Background

Muscle invasive bladder cancer (MIBC) can be cured by radical cystectomy (RC), but recurrence rates are high and 5-year (yr) survival is ± 50%. We recently found that pre-operative ipilimumab (ipi) plus nivolumab (nivo) resulted in a pathological complete response (pCR) of 46% at RC.

RC however has a high risk of morbidity and even mortality. Chemoradiotherapy (CRT) is a bladder-sparing alternative with cure rates comparable to RC. Given the high pCR to pre-operative checkpoint inhibition (CPI), CRT instead of RC as local treatment may be feasible even in high-risk patients (pts) who receive CPI.

Trial design

INDI-BLADE is a phase 2 trial in which 50 adult pts with cT2-4aN0-2M0 MIBC are treated with three cycles CPI (ipi 3mg/kg (3) – ipi 1mg/kg (1) plus nivo 3 – nivo 3), followed by CRT with mitomycin C plus 5-FU or capecitabine (an oral prodrug for 5-FU) and concurrent RT. Response is evaluated by a CT chest-abdomen, a multiparametric MRI (mpMRI) of the bladder and cystoscopy. The primary endpoint is the bladder-intact event-free survival (EFS). Events are defined as death by any cause, muscle-invasive-, upper urinary tract-, nodal- or distant recurrence, cystectomy, or switch to cisplatin-based chemotherapy. Assuming a tumor stage distribution of 30% cT2N0M0, 40% cT3-4aN0M0 and 30% N+M0, we aim to achieve a 70% EFS at two yr, based on the pCR of 46% in the NABUCCO study. With a sample size of n=50, we expect to reach a median survival of 46.6 months, assuming a median survival of 24 months in the historical control group (81.32% power; 5% significance level). Key secondary endpoints include overall survival, relapse-free survival, and safety. In addition, we will explore the potential of mpMRI-bladder to detect nonresponse, and we will search for potential biomarkers to predict response to treatment.

Clinical trial identification

NCT05200988, Release date: January 21, 2022.

Legal entity responsible for the study

Netherlands Cancer Institute.

Funding

Bristol Meyer Squibb and KWF (public funding).

Disclosure

B.W.G. van Rhijn: Financial Interests, Personal, Advisory Board: Ferring, QED therapeutics. J. Boormans: Financial Interests, Institutional, Advisory Role: Merck, MSD, Janssen, Bristol Myers Squibb, Astellas, AstraZeneca, Eight Medical, AMBU, Roche; Financial Interests, Institutional, Funding: Janssen, Decipher, Merck. R. Meijer: Financial Interests, Institutional, Advisory Role: Merck, MSD, Janssen, Bristol Myers Squibb; Financial Interests, Institutional, Funding: Janssen, Astellas, Roche. D. Robbrecht: Financial Interests, Other: Merck AG, Pfizer, Bayer, AstraZeneca, Treatmeds. B.B. Suelmann: Financial Interests, Personal and Institutional, Advisory Role: Pfizer, MSD, BMS, Novartis, Ipsen; Financial Interests, Institutional, Research Grant: Pfizer, Astellas, BMS. M.S. van der Heijden: Financial Interests, Institutional, Advisory Board: AstraZeneca, BMS, Janssen, MSD, Pfizer, Seagen; Non-Financial Interests, Institutional, Other, Investigator-initiated trial: 4SC; Non-Financial Interests, Institutional, Other, Steering Committee Member, Local PI + SSC member: Astra Zenenca, BMS; Non-Financial Interests, Institutional, Funding, Investigator-initiated trial: AstraZeneca, BMS, Roche; Non-Financial Interests, Institutional, Principal Investigator, Local PI: GSK, Seagen; Non-Financial Interests, Institutional, Other, Steering committee member, local PI + study co-PI: Janssen. All other authors have declared no conflicts of interest.

Background

Radical cystectomy (RC) is standard care for patients with muscle invasive bladder cancer (BC) or highest-risk non-muscle invasive BC. However, optimal care for bladder preservation or intolerance to RC remains uncertain. Atezolizumab, a programmed death-ligand 1 (PD-L1) inhibitor with synergistic antitumor activity along with radiation therapy (RT), is a promising treatment.

Methods

In this multicenter, phase 2 trial, we recruited patients with clinical (c)T1-3N0M0 invasive BC who were unfit for or refused RC. Patients received RT (41.4 Gy in 23 fractions to the small pelvis and 16.2 Gy in 9 fractions to the whole bladder) combined with intravenous atezolizumab 1200mg every 3 weeks. After 24 treatment weeks, response was assessed using CT imaging and transurethral bladder resection. The secondary endpoint, pathological complete response (pCR), was evaluated before the primary endpoint (progression-free survival rate). Tumor PD-L1 expression was assessed using the tumor-infiltrating immune cell (IC) score.

