Cisplatin-based Neoadjuvant Chemotherapy Research Articles

Clinical indications for necessary and discretionary hospital readmissions after radical cystectomy.

To assess predictors, indicators and medical necessity of readmissions after neoadjuvant chemotherapy and radical cystectomy in order to identify opportunities for reducing readmission rates. Records for patients treated with cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy between 2007 and 2017 were reviewed for 90-day complications and readmission. Readmissions were classified as necessary vs. discretionary based on independent clinician review. The association between postoperative complications and necessary or discretionary readmission were examined with adjusted regression models. Among a total of 250 patients, 76 patients (30.4%) were readmitted within 90 days of surgery (19 discretionary and 57 necessary). Age, insurance coverage, and comorbidity were similar between readmitted and non-readmitted patients. Readmission was more likely after neobladder than ileal conduit (39% vs. 23%, P = 0.02). Major (grade ≥ 3) complications within 90-day of surgery including index admission and post-discharge period were significantly more common among re-admitted patients compared to patients who were not readmitted (40% in necessary, 21% in discretionary, 3% in none, P < 0.001). Median length of stay on readmission was twice as long in necessary cases compared to discretionary cases (5 vs. 2.5 days, P < 0.001). Gastrointestinal and infectious complications were associated with discretionary readmission in adjusted analyses, while infectious, renal/genitourinary and thromboembolic complications were associated with necessary readmission. Twenty-five percent of readmissions were categorized as discretionary and were driven primarily by low-grade gastrointestinal complications, marginal oral intake and failure to thrive, suggesting that better coordinated post-discharge supportive care could help avoid a substantial proportion of readmissions.

SEOM-SOGUG clinical guideline for localized muscle invasive and advanced bladder cancer (2021)

Most muscle-invasive bladder cancer (BC) are urothelial carcinomas (UC) of transitional origin, although histological variants of UC have been recognized. Smoking is the most important risk factor in developed countries, and the basis for prevention. UC harbors high number of genomic aberrations that make possible targeted therapies. Based on molecular features, a consensus classification identified six different MIBC subtypes. Hematuria and irritative bladder symptoms, CT scan, cystoscopy and transurethral resection are the basis for diagnosis. Radical cystectomy with pelvic lymphadenectomy is the standard approach for muscle-invasive BC, although bladder preservation is an option for selected patients who wish to avoid or cannot tolerate surgery. Perioperative cisplatin-based neoadjuvant chemotherapy is recommended for cT2-4aN0M0 tumors, or as adjuvant in patients with pT3/4 and or pN + after radical cystectomy. Follow-up is particularly important after the availability of new salvage therapies. It should be individualized and adapted to the risk of recurrence. Cisplatin–gemcitabine is considered the standard first line for metastatic tumors. Carboplatin should replace cisplatin in cisplatin-ineligible patients. According to the EMA label, pembrolizumab or atezolizumab could be an option in cisplatin-ineligible patients with high PD-L1 expression. For patients whose disease respond or did not progress after first-line platinum chemotherapy, maintenance with avelumab prolongs survival with respect to the best supportive care. Pembrolizumab also increases survival versus vinflunine or taxanes in patients with progression after chemotherapy who have not received avelumab, as well as enfortumab vedotin in those progressing to first-line chemotherapy followed by an antiPDL1/PD1. Erdafitinib may be considered in this setting in patients with FGFR alterations. An early onset of supportive and palliative care is always strongly recommended.

Systematic Review and Meta-Analysis of Cisplatin Based Neoadjuvant Chemotherapy in Muscle Invasive Bladder Cancer.

Cisplatin-based neoadjuvant chemotherapy is the standard of care for muscle invasive bladder cancer (MIBC). To compare the efficacy and safety of the two most commonly used cisplatin-based regimens; gemcitabine, and cisplatin (GC) vs. accelerated (dose-dense: dd) or conventional methotrexate, vinblastine, adriamycin, and cisplatin (MVAC). We searched MEDLINE, Embase, Scopus and other sources. Outcomes of interest included overall survival, downstaging to pT≤1, pathologic complete response (pCR), recurrence, and toxicity. Meta-analysis was conducted using the random-effects model. We identified 24 studies. Efficacy outcomes were comparable between MVAC and GC for MIBC. dd-MVAC was associated with favorable efficacy compared to GC in terms of downstaging (OR 1.45; 95%CI 1.15-1.82) and all-cause mortality at longest follow-up (OR 0.63; 95%CI 0.44-0.81). However, GC was associated with a better safety profile in terms of febrile neutropenia (OR 0.32; 95%CI 0.13-0.80), anemia (OR 0.32; 95%CI 0.18-0.54), nausea and vomiting (OR 0.27; 95%CI 0.12-0.65) compared to dd-MVAC. Compared to MVAC, patients receiving GC had an increased risk of developing grade 3-4 thrombocytopenia (OR 4.70; 95%CI 1.59-13.89) and a lower risk of nausea and vomiting (OR 0.05; 95%CI 0.01-0.31). Certainty in the estimates was very low for most outcomes. Efficacy and safety outcomes were comparable between MVAC and GC for MIBC. Including non-peer-reviewed studies showed higher efficacy with dd-MVAC. A phase III randomized trial comparing the two regimens is needed to guide clinical practice.

