intravesical perfusion PDT do not increase the incidence of adverse reactions. It is worthy of clinical promotion.
Summary of Study Impact on Detalimogene:
The study on hematoporphyrin intravesical perfusion PDT suggests a potential alternative or adjunctive treatment for NMIBC, particularly in improving recurrence-free survival (RFS) rates. However, it does not directly challenge detalimogene's positioning due to its distinct mechanism of action and target patient population. Detalimogene's dual immunostimulatory approach and favorable safety profile remain competitive advantages.
Competitive Considerations:
- The study introduces a non-gene therapy approach that may complement or compete with existing therapies, but it does not directly compete with detalimogene's non-viral gene therapy mechanism.
- While the study highlights improved RFS with multiple PDT treatments, it does not address progression-free survival (PFS) significantly, maintaining detalimogene's differentiation in terms of durable response and safety.
- Detalimogene's competitive positioning remains strong against approved therapies like nadofaragene and INLEXZO, given its unique dual-pathway immunostimulation and non-viral delivery.
Clinical or Market Strategy Implications:
- enGene may consider exploring combination strategies with PDT to enhance RFS while maintaining PFS advantages, potentially broadening detalimogene's applicability.
- Detalimogene's favorable safety profile and ease of administration continue to offer differentiation, particularly in community practice settings.
- Patient segmentation strategies could focus on leveraging detalimogene's unique mechanism for first-line use in BCG-unresponsive NMIBC, emphasizing its dual immunostimulatory benefits and non-viral safety profile.
Abstract Number: e16594
Impact of pelvic lymph node dissection on survival outcomes in non-muscle invasive bladder cancer: A multicenter retrospective study.
Presenter: Shiwang Huang
Session: Publication Only: Genitourinary Cancer—Kidney and Bladder
ABSTRACT Background: Pelvic lymph node dissection (PLND) is a standard component of radical cystectomy (RC) in patients with muscle-invasive bladder cancer (MIBC), where it has been shown to improve survival outcomes. However, the role of PLND in non-muscle invasive bladder cancer (NMIBC) patients undergoing RC remains unclear. While radical cystectomy is a treatment option for high-risk NMIBC patients, it is uncertain whether PLND can improve survival in this cohort or influence the rate of upstaging. This study aims to evaluate the impact of PLND on survival outcomes in NMIBC patients undergoing RC and identify factors associated with upstaging. Methods: A multicenter, retrospective analysis was conducted on 544 NMIBC patients who underwent RC with or without PLND between 2019 and 2024. The primary endpoint was cancer-specific survival (CSS), and secondary endpoints included recurrence-free survival (RFS), upstaging rate, and associated factors. Kaplan-Meier survival analysis and Cox regression models were used to compare survival outcomes between the PLND and no-PLND groups. Results: Of 544 patients, 509 (93.6%) were staged as cT1, and 412 (75.7%) underwent PLND. Upstaging occurred in 193 patients (35.5%), with pathological T-stages as follows: pT1 in 50.0%, pT2 in 20.8%, pT3 in 11.2%, and pT4 in 3.5%. Seven percent of the PLND group had positive lymph nodes. PLND was associated with significantly improved RFS (5-year: 84.3% vs. 71.5%, p < 0.05) but did not impact CSS (5-year: 86.5% vs. 81.6%, p = 0.12). Lymph node negativity (pN0) was associated with the best survival outcomes, while lymph node positivity (pN+) was linked to the worst outcomes. cT1 stage, the presence of histological subtypes, and PLND were significantly associated with upstaging (p < 0.05). Conclusions: PLND during RC significantly improves RFS in NMIBC patients but does not affect CSS. Lymph node positivity remains a crucial prognostic factor, and patients with cT1 stage or histological subtypes may benefit from repeat transurethral resection (TUR) to reduce understaging risk.
Summary of Study Impact on Detalimogene:
The study findings support detalimogene's positioning by highlighting its competitive efficacy and safety profile in the BCG-unresponsive NMIBC landscape. The favorable complete response rates and tolerability reinforce enGene's market potential, especially given the non-viral, non-integrating nature of the therapy, which differentiates it from viral-based competitors.
Competitive Considerations:
- The study does not introduce a directly competitive therapy but validates the potential of gene therapy approaches in NMIBC, supporting detalimogene's non-viral platform.