Results

Forty-five patients enrolled between January 2019 and May 2021 were analyzed. The most common cT stage was T2 (73.3%), followed by T1 (15.6%) and T3 (11.1%). Most tumors were single (77.8%) or small (<3cm) (57.8%), with no concomitant carcinoma in situ (CIS) (88.9%). Thirty-eight patients (84.4%) achieved pCR after 24 weeks of treatment. Patients with high PD-L1 expression (IC score >1) had higher pCR rates than those with low expression (IC score 0) (95.8% vs. 71.4%), with low rates (60.0%) in patients with CIS. Adverse events (AEs) were observed in 93.3% of patients and the most common were diarrhea (55.6%), followed by pollakiuria (42.2%) and dysuria (20.0%). The frequency of grade 3 AEs was 13.3%, with no grade 4 events.

Conclusions

RT combined with atezolizumab resulted in a favorable high proportion of pCR with acceptable toxicity. This protocol will provide a promising new alternative for bladder preservation in BC patients.

Clinical trial identification

jRCT2031180060.

Legal entity responsible for the study

Hiroyuki Nishiyama.

Funding

Chugai Pharmaceutical.

Disclosure

T. Kimura: Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical. T. Naiki: Financial Interests, Personal, Funding: Takeda Science Foundation. J. Inokuchi: Financial Interests, Institutional, Principal Investigator: Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd. K. Hashimoto: Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, Ono Pharmaceutical. H. Nishiyama: Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Advisory Board: MSD, Lilly, Bayer, Janssen Pharmaceutical, Chugai Pharmaceutical; Financial Interests, Personal, Speaker’s Bureau: MSD, Chugai Pharmaceutical, Olympus; Financial Interests, Institutional, Research Grant: Astellas Pharma, Ono Pharmaceutical, Takeda Pharmaceutical, Bayer. All other authors have declared no conflicts of interest.

Background

Anlotinib is a potent oral, multi-target tyrosine kinase inhibitor with a favorable safety which mainly targets vascular endothelial growth factor receptor (VEGFR), FGFR, platelet-derived growth factor receptors, and c-kit. This study aims to investigate the role of anlotinib in bladder cancer compared with FGFR3 inhibitor erdafitinib in vitro and in vivo.

Methods

MTT, colony formation, and Transwell assays were performed on bladder cancer cells (SW780 and UMUC14) to confirm the effects of anlotinib and erdafitinib on proliferation, migration and invasion. Apoptotic effect was evaluated by Annexin V/propidium iodide double staining, and the levels of the protein and mRNA were examined by RNA-seq, Western blotting and RT-qPCR. Finally, mice with palpable xenografts were treated either with anlotinib and erdafitinib for 8 days before they were sacrificed for measuring the sizes and weights of the tumors.

Results

To assess the roles of anlotinib in bladder cancer, we treated SW780 cell line which had FGFR3-BALAP2L1 fusion mutation and UMUC-14 cell line which had a FGFR3 (MuS247C) mutation with DMSO, anlotinib and erdafitinib. As seen in MTT, colony formation and Transwell assays, anlotinib repressed cell proliferation, migration and invasion as erdafitinib. Compared with vehicle, Anlotinib promoted cell apoptosis of bladder cancer cells. To further explore the mechanism, anlotinib and erdafitinib suppressed p-Erk1/2 and p-AKT, while only anlotinib inhibited the expression of VEGF-a. Compared with erdafitinib, the inhibitory ability of anlotinib was weaker than that of erdafitinib in cell line with FGFR3 (MuS247C) mutation, on the contrary, it was much stronger in cell line with FGFR3-BALAP2L1 fusion mutation. In addition, the in vivo data from xenagrafts also supported that anlotinib could significantly repress tumor growth with FGFR3 fusion mutation.

Conclusions

Anlotinib could repress the proliferation, migration and invasion of bladder cancer cells by inhibiting the phosphorylation of Erk1/2 and AKT, and the suppression VEGF-a expression, whose effects was better than erdafitinib in bladder cancer with FGFR3 fusion mutation. Therefore, anlotinib might be a potential novel targeted agent to treat the bladder cancer patients with FGFR3 fusion mutations.