Implications for Efficacy and Safety of Total Dose and Dose-Intensity of Neoadjuvant Gemcitabine-Cisplatin in Muscle-Invasive Bladder Cancer: Three-Week Versus Four-Week Regimen.

Neoadjuvant cisplatin-based chemotherapy is standard care prior to radical cystectomy in patients with muscle-invasive bladder cancer (MIBC). To assess efficacy and safety of two commonly used neoadjuvant schedules with different total doses and dose-intensities of gemcitabine and cisplatin (GC). Data were collected retrospectively from all patients treated between 2010 and 2018 with neoadjuvant chemotherapy according to clinical routine at seven centres in Sweden and Denmark. Patients in Sweden received three cycles of a 4-week schedule (GC-4w: cisplatin 70 mg/m2 day 1, gemcitabine 1000 mg/m2 days 1, 8, 15, q 28 days) and in Denmark four cycles of a 3-week schedule (GC-3w: cisplatin 70 mg/m2 day 1, gemcitabine 1000 mg/m2 days 1, 8, q 21 days). Primary endpoint was pathological response at cystectomy (pT0N0 and < pT2N0). A total of 251 patients were treated with GC-4w and 455 with GC-3w. pT0N0 was significantly higher for patients treated with GC-3w compared to GC-4w, 46% versus 32% (adjusted odds ratio [aOR] 1.80; 95% confidence interval [CI] 1.16-2.80; P = 0.009); and for < pT2N0 60% versus 47% (aOR 1.08; 95% CI 0.70-1.66; P = 0.743). There were no significant differences between GC-4w and GC-3w regarding survival parameters. GC-3w patients discontinued treatment more frequently and showed a higher degree of neutropenia. A significantly higher complete response-rate was observed in the patient group treated with the more cisplatin-dose-intense 3-week schedule. The side-effect profile was in favor of the 4-week approach while relapse-free and overall survival were similar.

Adjuvant infigratinib as targeted therapy for patients with muscle-invasive urothelial carcinoma harboring susceptible FGFR3 genetic alterations: A randomized, double-blind, placebo-controlled, phase 3 trial (PROOF 302).

TPS580 Background: Radical surgery is the mainstay of treatment for muscle-invasive upper tract urothelial cancer (UTUC) and urothelial bladder cancer (UBC). However, even when surgery is combined with cisplatin‐based (neo)adjuvant chemotherapy, recurrence rates are high. Many patients (pts) are ineligible for, do not respond to, or refuse cisplatin-based chemotherapy because of toxicity concerns. Fibroblast growth factor receptor 3 ( FGFR3) genetic alterations occur in 21–38% of muscle-invasive UTUC, and in approx. 20% of invasive UBC. Infigratinib (BGJ398) is an ATP-competitive FGFR1–3 selective oral tyrosine kinase inhibitor that has clinical activity and tolerability in pts with advanced/metastatic urothelial carcinoma (UC) harboring susceptible FGFR3 alterations. PROOF 302 was designed to investigate the efficacy and safety of adjuvant infigratinib in pts with high-risk, muscle-invasive UC (85% UTUC) and susceptible FGFR3 alterations. Methods: PROOF 302 is a global, multicenter, randomized, double-blind, placebo-controlled, phase 3 trial (NCT04197986). Eligible pts have high-risk, muscle-invasive UTUC (85%) or UBC (15%) with susceptible FGFR3 alterations (mutations, gene fusions or rearrangements) confirmed by FoundationOne CDx test, and are ≤120 days following nephroureterectomy, distal ureterectomy, or cystectomy. The study protocol was amended to include pts with carcinoma in situ at surgical margins and those who refuse cisplatin-based chemotherapy (in addition to pts allowed to enroll if ineligible for perioperative cisplatin-based chemotherapy). Eligible pts are M0 and have either disease stage ≥ypT2 and/or yN+ after cisplatin-based neoadjuvant chemotherapy or ≥pT2 pN0–2 or pN+ (UTUC); and ≥pT3 or pN+ (UBC) if not treated with cisplatin-based neoadjuvant chemotherapy. Pts are randomized 1:1 to receive oral infigratinib 125 mg or placebo QD on days 1–21 of a 28-day cycle for up to 52 weeks (13 cycles) or until recurrence, unacceptable toxicity, or death. Primary endpoint: centrally reviewed disease-free survival (DFS) analyzed via stratified log-rank test and Cox model (hazard ratio). Secondary endpoints: investigator-reviewed DFS, metastasis-free survival, overall survival, safety/tolerability. Exploratory endpoints: quality of life, pharmacokinetics, determination of the prevalence of genomic alterations and correlation with features of UC, genomic and proteomic assessment of tumor tissue and cell-free DNA samples from baseline and at recurrence to identify the predictive/prognostic value of biomarkers. PROOF 302 is actively enrolling as of Sep 2021. A second Data Monitoring Committee meeting is planned for Dec 2021. The last pt is expected to complete treatment in 2024. Clinical trial information: NCT04197986.

Use of perioperative treatment (tx) among patients (pts) undergoing radical resection (RR) for muscle-invasive urothelial cancer (MIUC) in France, Germany, Italy, Spain, the United Kingdom, the United States, Canada, China, and Japan.