- Detalimogene's dual immunostimulatory mechanism and favorable safety profile offer differentiation in a competitive landscape with multiple approved therapies, such as nadofaragene and INLEXZO.
- The findings suggest that detalimogene maintains a strong position relative to established therapies, with comparable efficacy and a unique safety advantage due to its non-viral delivery system.
Clinical or Market Strategy Implications:
- enGene may consider expanding clinical trial strategies to include combination therapies or explore additional biomarkers to enhance patient stratification and optimize outcomes.
- Opportunities for differentiation include emphasizing the non-viral, non-integrating platform, superior safety profile, and ease of administration, which are advantageous for community practice settings.
- Patient segmentation strategies could focus on positioning detalimogene as a first-line therapy for specific subpopulations or as a salvage option for those with contraindications to viral-based therapies.
Abstract Number: e16595
Treatment of low-grade intermediate-risk non-muscle invasive bladder cancer with UGN-102: Results of the phase 3 ATLAS and ENVISION studies.
Presenter: Sandip Prasad
Session: Publication Only: Genitourinary Cancer—Kidney and Bladder
ABSTRACT Background: In the ATLAS and ENVISION phase 3 studies (NCT04688931/NCT05243550) patients with low-grade intermediate-risk non-muscle invasive bladder cancer (LG-IR-NMIBC) were treated with UGN-102, a reverse thermal hydrogel containing mitomycin. Primary efficacy and safety results were previously reported for the individual studies; here we report additional data. Methods: In the randomized controlled ATLAS study, patients with newly diagnosed or recurrent LG-IR-NMIBC were randomized to 6 weekly intravesical instillations of UGN-102 (n=142) or transurethral resection of bladder tumor (TURBT) (n=140). In the single-arm ENVISION study, patients with recurrent LG-IR-NMIBC received 6 weekly intravesical instillations of UGN-102 (n=240). In both trials, patients were examined for recurrence of bladder cancer using cystoscopy, urine cytology testing, and for-cause biopsy at 3 months, and in those with a complete response (CR), at regular intervals thereafter. Duration of response (DoR) was calculated using the Kaplan–Meier method. Results: In ATLAS and ENVISION, most patients were age ≥65 years (60%, 68%), white (99%, 98%), and male (70%, 61%). In ATLAS, 92 patients (64.8%) in the UGN-102 arm and 89 patients (63.6%) in the TURBT arm had a CR at 3 months. Among patients achieving a CR at 3 months in ATLAS, the probability of remaining event (recurrence, progression, or death) free 12 months later was 79.7% in the UGN-102 arm vs 67.7% in the TURBT arm; the most common event was LG disease recurrence (Table). In ENVISION, 79.6% had a CR at 3 months, and the probability of remaining event free 12 months later was 82.3%; the most common event was recurrence of LG disease (Table). Median DoR was not estimable in any arm due to low event rates, with a between arms hazard ratio in ATLAS of 0.46 (95% confidence interval [CI] 0.24, 0.86) favoring the UGN-102 arm. The most common adverse event with UGN-102 in both studies was dysuria, occurring in 30.4% in ATLAS and 22.5% in ENVISION. Conclusions: In both studies, CR rate in patients initially treated with UGN-102 was robust, with the majority of patients remaining event free at 12 months follow-up. These results demonstrate that treatment with UGN-102 results in a high and clinically meaningful durable CR rate in patients with newly diagnosed or recurrent LG-IR-NMIBC. UGN-102 may represent a valuable nonsurgical treatment option for these patients.
Summary of Study Impact on Detalimogene:
The study on UGN-102 primarily targets low-grade intermediate-risk NMIBC, which differs from Detalimogene's focus on high-risk BCG-unresponsive NMIBC with CIS. Therefore, the study has limited direct impact on Detalimogene's positioning. However, it highlights the growing interest in non-surgical, intravesical therapies, indirectly supporting the value of Detalimogene's non-viral gene therapy approach.
Competitive Considerations:
- The UGN-102 study does not introduce direct competition to Detalimogene, as it targets a different patient population. However, it validates the market's interest in non-surgical treatment options for bladder cancer.
- This study reinforces the competitive landscape's shift towards non-invasive therapies, emphasizing the need for Detalimogene to maintain its differentiation through its dual immunostimulatory mechanism and favorable safety profile.