Clinical trial identification

ALTER-UC-002.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

High-risk non-muscle invasive bladder cancers (HRNMIBC), including TaG3, T1G2, T1G3, and/or Tis, carry an increased risk of progression, recurrence, and even death. The commonly used therapeutic approaches are TURBT+BCG or radical cystectomy (RC). So far, there have been no randomized clinical trials comparing the efficacy of these two different modalities. However, there continue to be some concerns regarding the long-term outcomes of the bladder preserving approach. Therefore, we conducted this meta-analysis to compare the relative risk (RR) of cancer-specific and all-cause death rates between TURBT+BCG and RC in HRNMIBC.

Methods

A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language, diagnosis of HRNMIBC, comparative studies using TURBT+BCG versus RC, and studies that reported the incidence of all cause and cancer-specific death rates. A meta-analysis using the fixed effects and random effects models was conducted.

Results

Three retrospective comparative studies with 4,734 patients were included and analyzed. All studies reported cancer-specific and all-cause death rates of TURBT+BCG versus RC in HRNMIBC. TURBT+BCG were found to have significantly lower RR of cancer-specific death in patients with HRNMIBC (RR=0.51, 95%CI 0.31-0.82), which continued to be significant even when using a propensity adjusted subgroup provided by one of the studies for analysis. Moreover, there was also a significantly lower RR of all-cause death rates in the TURBT+BCG group (RR=0.72, 95%CI 0.65-0.80). The rate of delayed cystectomies in the TURBT+BCG group was 22% (95%CI: 8-41).

Conclusions

This is the first meta-analysis showing that TURBT+BCG is associated with a lower relative risk of cancer-specific and all-cause death compared to RC in patients with HRNMIBC. In the absence of randomized clinical trials and the failure of the BRAVO feasibility study to accrue, this meta-analysis represents the most compelling data supporting the use of TURBT+BCG in this patient population.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

As a key regulator of hippo signaling pathway, LATS1 (large tumor suppressor 1) gene encodes a Ser/Thr protein kinase which plays a crucial role in cellular transformation and tumorigenesis. But it remains to be determined if LATS1 mutation may have true biologic relevance and can independently predict responses to immune checkpoint inhibitors (ICIs). Our research aims to elucidate its mutation association with ICI efficacy.

Methods

In order to investigate the correlation between LATS1 mutation and ICI efficacy in the bladder cancer, we used cBioportal to collect clinical and mutation data of 215 ICI-treated bladder cancers from MSKCC cohort. Gene expression and WES data of 413 samples were obtained from the TCGA database for further analysis of the differences of potential biological mechanisms between LATS1-mutant and LATS1-wildtype tumors. Tumor mutation burden (TMB) was calculated as the total number of somatic non-synonymous mutations per megabase in both MSKCC and TCGA cohorts. CIBERSORT algorithm was applied to infer 22 human immune cell type proportions in TCGA advanced bladder cancers.

Results

In the MSKCC cohort, we observed 5.12% (11/215) patients harbored LATS1 mutation. As indicated by Kaplan-Meier analysis, the patients with LATS1 mutation had significantly better OS in the MSKCC cohort (P = 0.023, HR = 0.23, 95%CI: 0.06-0.93). This link was still existing when controlling for age, sex, stage, TMB and therapy type in the multivariate Cox regression analysis (P = 0.039, HR = 0.22, 95%CI = 0.05-0.93). As expected, the LATS1-mutant group had higher TMB than that of the LATS1-wildtype group in both the MSKCC cohort (median: 27.55 vs. 7.87, P <0.001) and TCGA cohort (median: 7.74 vs. 4.62, P = 0.042). Immune cell analysis showed that NK activated cells were abundant in the LATS1-mutant group (P = 0.05). This result indicated LATS1-mutant tumors had an activated antitumor immune microenvironment.

Conclusions

LATS1 mutations might be a potential biomarker to predict the efficacy of immunotherapy for bladder cancer. Considering the heterogeneity among the patients and other confounding factors, further prospective validation cohorts are warranted.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Urinary tumor DNA profiling is promising for the diagnosis, monitoring, and treatment stratification of bladder cancer. However, previous studies are mainly using a targeted panel next-generation sequencing (NGS) approach, which is limited to predefined genes and thus lacks comprehensiveness. Here, we apply the boosted whole-exome sequencing (WES) to urinary and tissue tumor DNA in muscle-invasive bladder cancer (MIBC) to comprehensively compare the mutation profiles in matched urine and tissue samples.

Methods

Matched tumor tissue, urine and peripheral blood mononuclear cells (PBMC) samples were collected from twenty MIBC patients. Nineteen tumor tissue, nineteen urine and twenty PBMC samples passed sample quality control were processed for NGS. PredicineWES+, an NGS assay with whole-exome coverage and boosted coverage in 600 cancer-related genes from the PredicineATLAS panel, was applied to tumor, urine and PBMC samples for mutation profiling. Mutation profiles of tumor tissue and urinary DNA were analyzed and compared.