467 Background: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by RR is the standard of care in cisplatin-eligible pts with MIUC. Adjuvant chemotherapy (AC) with cisplatin-based tx may be offered to those not given NAC. The unmet need this survey tried to evaluate is the post-RR burden of disease, quality of life (QoL) and perioperative tx patterns among MIUC pts. Methods: Real-world descriptive data were drawn from Adelphi’s MIUC Disease-Specific Programme: A point-in-time survey conducted with clinical/medical oncologists/urologists and their pts in 9 countries between January and June 2021. Physicians completed a survey on their pts’ clinical characteristics and tx patterns, while pts voluntarily completed a series of patient-reported outcome measures. Results: Of 2178 pts (data provided by 320 physicians), 30% received NAC only, 26% received AC only, 38% received no NAC or AC tx, and 6% received both. 1744 pts had initial tumour in the bladder; 35% received NAC only, 24% AC only, 35% no NAC or AC tx, and 6% received both. Of 387 pts with upper-tract urothelial carcinoma (UTUC), 51% received no NAC/AC tx, 35% received AC only, and 12% NAC only. More pts with T3 disease received no NAC/AC tx (36%) or NAC (35%) than AC (24%). Of 734 pts with nodal disease, 36% received NAC only. Of all pts, 60% experienced symptoms at data abstraction: 50% in pts who received NAC only, 71% in pts who received AC only and 82% in pts of those who received both. Pts reported similar EQ-5D-5L utility index scores (mean = 0.86; range: 0.84 [AC only] to 0.89 [NAC only]). Overall, feeling pain (40%) and stress (39%) were the EQ-5D domains with the worst scores. Pts who received AC only reported nominally lower EQ-5D visual analogue scale scores (71.11) compared with pts who received no NAC/AC (73.17) or pts who received NAC only (75.05). EORTC QLQ-C30 Global Health Status scores were 60.0 in pts who received AC only, 64.1 in pts who received NAC only or no NAC/AC, and 66.7 for pts who received both NAC and AC. Conclusions: Nearly 40% of pts remain untreated in either NAC or AC setting in 9 countries. A higher proportion of pts with UTUC go untreated. AC was more frequently used in UTUC vs BC pts; and in pts with Tis. NAC was implemented more frequently in pts T3 disease and in those with N+ disease. Pts who received AC appear to have nominally worse QOL and more symptoms, further demonstrating the need for efficacious adjuvant tx that does not decrease post-RR QoL.[Table: see text]

Neoadjuvant nivolumab (N) +/- ipilimumab (I) in cisplatin-ineligible patients (pts) with muscle-invasive bladder cancer (MIBC).

498 Background: Cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy (RC) confers survival benefit but a substantial subset of MIBC pts are cisplatin-ineligible. We conducted a phase II trial of N±I neoadjuvant therapy for cisplatin-ineligible MIBC. Methods: Cisplatin-ineligible pts with MIBC (cT2-T4aN0M0) were enrolled into 2 consecutive cohorts of 15 pts each (C1: N 3 mg/kg q 2 weeks (wk) x 5; C2: I (3mg/kg) + N (1mg/kg) wk 0 and 6, with N (3mg/kg) wk 3 and 9). A 3rd cohort was planned (C3: I (3mg/kg) + N (1mg/kg) q 3 wk x 3). Primary endpoint (EP) was eligibility for planned RC within 60 days without delay from treatment-related adverse events (TRAEs) or progressive disease (PD). Secondary EPs included pathologic downstaging (PaDo, &lt;ypT2pN0) and complete response (pCR, ypT0pN0) rates, recurrence-free survival (RFS), and safety. Exploratory EP was event-free survival (EFS). Results: From 8/2018-5/2021, 15 pts were enrolled onto C1 and C2 (N = 30). Median age 76 (range 53-87), 80% male, with median Charlson comorbidity score of 1 (range 0-5). In C1 and C2, 14/15 and 6/15 pts received all planned treatment, respectively. In C2, 7/15 received ≤ 50% of planned doses. In C1, 11 pts underwent RC, 2 had PD before RC, 1 did not undergo RC due to TRAE, and 1 declined RC. Overall, 12/15 met the primary EP. For C2, 9 pts underwent RC, 3 had PD before RC, 2 did not undergo RC due to AE (1 of which was TRAE), and 1 opted for radiation, with 8/15 meeting the primary EP. C3 was dropped due to C2’s failure to meet the primary EP. In C1, 4 pts had PaDo (26%), with 2 pCRs (13%). In C2, 3 pts had PaDo (20%), with 1 pCR (7%). In C1, 1 pt who did not undergo RC due to TRAE had clinical CR of 13.2 months (mos) but died of sepsis at 16.1 mos; 2 pts in C2 who did not undergo RC have ongoing clinical CR at 16.1 and 10.8 mos follow-up (f/u). For time-to-event EPs, see Table. In C1, the only observed grade 3-4 TRAE was myocarditis (n=1, 7%). In C2, 4 pts (27%) had grade 3-4 TRAE, including elevated lipase (20%), pneumonitis (13%), fatigue (13%), and elevated AST + ALT(13%). Median tumor mutation burden was 8.8/megabase; DNA damage response genes were altered in 31% of pts and FGFR3 in 14%, with no genomic correlation with PaDo. For C1, 4/10 had baseline PD-L1 expression on ≥1% of tumor cells; 1 had PD-L1 ≥5%. Conclusions: In this cohort of cisplatin-ineligible pts with MIBC and comorbidities, neoadjuvant N was well tolerated. N+I was associated with greater toxicity resulting in RC delays. Pathologic response rates were low in both cohorts, raising questions about utility of treatment intensification in cisplatin-ineligible patients. Some pts who did not undergo RC due to TRAEs had sustained clinical CR. Clinical trial information: NCT03520491. Clinical trial information: NCT03520491. [Table: see text]

Randomized phase II trial of gemcitabine, avelumab and carboplatin versus no neoadjuvant therapy preceding surgery for cisplatin-ineligible muscle-invasive urothelial carcinoma (MIUC): SWOG GAP trial (S2011).