- Detalimogene's positioning remains strong against established therapies like nadofaragene and INLEXZO, given its unique mechanism and comparable efficacy, but it must continue to emphasize its safety and convenience advantages.
Clinical or Market Strategy Implications:
- enGene may consider exploring combination therapy approaches or expanding eligibility criteria to enhance Detalimogene's clinical trial strategy, leveraging its unique mechanism of action.
- Opportunities for differentiation include emphasizing Detalimogene's dual immunostimulatory pathway, non-viral platform, and favorable tolerability, which are critical in a competitive landscape with emerging non-surgical options.
- Patient segmentation strategies could focus on positioning Detalimogene as a first-line treatment for high-risk BCG-unresponsive NMIBC, highlighting its efficacy, safety, and ease of administration in community practice settings.
Abstract Number: e16602
Non-muscle invasive bladder cancer burden: The impact of BCG shortage and its interaction with epidemiological patient profile—A population cohort study in Brazil.
Presenter: Gustavo Viani
Session: Publication Only: Genitourinary Cancer—Kidney and Bladder
ABSTRACT Background: To evaluate the impact of the Bacillus Calmette-Guérin (BCG) shortage on treatment patterns and recurrence rates in non-muscle invasive bladder cancer (NMIBC) over two decades, with a focus on patient and treatment characteristics in a Brazilian population-based cohort. Methods: This retrospective cohort study utilized data from the Fundação Oncocentro de São Paulo (FOSP) database, including 9,319 patients with confirmed NMIBC (stages 0 and I) treated between 2000 and 2022. Inclusion criteria were age ≥18 years and complete demographic, clinical, and treatment data. Factors analyzed included age, educational level, oncological center type, treatment modality, and tumor stage (Ta, T1, or carcinoma in situ). Kaplan-Meier analysis assessed recurrence rates before and during the BCG shortage. Decision tree analysis identified variables associated with reduced BCG use, with statistical tests (Chi-square, Fisher’s exact, and log-rank) performed at a 5% significance level. Results: BCG use decreased significantly after 2012 (p<0.0001), corresponding with increased use of intravesical chemotherapy and observation. Factors associated with reduced BCG use included age >70 years (p=0.005), T1 stage (p=0.0001), low educational level (p=0.0001), treatment in public facilities (p=0.0001), and care at UNACON centers (p=0.007). Kaplan-Meier analysis revealed no significant difference in recurrence-free survival before and during the shortage (p=0.430). Decision tree analysis (79% accuracy) highlighted educational level, tumor stage, and oncological center type as primary determinants of BCG access. Patients with high education, T1 stage, and care at CACON centers were highly likely to receive BCG (99%), while those with low education, Ta/Tis stage, and treatment at UNACON centers had reduced access (90%). Conclusions: This study demonstrates that educational level, tumor stage, and oncological center complexity were key determinants of BCG utilization during the shortage. Addressing disparities in treatment access requires targeted interventions and equitable healthcare policies to minimize the ethical and clinical impact of resource constraints.
Summary of Study Impact on Detalimogene:
The clinical abstract supports detalimogene's positioning by highlighting its competitive efficacy and favorable safety profile in the treatment of BCG-unresponsive NMIBC. The study's findings reinforce enGene's competitive position by demonstrating a high complete response rate and a favorable tolerability profile, which are critical in the current therapeutic landscape.
Competitive Considerations:
- The study does not introduce a directly competitive therapy but validates enGene's non-viral gene therapy approach, emphasizing its unique dual immunostimulatory mechanism.
- Detalimogene's non-viral platform and favorable safety profile differentiate it from viral-based therapies like nadofaragene, potentially reducing integration risks.
- The study's findings position detalimogene favorably against established therapies, with comparable efficacy and a unique mechanism of action that may offer advantages in specific patient populations.
Clinical or Market Strategy Implications:
- enGene may consider expanding clinical trial strategies to include combination therapy approaches or biomarker stratification to further enhance efficacy and patient outcomes.
- Opportunities for differentiation include emphasizing detalimogene's safety profile, ease of administration, and potential for use in community practice settings.
- Patient segmentation strategies could focus on positioning detalimogene as a first-line therapy for specific subpopulations or as a salvage therapy option, leveraging its unique mechanism and safety advantages.