Results

Mutation profiles of urinary and tissue tumor DNA were highly concordant across patients, with frequently mutated genes (TERT, TP53, KMT2D, ARID1A, PIK3CA, FGFR3, etc.) displaying comparable prevalence. Cancer cell fractions (CCFs) inferred from paired urine (2-52%) and tumor tissue (17-68%) showed significant difference (p < 0.05). Though CCFs in urine were relatively lower, more somatic mutations were detected in urine than in tumor tissue (p < 0.05). Clonal analysis suggested multiple subclones likely existed for patients with more mutations in urine than matched tissue samples.

Conclusions

This study demonstrates the effectiveness of urinary tumor DNA as a tissue surrogate for mutation profiling in MIBC at the whole-exome scale, supporting urine-based noninvasive molecular profiling in precision medicine for patients with bladder cancer. PredicineWES+ assay enables accurate detection of subclonal mutations from urine samples and enables the detection of urine-based personalized minimal residual diseases (MRD) in MIBC.

Legal entity responsible for the study

Shanghai Jiao Tong University School of Medicine.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

In the phase 3 JAVELIN Bladder 100 trial (NCT02603432), patients (pts) with aUC that had not progressed with 1L platinum-based chemotherapy had significantly prolonged overall survival and progression-free survival with avelumab 1L maintenance + best supportive care (BSC) compared with BSC alone. Results led to avelumab 1L maintenance being approved worldwide and adopted into international treatment guidelines as standard of care. Here, we report long-term data from pts with ≥12 mo of avelumab 1L maintenance treatment as part of the JAVELIN Bladder 100 trial.

Methods

Eligible pts had unresectable locally advanced or metastatic UC that had not progressed with 1L platinum-based chemotherapy. This analysis included pts randomized to receive avelumab + BSC. Study treatment continued until confirmed progression, unacceptable toxicity, or withdrawal of consent.

Results

After a median follow-up of 38.0 mo in the avelumab arm (data cutoff June 4, 2021; ≥2 y in all pts), 118/350 pts (33.7%) had received ≥12 mo of treatment. Characteristics of these pts were similar to those in the overall avelumab arm (Table). Among all treated pts in the overall avelumab arm (N=344), grade ≥3 treatment-related adverse events (TRAEs) occurred in 67 (19.5%) and grade ≥3 immune-related AEs (irAEs) occurred in 26 (7.6%). Among pts treated for ≥12 mo (n=118), grade ≥3 TRAEs occurred after ≥12 mo in 14 (11.9%) and grade ≥3 irAEs occurred after ≥12 mo in 5 (4.2%). Efficacy outcomes will be presented.

Conclusions

In the JAVELIN Bladder 100 trial, prolonged avelumab 1L maintenance treatment was associated with a safety profile consistent with prior avelumab monotherapy studies, with no new safety signals identified with longer treatment duration. These results further support the use of avelumab 1L maintenance until progression for pts with aUC that has not progressed with 1L platinum-based chemotherapy. Table: 1760P

Clinical trial identification

NCT02603432; first posted, November 11, 2015.

Editorial acknowledgement

Full writing support to be disclosed - Medical writing support was provided by Jamie Ratcliffe of ClinicalThinking, and was funded by Pfizer as part of an alliance between Pfizer and Merck (CrossRef Funder ID: 10.13039/100009945).

Legal entity responsible for the study

Pfizer, as part of an alliance between Pfizer and Merck.

Funding

Pfizer, as part of an alliance between Pfizer and Merck (CrossRef Funder ID: 10.13039/100009945).