TPS591 Background: Neoadjuvant cisplatin-based combination chemotherapy improves survival in cisplatin-eligible patients (pts) with muscle invasive bladder cancer (MIBC). An unmet need exists in cisplatin-ineligible pts with MIUC who are offered upfront surgery. Neoadjuvant immune checkpoint inhibitors (ICIs) have been demonstrated to be safe and active although the benefit may not extend to the majority of pts. The combination of GCa and an ICI has been demonstrated to be safe and active in cisplatin-ineligible metastatic urothelial carcinoma. In the neoadjuvant setting, combination GCa and an ICI may improve outcomes across a broad group of MIUC by delivering early systemic therapy to pts with cisplatin-ineligible MIUC. We hypothesized that the combination of GCa and avelumab, a PD-L1 inhibitor, may improve pathologic complete remissions (pCR) and long-term outcomes compared to upfront surgery for MIUC (S2011, NCT04871529). Methods: This multicenter, randomized (1:1), open-label phase II trial is comparing the combination of GCa and avelumab (Arm A) as neoadjuvant therapy vs. upfront surgery (Arm B) for pts with cisplatin-ineligible MIUC including MIBC and high-risk upper tract urothelial carcinoma (UTUC). Adjuvant therapy following radical cystectomy, nephroureterectomy or ureterectomy is deferred to investigator discretion in both arms. Eligible pts include those with MIBC or high-grade UTUC with a predominant urothelial component who are cisplatin-ineligible (≥1 of: Zubrod performance status [PS] = 2, creatinine clearance [CrCl] 30 to &lt; 60 ml/min, neuropathy &gt; grade 1, hearing loss &gt; grade 1, congestive heart failure &gt; grade 2). The primary objective is pCR. The stratification factors include clinical stage (cT2N0M0 vs cT3-4aN0M0), Zubrod-PS (0-1 vs 2), CrCl (30 to &lt; 60 vs ≥ 60 ml/min). With 178 evaluable pts, the trial will have a power of 90% (using a 1-sided alpha 0.05) to detect pCR rate improvement from 15% to 35%. The secondary objectives are toxicities, resectability rates, surgical complications, event-free survival (EFS) and overall survival (OS). Correlative studies include tumor molecular profiling, blood immune studies, circulating tumor-DNA profiling and radiomics. Arm A receives gemcitabine 1000 mg/m2 IV days 1, 8 every 3 weeks x 4 cycles, carboplatin AUC 4.5 (escalated to AUC 5 from cycle 2 if tolerated in cycle 1) IV day 1 every 3 weeks x 4 cycles and avelumab 800 mg IV day 1 every 2 weeks x 6 cycles. Surgery is performed 4-8 weeks after the last neoadjuvant administration. The trial is funded by NIH/NCI grants U10CA180888, U10CA180819, U10CA180821, U10CA180820, U10CA180868, and in part by EMD Serono, as part of an alliance between the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945) and Pfizer. Clinical trial information: NCT04871529.

Randomized phase 2 umbrella study of various neoadjuvant therapies for patients with muscle-invasive urothelial carcinoma of the bladder (MIBC) who are cisplatin-ineligible or refuse cisplatin therapy and undergoing radical cystectomy (Optimus).

TPS599 Background: A growing body of data support that the key to generating anti-tumor immune responses triggered by administration of immuno-oncology (IO) agents, is the activation and invasion of T lymphocytes. Checkpoint inhibitors (CPIs) are being actively explored in the neoadjuvant setting of MIBC. CPIs documented 30-40% pathologic complete response-rates (ypT0N0) in previous trials. Increasingly, novel IO agents are being developed in combinations with anti PD(L)-1 therapies. Understanding the changes in the tumor microenvironment that occur with the addition of novel immunomodulating agents to PD(L)-1 inhibitors can help inform whether a compound is viable for further development. The OPTIMUS trial is a window of opportunity, neoadjuvant platform design study in MIBC patients that are cisplatin-ineligible. The study investigates the addition of the indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor epacadostat to the PD-1 inhibitor retifanlimab. The platform design allows for investigation of other novel immune-modulating combinations. Methods: This is an open-label, randomized, Phase 2, multi-treatment group, window-of-opportunity, platform study for participants with MIBC undergoing radical cystectomy who refuse or are not eligible for cisplatin-based neoadjuvant chemotherapy (NCT04586244). Participants are randomized based on tumor tissue PD-L1 CPS ≥ 10 or PD-L1 CPS &lt; 10 to one of the following treatment groups: Treatment Group A (epacadostat + retifanlimab); Treatment Group B (retifanlimab monotherapy); Treatment Group C (epacadostat monotherapy). 18 patients will be enrolled in each of Treatment Groups A and B. 9 patients will be enrolled into Treatment Group C. Total treatment duration is a maximum of 10 weeks. The platform study design allows for addition of future treatment groups. Pre-treatment biopsy is obtained through transurethral resection of bladder tumor (TURBT), followed by neoadjuvant treatment, followed by radical cystectomy. In all treatment groups, tissue from the surgical specimen(s) is collected and compared with the initial pre-treatment samples. The primary endpoint is the change from baseline in CD8+ lymphocytes within resected tumor. Secondary endpoints include safety and tolerability, rates of ypT0N0 response, and major pathologic response. Exploratory analyses include tumoral changes in gene cell expression profile, immune-cell protein and metabolic marker levels, and spatial relationships between cell types. Plasma is also collected and will be investigated for changes in cytokines and other inflammatory or metabolic markers. Clinical trial information: NCT04586244.