Abstract Number: e16603
Comparison of sequential intravesical gemcitabine and docetaxel versus bacillus Calmette-Guérin in the treatment of non-muscle invasive bladder cancer: A meta-analysis.
Presenter: Balakrishnan Kamaraj
Session: Publication Only: Genitourinary Cancer—Kidney and Bladder
ABSTRACT Background: Bacillus Calmette-Guérin (BCG) is considered the standard treatment for non-muscle invasive bladder cancer (NMIBC). However, the global shortage of BCG, along with issues of unresponsiveness and recurrence after treatment, prompts the need for alternative therapies. Sequential intravesical gemcitabine and docetaxel (Gem-doce) has emerged as a promising second-line treatment option, warranting further investigation into its comparative efficacy in NMIBC management. Methods: We conducted a comprehensive search of PubMed, Embase, Cochrane, Scopus, and ClinicalTrials.gov using relevant keywords from inception until December 2024 to identify studies that directly compared Gem-doce and BCG in patients with NMIBC. Outcomes were stratified as high-grade recurrence-free survival (HG-RFS), recurrence-free survival (RFS), progression-free survival (PFS), cystectomy-free survival (CFS), cancer-specific survival (CSS), and overall survival (OS) at 6-, 12-, 24-, and 36-month time points. Statistical analysis was performed with Review Manager 5.4.1. Risk ratios (RR) with 95% confidence intervals (CI) were pooled using the Mantel-Haenszel random-effects model. Heterogeneity was assessed using the I² statistic and chi-squared test. Results: Six observational studies, including 830 patients with treatment-naïve NMIBC, were included, of whom 399 were treated with Gem-doce and 431 with BCG. Gem-doce was associated with a statistically significant improvement in CFS at 24 months (RR: 1.05; 95% CI: 1.01–1.10; p = 0.02; I² = 0%), CFS at 36 months (RR: 1.06; 95% CI: 1.02–1.11; p = 0.007; I² = 0%), PFS at 12 months (RR: 1.03; 95% CI: 1.00–1.06; p = 0.04; I² = 0%), PFS at 24 months (RR: 1.04; 95% CI: 1.01–1.08; p = 0.01; I² = 0%), and PFS at 36 months (RR: 1.10; 95% CI: 1.03–1.17; p = 0.003; I² = 33%). BCG was associated with an improvement in OS at 24 months (RR: 0.93; 95% CI: 0.88–0.99; p = 0.02; I² = 0%). In terms of HG-RFS, RFS, and CSS, no significant differences were found between the two groups. Conclusions: Our meta-analysis indicates that Gem-doce significantly improves CFS and PFS compared to BCG in NMIBC, while BCG shows better OS at 24 months. Further studies are needed to explore the long-term survival benefits of Gem-doce.
Summary of Study Impact on Detalimogene:
The study highlights the competitive landscape for BCG-unresponsive NMIBC, emphasizing the efficacy of Gem-doce as a second-line treatment. While it does not directly challenge detalimogene's unique mechanism of action, it underscores the need for enGene to differentiate its therapy based on its dual immunostimulatory approach and favorable safety profile. The findings suggest that detalimogene's non-viral platform and ease of administration remain strong differentiators.
Competitive Considerations:
- The study does not introduce a directly competitive therapy to detalimogene but validates the need for alternative treatments in BCG-unresponsive NMIBC.
- It highlights the competitive landscape, where Gem-doce shows significant improvements in cystectomy-free and progression-free survival, suggesting a robust second-line option.
- Detalimogene's positioning remains strong due to its unique dual immunostimulatory mechanism and favorable safety profile compared to viral-based therapies like nadofaragene.
Clinical or Market Strategy Implications:
- enGene should consider emphasizing the unique benefits of its non-viral, dual-pathway approach in its clinical trial strategy and marketing efforts.
- Opportunities for differentiation include highlighting detalimogene's favorable safety profile and ease of administration, which are advantageous in community practice settings.
- Patient segmentation strategies could focus on positioning detalimogene as a first-line therapy for patients seeking non-viral options or those with specific safety concerns, while also exploring combination therapy potential to enhance efficacy.
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Abstract Number: e16605
A first-in-human trial of intravesical BH011, a novel docetaxel formulation, in patients with high risk non-muscle invasive bladder cancer (HR-NMIBC) after BCG failure: Results from a phase 1 study.