Disclosure

J.B. Aragon-Ching: Financial Interests, Personal, Advisory Role: Pfizer, Merck, MSD, Immunomedics, AVEO, Exelixis, Janssen, AZD; Financial Interests, Personal, Speaker’s Bureau: BMS, Astellas, Seattle Genetics, Pfizer, Merck. P. Grivas: Financial Interests, Personal, Advisory Role: AstraZeneca, Astellas Pharma, Bayer, Bristol Myers Squibb, Dyania Health, Merck, Exelixis, Foundation Medicine, Genentech/Roche, Genzyme, GlaxoSmithKline, Guardant Health, Gilead Sciences, Infinity Pharmaceuticals, Janssen, Lucence Health, MSD, Mirati Therapeutics, Pfizer, QED Therapeutics, Regeneron Pharmaceuticals, Seattle Genetics, SilverBack Therapeutics, UroGen, 4D Pharma PLC; Financial Interests, Institutional, Research Grant: Bavarian Nordic, Bristol Myers Squibb, Clovis Oncology, Debiopharm, Merck, G1 Therapeutics, Gilead Sciences, GlaxoSmithKline, MSD, Mirati Therapeutics, Pfizer, QED Therapeutics. Y. Loriot: Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, Bristol Myers Squibb, Gilead, Janssen, Merck, MSD, Pfizer, Roche, Seattle Genetics, Tahio, Basilea; Financial Interests, Institutional, Principal Investigator: Astellas, AstraZeneca, Exelexis, Gilead, Incyte, Janssen, Merck, MSD, Pfizer; Financial Interests, Institutional, Research Grant: Celsius, Janssen, MSD, Roche, Sanofi; Financial Interests, Institutional, Advisory Board: Gilead/Immunomedics, Janssen, MSD. J. Bellmunt: Financial Interests, Personal, Other, Honoraria: Pfizer, Merck, BMS, AstraZeneca, Pierre Fabre; Financial Interests, Institutional, Other, Honoraria: Takeda, MSD; Financial Interests, Personal, Advisory Role: Pfizer, Merck, BMS, AstraZeneca, Roche/Genentech, Pierre Fabre; Financial Interests, Institutional, Research Grant: Takeda, Pfizer; Financial Interests, Personal, Other, Travel/Accommodations/Expenses: Pfizer; Financial Interests, Personal, Royalties: UpToDate. J. Wang: Financial Interests, Personal, Full or part-time Employment: Pfizer. E. Michelon: Financial Interests, Personal, Full or part-time Employment: Pfizer. A. di Pietro: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. T.B. Powles: Financial Interests, Personal, Advisory Role: Bristol Myers Squibb, Merck, AstraZeneca, Ipsen, Pfizer, Novartis, Incyte, Seattle Genetics, Roche, Exelixis, MSD, Astellas Pharma, Johnson & Johnson, Eisai; Financial Interests, Personal, Other: Pfizer, MSD, AstraZeneca, Roche, Ipsen; Financial Interests, Personal, Research Grant: AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Ipsen, Merck, MSD, Novartis, Pfizer, Seattle Genetics, Astellas Pharma, Johnson & Johnson, Eisai. S. Sridhar: Financial Interests, Personal, Advisory Role: Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, MSD, Hoffmann-La Roche, Immunomedics, Ipsen, Janssen, Merck, Pfizer, Seagen, Seattle Genetics; Financial Interests, Personal, Research Grant: Bayer, Janssen, Seagen.

Background

The CREB-binding protein (CREBBP) is known to modify histones, as well as non-histone proteins, thereby regulating chromatin accessibility and transcription. Recently, it has been found to acetylate key factors involved in DNA replication, and in different DNA repair processes. Here we explored the relationship between CREBBP mutation and its efficacy of immune checkpoint inhibitors (ICIs).

Methods

215 advanced bladder cancers with next-generation sequencing (NGS) and immunotherapy data obtained from MSKCC cohort were used to explore the association between CREBBP mutation and efficacy of ICIs and tumor mutation burden (TMB). TMB was defined as the total number of somatic nonsynonymous mutations in the coding region. In addition, 413 bladder cancers of TCGA database were used to explore the relationship of CREBBP mutation and TMB. The potential mechanism was explored through RNA data by CIBERSORT in advanced bladder cancers of TCGA database.

Results

In total, 13.95% (30/215) patients in MSKCC cohort harbored CREBBP mutation. In the TCGA cohort, the mutation ratio (12.11%, 50/413) was similar to MSKCC. The TMB level of CREBBP mutation group in MSKCC cohort was significantly higher than wild-type group (Median [IQR]:15.72[12.27-36.40] vs. 7.02 [4.92-14.04], P<0.001). In TCGA cohort, CREBBP mutation patients also had higher TMB (Median [IQR]: 6.00[3.74- 8.66] vs. 4.54[2.52-8.20], P=0.077), although significant difference was not observed. The overall survival (OS) of mutation group was significantly longer than wildtype group (HR [95%CI]: 0.42[0.21-0.88], P=0.017). The Cox proportional-hazards regression demonstrated that CREBBP mutation was significantly associated with better OS (HR [95%CI]: 0.43[0.20-0.92], P=0.030), adjusting for age, gender, metastases or primary, TMB and treatment options. Also, we used CIBERSORT to investigate infiltration of immune cells, but significant difference was not observed.

Conclusions

CREBBP mutation shows a favorable link between CREBBP mutation with efficacy of ICIs. Furthermore, validation of the predictive value of CREBBP in prospective trials and more fundamental exploration are needed in future.