An open-label, phase 2 study of personalized approach with perioperative immunotherapy for bladder preservation in muscle-invasive urothelial bladder carcinoma (MIBC).

TPS590 Background: Radical cystectomy (RC) without neoadjuvant chemotherapy is standard-of-care for cisplatin (cis)-ineligible pts (and those refusing cisplatin) with MIBC. Checkpoint inhibitors (CPIs) are being actively explored in the perioperative setting. CPIs documented a 42% pathologic complete response-rate (ypT0N0) in our previous trial (PURE-01, NCT02736266). In this trial, programmed cell-death ligand-1 (PD-L1) expression was associated with ypT0N0 response ( Necchi A, et al. Eur Urol. 2019), and a cohort of PD-L1+ pts who refused RC are still alive at long-term follow-up ( Bandini, Ann Oncol 2020). Initial data from trials aimed at delivering a systemic therapy while sparing any local therapy on the bladder tumor in highly-selected pts are promising ( Galsky, 2021, Geynisman, 2021). Sasanlimab (SASI) is a humanized, hinge region–stabilized (21) IgG4 mAb directed against human PD-1. Sasanlimab is currently being tested subcutaneously (SQ) in a phase III study in non-MIBC. Our hypothesis is that SASI can be offered in PD-L1+ pts as an exclusive therapeutic option instead of any additional treatment, after a clinical complete response (cCR) with an induction phase. Methods: This is a Phase 2, open-label, non-randomized, single-cohort study in pts with MIBC who are ineligible or unwilling to receive cisplatin-based neoadjuvant chemotherapy. The study will include pts with a PD-L1 CPS≥10% in tumor biopsy.Other key inclusion criteria: UC histology, an ECOG PS 0−1. Cis-ineligibility is defined as one of the following: glomerular filtration rate ≥30 but &lt; 60 mL/min, or CTCAE v5 ≥grade 2 hearing loss or peripheral neuropathy. Key exclusion criteria: clinical evidence of ≥N1 or metastatic disease or UC in upper urinary tract; prior systemic therapy, radiation therapy, or prior RC. Pts will undergo a transurethral resection of the bladder (TURBT), a CT scan, and a 18FDG-PET/CT scan. SASI will be administered SQ at the recommended dose of 300mg for a total of 3 cycles every 4 weeks prior to redo-TURBT. Pts who will achieve a cCR (i.e., no evidence of residual viable tumor at re-TURBT sample, urinary cytology and imaging tests) will receive additional SASI treatment for a total period of 12 months, every 4 weeks. Pts with non-CR will be excluded from the study and start treatment according to guidelines or investigator preference. Primary endpoint: event-free survival (EFS). Secondary endpoint: proportion of cCR. According to Simon's 2-stage MinMax design, a total of 55 pts will be included, and we anticipate the need for enrolling 110 pts for the neoadjuvant phase of the study. This assumption will correspond to the need for screening approximatively 220 pts onto this trial. Exploratory analyses will include: artificial intelligence through multiparametric bladder MRI/PET, and ctDNA analyses pre-post neoadjuvant period. Clinical trial information: 2021-001649-10.

A phase 3, randomized, open-label, multicenter, global study of the efficacy and safety of durvalumab (D) + tremelimumab (T) + enfortumab vedotin (EV) or D + EV for neoadjuvant treatment in cisplatin-ineligible muscle-invasive bladder cancer (MIBC) (VOLGA).