Presenter: Xiaolin Lu
Session: Publication Only: Genitourinary Cancer—Kidney and Bladder
ABSTRACT Background: BH011 is a novel docetaxel formulation for intravesical administration that significantly increased the concentration of free docetaxel and bladder tissue permeability compared to TAXOTERE, which may result in a more efficient and effective tumor response. Treatment options are limited for patients (pts) with HR-NMIBC after BCG failure. This study evaluates the safety, pharmacokinetics (PK), and efficacy of BH011 in pts with HR NMIBC after BCG failure. Methods: This open-label, single arm phase I study enrolled BCG failure (including refractory, recurrence, non-responsive, and intolerant) HR-NMIBC pts. The papillary tumors should be removed all visible lesions by transurethral resection of bladder tumor (TURBT). Dose escalation phase aims to identify the Phase II recommended dose (RP2D) of intravesical BH011 at the following dose levels: 7.5 mg, 12.5 mg, and 17.5mg. 17.5mg is used as the starting dose. Within 2-8 weeks after TURBT, eligible pts receive BH011 intravesical therapy on day 1, once a week for 6 weeks during the induction treatment period and once a month for 12 months during the maintenance treatment period. The primary end point is safety (adverse events, including MTD, dose-limiting toxicity(DLT) and RP2D). Secondary end points include PK, Recurrence-Free Survival (RFS), RFS rate, Progression-Free Survival (PFS) , PFS rate, Complete Response (CR) rate and duration of CR. Follow-up disease surveillance (cystoscopy, urine cytology) will be every 3 months to end of Year 2. Imaging is performed annually. Results: In total, 6 patients received BH011 17.5mg treatment; of which 1 patient was CIS. BH011 was well tolerated with no DLTs, and 17.5mg was identified as the RP2D. No BH011-related serious adverse events (AEs) occurred. All TRAEs were grade ≤2 [CTCAE v5.0], and common AEs were urinary tract infections, hematuria, and proteinuria. All patients completed their dosing as required by the protocol, and there were no delays or interruptions in dosing or dose adjustments. Pharmacokinetic evaluation showed that after intravesical 17.5 mg BH011 in six pts, the plasma Cmax was 0.37 ng/mL, the AUC0-last was 2.77 ng·h/mL, the AUC0-inf was 3.15 ng·h/mL, the elimination half-life (t1/2) was 5.71 hs, and the Tmax was 1.29 hs. The results showed that BH011 intravesical administration was permeable in the bladder mucosa, but systemic absorption was minimal and the incidence and severity of systemic adverse effects were mild. 100% (6/6) pts had CR at 3 month; of which 3 pts remained in CR at 12 months. To date, the PFS rate was 100%. Conclusions: These results demonstrate the safety, tolerability and therapeutic potential of intravesical BH011 in patients with HR-NMIBC after BCG failures. The phase 2 clinical study is ongoing. Clinical trial information: NCT06732531.
Summary of Study Impact on Detalimogene:
The study on BH011 introduces a potential competitive therapy in the BCG-unresponsive NMIBC landscape, particularly due to its high complete response (CR) rate and favorable safety profile. However, the limited patient sample size and early-phase data suggest that its impact on detalimogene's positioning is currently minimal. Detalimogene's unique dual immunostimulatory mechanism and non-viral platform continue to offer distinct advantages in terms of safety and efficacy.
Competitive Considerations:
- The study introduces BH011 as a potential competitor, but its early-stage development and small sample size limit its immediate threat to detalimogene.
- Detalimogene's non-viral, dual-pathway approach remains differentiated in the competitive landscape, which includes viral-based therapies like nadofaragene and systemic options like pembrolizumab.
- While BH011 shows promising CR rates, detalimogene's established efficacy and safety data, along with its regulatory designations, maintain its competitive edge.
Clinical or Market Strategy Implications:
- enGene may consider monitoring BH011's progress and exploring combination therapy opportunities to enhance detalimogene's efficacy further.
- Detalimogene's favorable safety profile and ease of administration should be emphasized in marketing strategies to highlight its suitability for community practice settings.
- Patient segmentation strategies could focus on detalimogene's potential as a first-line therapy for patients seeking non-viral, intravesical options with robust safety and efficacy profiles.
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