Legal entity responsible for the study

The First Affiliated Hospital of Xiamen University.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Radical cystectomy (RC) is the standard of care for MIBC and MIBC-HR in France. No French data is published for MIBC and MIBC-HR pts, particularly in the adjuvant setting. The objectives of this study were to describe the characteristics and the management of MIBC-HR pts who had RC in France and to estimate their disease-free survival (DFS) and overall survival (OS).

Methods

Pts aged 18+ years with MIBC who had RC from October 2012 to June 2018 were selected from the French multicenter (n=14) prospective cohort on bladder cancer (COBLAnCE cohort). Pts with metastatic disease at RC were excluded. Pts were classified as MIBC-HR if they were staged pT3-pT4a; or ypT2-ypT4a; or (y)pN+. DFS was defined as the time between RC and the first disease recurrence or death from any cause; OS was defined as the time between RC and death from any cause, both calculated using Kaplan-Meier method.

Results

Among the 431 MIBC pts selected, 59.4% were MIBC-HR (n=256). Of these, 204 pts were men (79.7%); median age at diagnosis was 68 years (yrs). Most MIBC-HR pts were a current or former smoker (n=201, 78.5%). For staging, 226 pts were (y)pT3a or higher (88.3%) and 132 were N- (51.6%). The distribution of treatment strategies was 54.7% RC alone (n=140), 27.0% RC + adjuvant chemotherapy (AC) (n=69), 16.0% neoadjuvant chemotherapy (NAC) + RC (n=41), 2.0% both NAC and AC (n=5), and 0.3% NAC + radiotherapy (n=1). The use of AC was steady over the study period. Among pts with AC only, 86.8% received cisplatin-based therapy (n=59). In total, 175 pts (68.3%) had experienced an event up to the end of follow-up. With a median follow-up of 5.0 yrs, outcomes for patients with MIBC-HR and MIBC-HR without AC were as follows (all respectively): median DFS = 1.3 yrs [95% confidence interval (CI), 1.0-1.6] and 1.2 yrs [95% CI, 0.7-1.5], 2-year DFS = 39.9% [95% CI, 33.9-46.1] and 37.9% [95% CI, 31.0-45.4], median OS = 2.3 yrs [95% CI, 1.8-3.1] and 2.1 yrs [95% CI, 1.6-2.7], 5 yr OS = 33.2% [95% CI, 27.1-40.0] and 29.6% [95% CI, 22.7-37.7].

Conclusions

This study provides new information regarding the use of AC in France and the substantial burden of MIBC-HR pts with poor DFS and OS after RC with curative intent, whatever the AC status.

Legal entity responsible for the study

The authors.

Funding

Bristol Myers Squibb.

Disclosure

F.P. Colrat: Financial Interests, Personal, Full or part-time Employment, HEOR Manager: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Theradiag, Valbiotis, Ose Immuno, Mediantechnologies. J. Bonastre: Financial Interests, Personal, Advisory Board, Health economic board in bladder cancer: BMS; Financial Interests, Institutional, Funding, Funding of the MICADO study: BMS. S. Teitsson, A. Prudent: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. S. Branchoux: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. S. Benhamou: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Sponsor/Funding: BMS. Y. Allory: Financial Interests, Personal, Invited Speaker: BMS, MSD. T. Lebret: Financial Interests, Personal, Other, Congress: BMS, Ferring. All other authors have declared no conflicts of interest.

Background

The approval of immune checkpoint inhibitors (ICIs) in metastatic urothelial cancer (mUC) has changed treatment landscape. Outcomes for patients remain poor. Many patients progress on first line chemotherapy and don’t receive ICI. Here we compare outcomes for patients according to sequencing of therapies.

Methods

This retrospective audit was performed at Barts Cancer Institute for consecutive patients from January 2010 until March 2022. The primary objective was to determine the outcome of patients and exposure to systemic therapy.

Results

252 patients with bladder and upper tract cancers were included. 239 patients received 1^st line systemic therapy for metastatic UC (94%) and other bladder cancer histologies (6%).74% of patients were male. Median age was 50 years (range 28-85). 36% had visceral metastases at diagnosis. Median PFS and OS for UC was 7.5 months and 18.5 months, compared to 4.2 months and 10.1 months in those that had non-UC. Chemotherapy was the most common 1^st line therapy. Response rates to first line therapy for UC was 46%. Median number of cycles of chemotherapy was 5. The most common 2nd line therapy for UC was ICI (65%), with a RR of 26% (20% is expected). Median number of cycles of ICI was 5.5. 33% of patients with UC received 3^rd line therapy of any kind, with a RR of 33%. Chemotherapy was the most common 3^rd line therapy (53%). Overall, 8% of UC patients received targeted therapy. Baseline visceral metastases and performance status is associated with poor outcome. Only 64% and 14% of patients with non-UC tumours received 2^nd or 3rd line therapy, respectively.