TPS579 Background: The standard management of MIBC involves neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy and pelvic lymph node dissection. Approximately 40% of patients with MIBC are cisplatin ineligible, the standard of care (SoC) for these patients is to proceed directly to cystectomy as there are no effective or approved neoadjuvant therapies in this setting. Only nivolumab has been approved as adjuvant treatment for patients who are at high risk of recurrence after radical resection. Given this, there remains an unmet need. D (anti–PD-L1 antibody) +T (anti–CTLA-4 antibody) have demonstrated a manageable safety profile with clinical activity in metastatic urothelial carcinoma and in a phase 2 neoadjuvant trial, D+T showed anti-tumor activity, including meaningful pathologic complete responses (pCR), in cisplatin-ineligible MIBC with high-risk features. Targeted cytotoxic antibody drug conjugates (ADCs) are known to have the potential to induce immunogenic tumor cell death, which promotes activation and recruitment of immune cells. EV is a vedotin ADC comprising an antibody against Nectin-4 linked to a microtubule-disrupting agent MMAE that has demonstrated efficacy in, and is approved for, advanced urothelial cancer. Thus, we hypothesize that EV in combination with PD-L1 inhibition, with or without CTLA-4 inhibition, may improve outcomes in patients with MIBC by downstaging of disease before cystectomy and that adjuvant therapy with D or D+T may further improve time to disease relapse. Methods: VOLGA (NCT04960709) is a phase 3, randomized, open-label, multicenter, international trial that will enroll ̃830 patients with MIBC. Eligible patients include those aged ³18 years with histologically or cytologically documented MIBC (transitional and mixed transitional cell histology), who are cisplatin ineligible and with a clinical stage of T2-4aN0-N1M0. Patients will be randomized to 3 arms to receive 3 cycles of neoadjuvant therapy Q3W as follows: (Arm 1) D (1500 mg day 1) +T (75 mg day 1) +EV (1.25 mg/kg Days 1 &amp; 8); (Arm 2) D (1500 mg day 1) +EV (1.25 mg/kg Days 1 &amp; 8); or (Arm 3) no neoadjuvant treatment (SoC). A safety run-in study is included. Following radical cystectomy, patients will then receive: (Arm 1) 1 cycle of T on Day 1 plus 9 cycles of D Q4W; (Arm 2) 9 cycles of D Q4W; or (Arm 3) either no adjuvant treatment (observation only) or adjuvant nivolumab in high-risk patients where available and approved (planned amendment). The dual primary endpoints are pCR and event-free survival. Secondary endpoints include overall survival, disease-free survival, pathologic downstaging rate to &lt; pT2, disease-specific survival, quality of life, immunogenicity, and pharmacokinetics. The study is actively enrolling. Clinical trial information: NCT04960709.

Dose-Intense Cisplatin-Based Neoadjuvant Chemotherapy Increases Survival in Advanced Cervical Cancer: An Up-to-Date Meta-Analysis.

Simple SummaryAlthough neoadjuvant chemotherapy has become standard care for many locally advanced cancer sites, the benefit of neoadjuvant chemotherapy remains unclear for the treatment of locally advanced cervical cancer. With this meta-analysis, we set out to demonstrate the benefit of using dose-intense cisplatin-based neoadjuvant chemotherapy in terms of overall survival and progression-free survival. Dose-intense cisplatin-based neoadjuvant chemotherapy followed by local therapy was significantly associated with a survival benefit in the treatment of locally advanced cervical carcinoma. Even though radiotherapy combined with weekly cisplatin-based chemotherapy remains standard of care for the treatment of locally advanced cervical cancer, our meta-analysis makes it possible to consider the use of dose-intense cisplatin-based neoadjuvant chemotherapy when local treatment is suboptimal and opens perspectives for designing new clinical trials in this setting.Purpose: We set out to demonstrate the benefit of using dose-intense cisplatin-based neoadjuvant chemotherapy in terms of overall survival and progression-free survival. Methods: We searched through MEDLINE and Cochrane Library databases up to May 2021 to identify randomized clinical trials comparing the benefit of using cisplatin-based neoadjuvant chemotherapy followed by local treatment with local treatment alone for the treatment of locally advanced cervical cancer. The PRISMA statement was applied. Results: Twenty-two randomized clinical trials were retrieved between 1991 and 2019, corresponding to 3632 women with FIGO stages IB2-IVA cervical cancer. More than 50% of the randomized clinical trials were assessed as having a low risk of bias. There was no benefit of neoadjuvant chemotherapy on overall survival, but there was significant heterogeneity across studies (I2 = 45%, p = 0.01). In contrast, dose-intense cisplatin at over 72.5 mg/m2/3 weeks was significantly associated with increased overall survival (RR = 0.87, p < 0.05) with no heterogeneity across the pooled studies (I2 = 36%, p = 0.11). The survival benefit was even greater when cisplatin was administered at a dose over 105 mg/m2/3 weeks (RR = 0.79, p < 0.05). Conclusion: Even though radiotherapy combined with weekly cisplatin-based chemotherapy remains standard of care for the treatment of locally advanced cervical cancer, our meta-analysis makes it possible to consider the use of dose-intense cisplatin-based neoadjuvant chemotherapy when local treatment is suboptimal and opens perspectives for designing new clinical trials in this setting. Neoadjuvant chemotherapy could be proposed when surgery is local treatment instead of standard chemoradiotherapy for the treatment of locally advanced cervical cancer.

Clinical Application of Circulating Tumor Cells and Circulating Endothelial Cells in Predicting Bladder Cancer Prognosis and Neoadjuvant Chemosensitivity.

PurposeTo investigate the role of circulating rare cells (CRCs), namely, circulating tumor cells (CTCs) and circulating endothelial cells (CECs), in aiding early intervention, treatment decision, and prognostication in bladder cancer.MethodsA total of 196 patients with pathologically confirmed bladder cancer, namely, 141 non-muscle invasive bladder cancer (NMIBC) and 55 muscle invasive bladder cancer (MIBC) patients. There were 32 patients who received cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC). Subtraction enrichment combined with immunostaining-fluorescence in situ hybridization (SE-iFISH) strategy was used for CTC/CEC detection. Kaplan–Meier analysis and Cox regression were used to evaluate the overall survival (OS) and recurrence-free survival (RFS). Receiver operator characteristic analysis was used to discriminate NAC sensitivity.ResultsCTCs and CECs were related to clinicopathological characteristics. Triploid CTCs, tetraploid CTCs, and total CECs were found to be higher in incipient patients than in relapse patients (P = 0.036, P = 0.019, and P = 0.025, respectively). The number of total CECs and large cell CECs was also associated with advanced tumor stage (P = 0.028 and P = 0.033) and grade (P = 0.028 and P = 0.041). Remarkably, tumor-biomarker-positive CTCs were associated with worse OS and RFS (P = 0.026 and P = 0.038) in NMIBC patients underwent TURBT. CECs cluster was an independent predictor of recurrence in non-high-risk NMIBC patients underwent TURBT (HR = 9.21, P = 0.040). For NAC analysis, pre-NAC tetraploid CTCs and small cell CTCs demonstrated the capability in discriminating NAC-sensitive from insensitive patients. Additionally, tetraploid CTCs and single CTCs elevated post-NAC would indicate chemoresistance.ConclusionCTCs and CECs may putatively guide in diagnosis, prognosis prediction, and therapeutic decision-making for bladder cancer.