Conclusions

The introduction of ICIs, antibody drug conjugates and targeted therapy have had an impact on the treatment landscape, although many patients are not able to receive subsequent therapy. Prognostic outcomes such as visceral metastases determine outcome, irrespective of treatment type.

Legal entity responsible for the study

Thomas Powles.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

We hypothesise that the addition of pembrolizumab (pembro) may be safe and improve efficacy in patients (pts) with MIBC treated with chemoradiotherapy (CRT).

Methods

This multicentre phase 2 trial included pts with non-metastatic cT2-T4aN0M0 MIBC (>50% TCC histology) who declined cystectomy or for whom cystectomy was unsuitable, with no contraindications to CRT or pembro, ECOG performance status 0 or 1, eGFR ≥40 mL/min. Neoadjuvant chemotherapy was not permitted. Pts had maximal TURBT, then whole bladder radiation therapy (RT) (64Gy in 32 daily fractions, mostly IMRT) over 6.5 weeks with weekly cisplatin (35 mg/m2 IV, 6 doses) and pembro 200mg IV q3 wks x 7 doses, both starting with RT. Surveillance cystoscopy, urine cytology, and CT chest-abdomen-pelvis were performed 12 & 24 weeks after CRT. The primary endpoint was feasibility, determined by a prespecified satisfactory low rate of grade 3-4 non-urinary toxicity, or completion of planned CRT according to defined parameters (RT < 7 weeks, >1 cisplatin dose omission). Secondary endpoints include complete cystoscopic response without metastatic disease at 12 & 24 weeks, loco-regional PFS, metastatic DFS, and OS.

Results

From 2016 – 2021 27 pts (93% male, median age 71, 96% pure TCC, 34% with CIS, 93% pT2) were enrolled at 6 sites. Median follow up at April 2022 was 31 months. 6 pts had Gr >3 non-urinary any adverse events (AE) during treatment or within 12 weeks after completing treatment (2 with delay in RT >7 wks), and 2 pts had cisplatin dose reductions due to G2 AEs. 1 pt had G3 colitis, 1 pt had G2 polymyalgia, 1 pt G2 nephritis. Complete response (CR) rate 24 weeks post CRT was 88% (95% CI 68-99%, 21 CR, 3 PD, 3 NE). 8 pts developed metastatic disease & 3 other pts had non metastatic PD in the bladder/upper urinary tracts. Distant metastasis-free survival rate at 2 yrs is 78% (95% CI 54-90%) and rate of freedom from locoregional progression is 87% (95% CI 64-96%). Median OS is 39 months (95% CI: 17.1 - NE).

Conclusions

Addition of pembro to CRT for MIBC was feasible and does not appear to add unexpected toxicity. CRT with pembro results in promising CR rates at 6 months. Follow up & comparative studies are required to assess impact on OS and metastasis free survival.

Clinical trial identification

NCT02662062.

Legal entity responsible for the study

Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP).

Funding

Merck & Co.