Pre-clinical and clinical studies on the role of RBM3 in muscle-invasive bladder cancer: longitudinal expression, transcriptome-level effects and modulation of chemosensitivity

BackgroundThe response to neoadjuvant cisplatin-based chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC) is impaired in up to 50% of patients due to chemoresistance, with no predictive biomarkers in clinical use. The proto-oncogene RNA-binding motif protein 3 (RBM3) has emerged as a putative modulator of chemotherapy response in several solid tumours but has a hitherto unrecognized role in MIBC.MethodsRBM3 protein expression level in tumour cells was assessed via immunohistochemistry in paired transurethral resection of the bladder (TURB) specimens, cystectomy specimens and lymph node metastases from a consecutive cohort of 145 patients, 65 of whom were treated with NAC. Kaplan-Meier and Cox regression analyses were applied to estimate the impact of RBM3 expression on time to recurrence (TTR), cancer-specific survival (CSS), and overall survival (OS) in strata according to NAC treatment. The effect of siRNA-mediated silencing of RBM3 on chemosensitivity was examined in RT4 and T24 human bladder carcinoma cells in vitro. Cellular functions of RBM3 were assessed using RNA-sequencing and gene ontology analysis, followed by investigation of cell cycle distribution using flow cytometry.ResultsRBM3 protein expression was significantly higher in TURB compared to cystectomy specimens but showed consistency between primary tumours and lymph node metastases. Patients with high-tumour specific RBM3 expression treated with NAC had a significantly reduced risk of recurrence and a prolonged CSS and OS compared to NAC-untreated patients. In high-grade T24 carcinoma cells, which expressed higher RBM3 mRNA levels compared to RT4 cells, RBM3 silencing conferred a decreased sensitivity to cisplatin and gemcitabine. Transcriptomic analysis revealed potential involvement of RBM3 in facilitating cell cycle progression, in particular G1/S-phase transition, and initiation of DNA replication. Furthermore, siRBM3-transfected T24 cells displayed an accumulation of cells residing in the G1-phase as well as altered levels of recognised regulators of G1-phase progression, including Cyclin D1/CDK4 and CDK2.ConclusionsThe presented data highlight the potential value of RBM3 as a predictive biomarker of chemotherapy response in MIBC, which could, if prospectively validated, improve treatment stratification of patients with this aggressive disease.

Natural bioactive compounds: a potential therapeutic strategy to sensitize bladder cancer to cisplatin treatment?

Bladder cancer (BC) is the tenth most common cancer, and its incidence is steadily rising worldwide, with the highest rates in developed countries. Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy is the standard therapy for patients with muscle-invasive bladder cancer. However, less than 50% of patients initially respond to this treatment and nearly all of them eventually develop resistance, which is an important barrier to long-term survival. Therefore, there is an urgent need to understand the mechanisms of cisplatin resistance in BC and develop ways to counteract them. Several preclinical studies have demonstrated that naturally derived bioactive compounds, such as phytochemicals and flavonoids, can enhance the antitumor activity of cisplatin, with minimal side effects, by targeting different pathways involved in cisplatin sensitivity and resistance. However, their poor bioavailability has been one of the main problems for their successful introduction into clinical practice. At present, however, many new formulations with greatly increased bioavailability are under study in several clinical trials with encouraging results.

Avelumab as neoadjuvant therapy in patients with urothelial non-metastatic muscle invasive bladder cancer: a multicenter, randomized, non-comparative, phase II study (Oncodistinct 004 - AURA trial)

IntroductionCisplatin-based neoadjuvant chemotherapy (NAC) followed by surgery is the standard treatment for patients with non-metastatic muscle invasive bladder cancer (MIBC). Unfortunately, many patients are not candidates to receive cisplatin due to renal impairment. Additionally, no predictive biomarkers for pathological complete response (pCR) are currently validated in clinical practice. Studies evaluating immune checkpoint inhibitors in the peri-operative setting are emerging with promising results. Clinical trials are clearly required in the neoadjuvant setting in order to improve therapeutic strategies.Methods and analysisOncodistinct 004 – AURA is an ongoing multicenter phase II randomized trial assessing the efficacy and safety of avelumab single-agent or combined to different NAC regimens in patients with non-metastatic MIBC. Patients are enrolled in two distinct cohorts according to their eligibility to receive cisplatin-based NAC. In the cisplatin eligible cohort, patients are randomized in a 1:1 fashion to receive avelumab combined with cisplatin-gemcitabine or with dose-dense methotrexate-vinblastine-doxorubicin-cisplatin. In the cisplatin ineligible cohort, patients are randomized at a 1:1 ratio to paclitaxel-gemcitabine associated to avelumab or avelumab alone. Primary endpoint is pCR. Secondary endpoints are pathological response and safety.Ethics and disseminationThe study is approved by ethics committee from all participating centers. All participants provide informed consent prior inclusion to the study. Once completed, results will be published in peer-reviewed journals.Trial registration numberClinicalTrials.gov (NCT03674424).

Different Responses to Neoadjuvant Chemotherapy in Urothelial Carcinoma Molecular Subtypes

BackgroundFor muscle-invasive bladder cancer (MIBC), no tissue biomarkers are available for clinical use to predict response to neoadjuvant chemotherapy. ObjectiveTo investigate how molecular subtypes impact pathological response and survival in patients receiving preoperative cisplatin-based chemotherapy. Design, setting, and participantsClassification of a retrospective cohort of 149 patients was performed by tumor transcriptomic profiling and immunostaining. A cohort treated with radical cystectomy alone and public data sets were used for comparison and external validation. Outcome measurements and statistical analysisComplete pathological response in the cystectomy specimen (ypT0N0) and survival were compared in predefined molecular subtypes. Differential gene expression and chemotherapy response were explored beyond molecular subtypes. Results and limitationsPatients with genomically unstable (GU) and urothelial-like (Uro) tumors had higher proportions of complete pathological response (16/31 [52%] and 17/54 [31%]), versus five out of 24 (21%) with the basal/squamous (Ba/Sq) subtype following neoadjuvant chemotherapy and radical cystectomy. Molecular subtype was independently associated with improved survival for patients with GU tumors (hazard ratio [HR] 0.29, 95% confidence interval [CI]: 0.11–0.79) and UroC tumors (HR 0.37, 95% CI: 0.14–0.94) compared with Ba/Sq tumors, adjusting for clinical stage. In addition, expression of the gene coding for osteopontin (SPP1) showed a subtype-dependent effect on chemotherapy response. ConclusionsUrothelial cancer of the luminal-like (GU and Uro) subtypes is more responsive to cisplatin-based neoadjuvant chemotherapy. A second-generation of subtype-specific biomarkers, for example, SPP1, may be a way forward to develop a more precision-based treatment approach for neoadjuvant chemotherapy in MIBC. Patient summaryThis study shows that tumor classification by gene expression profiling and molecular subtyping can identify patients who are more likely to benefit from chemotherapy before radical cystectomy for muscle-invasive bladder cancer. Together with other markers for response, molecular subtypes could have a role in selective administration of such chemotherapy.

Cisplatin, Neoadjuvant Chemotherapy and Bladder Cancer

Neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy (RC) or radiation therapy (RT) improves survival of patients with nonmetastatic, muscle-invasive bladder cancer (MIBC). The rationale dates to 1979 when George Prout, at the Massachusetts General Hospital in Boston, stated that MIBC is a systemic disease.1 He based this on the undisputed evidence that despite local treatment with RC or RT, more than half of patients die of distant metastases. Systemic therapy, integrated with local therapy, would be necessary to cure more patients.

Prediction of pathological response following neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer: the PRE-PREVENCYS trial

BackgroundThe recommended treatment for patients with non-metastatic muscle-invasive bladder cancer (MIBC) is neoadjuvant chemotherapy (NAC) and radical cystectomy (RC). Following NAC, 20–40% of patients experience a complete pathological response (pCR) in the RC specimen and these patients have excellent long-term overall survival. Subject to debate is, however, whether patients with a pCR to NAC benefit from RC, which is a major surgical procedure with substantial morbidity, and if these patients might be candidates for close surveillance instead. However, currently it is not possible to accurately identify patients with a pCR to NAC in whom RC might be withheld. The objective of this study is to assess whether pathological response in the RC specimen after NAC can be predicted based on clinical, radiological, and histological variables and on a wide set of molecular biomarkers assessed in tissue, blood and urine.MethodsThis is a multicentre, prospective cohort study, including patients with cT2a-T4a N0-N1 M0 urothelial cell MIBC who are scheduled to undergo cisplatin-based NAC followed by RC. Prior to start of therapy, a 2-Deoxy-2-[18F] fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) is performed. Response to NAC is evaluated by CT-scan. Blood and urine, including cytology, are prospectively collected for biomarker analyses before and after NAC. Immediately before RC, participants undergo cystoscopy with bimanual examination and a re-staging transurethral resection (TUR) of all visible cancerous lesions or with biopsies from scar tissue. Subsequently, RC is performed in all patients. Tissue from the diagnostic TUR, the re-staging TUR, and the RC specimen is examined for the presence of urothelial cancer carcinoma and DNA and RNA is isolated for molecular analysis. The primary endpoint is the pathological stage (ypTN) in the RC and ePLND specimen and its association with clinical response.DiscussionIf the PRE-PREVENCYS trial shows that the absence of residual disease after NAC in patients with MIBC is accurately predicted, a randomized controlled trial is scheduled comparing the overall survival of NAC plus RC versus NAC followed by close surveillance for patients with a clinically complete response (PREVENCYS trial).Trial registrationNetherlands Trial Register: NL8678; Registered 20 May 2020 https://www.trialregister.nl/trial/8678

This Month in Adult Urology

This Month in Adult Urology