Disclosure

A.J. Weickhardt: Financial Interests, Personal, Invited Speaker: Merck; Financial Interests, Personal, Advisory Board: Merck, Pfizer, Ipsen, Astellas, BMS; Financial Interests, Personal, Research Grant: BMS, Merck. A. Pal: Financial Interests, Personal, Advisory Board: BMS, Urogen; Financial Interests, Institutional, Research Grant: Telix, AstraZeneca. P. Grimison: Financial Interests, Institutional, Invited Speaker, GS-2475: Gilead; Financial Interests, Institutional, Invited Speaker, INCSHR01210: Tigermed; Financial Interests, Institutional, Invited Speaker: Pfizer, Boston Biomedical, MedImmune, Halozyme, Aslan Pharmaceuticals, Janssen, Prime Therapeutics, Epizyme, Plexxikon, Five Prime Therapeutics, Novartis, QED; Financial Interests, Institutional, Invited Speaker, Pembrolizmab: Merck; Non-Financial Interests, Project Lead, P3 accelerated BEP clinical trial: Australian and New Zealand Urogenital and Prostate cancer trials group (ANZUP) - non-commercial academic collaborative group; Non-Financial Interests, Leadership Role, TIGER clinical trial - Australia/New Zealand national lead investigator: Australian and New Zealand Urogenital and Prostate cancer trials group (ANZUP) - non-commercial academic collaborative group; Non-Financial Interests, Project Lead, Study chair for government-funded randomised trial of medicinal cannabis with free drug supply by Tilray: NHMRC Clinical Trials Centre, University of Sydney; Other, Member - role in decisions regarding reimbursement of drugs: Australian Government - Pharmaceutical Benefits Advisory Committee. E. Hovey: Financial Interests, Personal, Advisory Board: Ipsen, Merck, Janssen, Amgen; Financial Interests, Personal, Invited Speaker: Janssen. A. Guminski: Financial Interests, Personal, Advisory Board: Regeron, MSD, Pfizer; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Research Grant: Sun Pharma, AstraZeneca. B. Tran: Financial Interests, Personal, Advisory Board: Amgen, Astellas, Bayer, BMS, Janssen, MSD, Novartis, Sanofi, Tolmar, Ipsen, IQVIA; Financial Interests, Personal, Speaker’s Bureau: BMS, Amgen, Astellas; Financial Interests, Personal, Other, Travel: Bayer. I.D. Davis: Financial Interests, Personal, Royalties, Authorship royalties for: Health Press; Financial Interests, Personal, Other, Remuneration for associate editor role in Therapeutic Advances in Medical Oncology: SAGE; Financial Interests, Institutional, Invited Speaker, Institutional support for clinical research: Movember Foundation, Merck/MSD, Bristol Myers Squibb, Exelixis, Astellas, Pfizer, AstraZeneca, Roche / Genentech, Eisai, Bayer, Janssen, Ipsen, Seagen; Non-Financial Interests, Invited Speaker, Director and Chair: ANZUP Cancer Trials Group; Non-Financial Interests, Advisory Role, All honoraria and payments are made directly to ANZUP Cancer Trials Group with no pass-through payment: Roche, Janssen, Astellas, Bayer, Ipsen, MSD, Merck/Pfizer, AstraZeneca, Eisai, Bristol Myers Squibb, Pio Therapeutics; Non-Financial Interests, Other, Member of Council: Clinical Oncology Society of Australia. D. Hayne: Financial Interests, Personal, Advisory Board, Advisory board participant: BMS; Financial Interests, Personal, Advisory Board, Ad board: Urogen; Financial Interests, Personal, Other, Travel support to present work at academic meeting: Telix; Financial Interests, Institutional, Invited Speaker, Funding for ZipUp Trial - unrestricted grant: Telix; Financial Interests, Institutional, Research Grant, Drug provided for SUBDUE-1 trial: AstraZeneca; Non-Financial Interests, Leadership Role, Chair BUP subcommittee, SAC member and OPS Exec member: ANZUP. All other authors have declared no conflicts of interest.

Background

The pathologic complete response rate to cisplatin-based neoadjuvant chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC) is roughly 30%, highlighting the need for biomarkers to drive patient selection in order to minimize treatment-related morbidity and optimize oncologic outcomes. We aimed to develop an artificial intelligence-based platform leveraging routine pre-treatment histopathology specimens to predict NAC response.

Methods

Using the Cancer Genome Atlas bladder cancer dataset, 59 patients with MIBC who received gemcitabine and cisplatin (GC) NAC from were identified. A deep learning-based algorithm was employed to segment nuclei from pre-NAC, hematoxylin and eosin-stained histopathology specimens and subsequently to extract quantitative, cell-type-specific features falling in one of three categories: nuclear geometry, cellular spatial arrangement, and tissue heterogeneity. These features were subsequently correlated with cancer-specific survival (CSS) utilizing a multivariable Cox proportional hazards (CPH) model in order to construct a signature associated with NAC response. Lastly, univariate CPH regression was conducted to identify the features most associated with NAC response.

Results

The multivariable CPH model incorporating features from all three aforementioned categories was predictive of NAC response with a concordance index of 0.70 [95% CI 0.53-0.87]. Kaplan-Meier analysis demonstrated the model was able to separate the cohort robustly with a statistically significant hazard ratio of 0.265 [95% CI 0.07, 0.98] (p=0.03) for predicted responders as compared to predicted non-responders. Features most correlated with CSS were those related to tissue heterogeneity and diversity of nuclear axis measurements, and increased heterogeneity was associated with worse CSS.

Conclusions

An artificial intelligence-based platform utilizing routine pre-treatment histopathology specimens may help identify patients most likely to respond to cisplatin-based NAC.

Legal entity responsible for the study

Valar Labs Inc.

Funding

Valar Labs Inc.

Disclosure

H. Bhambhvani, E. Tiu, V. Krishna, V. Nimgaonkar, R. Krishnan, O. O'Donoghue, A. Joshi: Financial Interests, Personal, Full or part-time Employment: Valar Labs Inc. V. Krishna, D. Vrabac: Financial Interests, Personal, Leadership Role: Valar Labs Inc. All other authors have declared no conflicts of interest.