Cisplatin-ineligible Patients Research Articles

Study EV-103: Neoadjuvant treatment with enfortumab vedotin monotherapy in cisplatin-ineligible patients (pts) with muscle invasive bladder cancer (MIBC): Updated results for Cohort H.

4595 Background: Cisplatin-ineligible pts with MIBC have no established neoadjuvant treatment options known to prolong survival before undergoing radical cystectomy and pelvic lymph node dissection (RC+PLND), Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in urothelial cancer. In a phase 3 study, EV showed improved overall survival vs standard chemotherapy and a tolerable safety profile in pts with advanced urothelial cancer previously treated with a platinum agent and a PD-1/L1 inhibitor (Powles NEJM 2021). In Cohort H of the EV-103 phase 1b/2 study, preliminary results, including pathological complete response (pCR) and pathological downstaging (pDS) rates, showed antitumor activity in cisplatin-ineligible pts with MIBC who received neoadjuvant EV treatment (Petrylak ASCO GU 2022). Here we report updated results, including event-free survival (EFS) and subsequent cancer-related therapy. Methods: Cohort H of the EV-103 phase 1b/2 study (NCT03288545) enrolled cisplatin-ineligible pts with MIBC (T2-T4aN0M0) and ECOG PS ≤2 who were eligible for RC+PLND. Pts received neoadjuvant EV (1.25 mg/kg) on Days 1 and 8 every 21 days for 3 cycles before undergoing RC+PLND. The primary endpoint was pCR rate (ypT0 and N0) by central pathology review. Key secondary endpoints included pDS rate (ypT0, ypTis, ypTa, ypT1, and N0), EFS based on investigator assessment, and safety. Results: 22 pts (median age 74.5 yr, range 56-81) were enrolled and treated; 17 pts (77.3%) remain on study. Pts had stage cT2 (68.2%), cT3 (27.3%), or cT4 (4.5%) disease. 68.2% of pts had transitional cell carcinoma only; 31.8% had a mixed histology. 86.4% of pts completed all 3 cycles of EV treatment; the median duration of EV treatment was 2.1 months (range 0.7-2.3). The pCR rate was 36.4% (95% CI, 17.2, 59.3) and the pDS rate was 50.0% (95% CI, 28.2, 71.8). Median EFS has not been reached. The EFS rate at 12 months was 76.4% (95% CI, 52.2, 89.4). All pts underwent surgery with no delays due to EV-related TEAEs. The most common EV-related TEAEs were fatigue (45.5%), dysgeusia (36.4%), and alopecia (31.8%); 18.2% of pts had grade ≥3 EV-related TEAEs. 68.2% of pts had surgery-related TEAEs and 31.8% pts had grade ≥3 surgery-related TEAEs. The most common surgery-related TEAEs were procedural pain (18.2%), anaemia (13.6%), and constipation (13.6%). 3 pts died due to AEs unrelated to EV treatment; in 2 pts the AEs occurred >30 days after RC+PLND. 36.4% of pts received subsequent cancer-related therapy. Conclusions: Neoadjuvant EV monotherapy treatment showed promising results for antitumor activity and EFS with a manageable safety profile in cisplatin-ineligible pts with MIBC. These results support ongoing phase 2 and 3 programs in MIBC evaluating EV alone or combined with pembrolizumab (EV-103 Cohort L, KN-905, KN-B15). Clinical trial information: NCT03288545 .

Effect of extended treatment with IAP inhibitor xevinapant post radiotherapy (RT) on efficacy and the tumor microenvironment (TME) in preclinical models.

6027 Background: Xevinapant is a first-in-class, oral IAP (inhibitor of apoptosis protein) inhibitor designed to restore cancer cell sensitivity to apoptosis, induced by RT and chemotherapy, and enhance antitumor immunity. In a randomized phase 2 study of patients with unresected locally advanced squamous cell carcinoma of the head and neck, xevinapant + chemoradiotherapy (CRT) significantly improved 18-month locoregional control and improved 3-year progression-free survival and 5-year overall survival vs placebo + CRT. A phase 3 confirmatory study (TrilynX NCT04459715) and a phase 3 study to evaluate xevinapant + RT in post-operative, high-risk, cisplatin-ineligible patients (XRay Vision NCT05386550) are ongoing. In these studies, we investigate 3 additional cycles of xevinapant or placebo monotherapy after completing combination treatment. Based on the role of IAPs in apoptosis, immunity, and stromal activation, continual dosing of xevinapant post RT may have additional therapeutic benefits. Methods: MC38 syngeneic tumor-bearing mice were treated with vehicle control, RT alone (3.6Gy once daily [QD], 5 days), or RT + xevinapant (100 mg/kg QD, 1, 2, or 4 weeks). To assess treatment-mediated TME modulation, immune cells in tumors were evaluated by fluorescence-activated cell sorting (FACS)–based immunophenotyping, and tumor-specific T cell responses were investigated by enzyme-linked immunosorbent spot (ELISpot) assays. To understand the effect of xevinapant on RT-induced cancer associated fibroblast (CAF) activation, CAF gene expression was profiled on cell lines and patient-derived primary cultures. Results: Xevinapant + RT increased antitumor efficacy compared with vehicle control or RT alone. Moreover, RT in combination with extended dosing of xevinapant for 4 weeks significantly improved therapeutic efficacy and prolonged survival compared with RT + shorter xevinapant dosing durations. FACS analysis demonstrated trends of increased numbers of CD8+ T cells, natural killer cells, and dendritic cells and decreased numbers of regulatory T cells in mice treated with xevinapant + RT. FACS and ELISpot further suggested an increase in antigen-specific T cell counts from baseline with combination therapy arm vs vehicle control or RT alone. Xevinapant may also suppress RT-mediated CAF activation, as indicated by downregulation of activation markers and CAF-derived secretory proteins. Conclusions: In preclinical models, extended dosing of xevinapant for 4 weeks post RT improved antitumor efficacy. Our data suggest that the effect may be, in part, modulated by TME responses, including enhanced antitumor immunity and suppressed pro-tumorigenic phenotype of CAFs. Based on these results, further evaluation is warranted to determine the mechanisms that underscore the therapeutic benefit offered by extended dosing of xevinapant.

KEYNOTE-905/EV-303: A phase 3 study to evaluate the efficacy and safety of perioperative pembrolizumab or pembrolizumab plus enfortumab vedotin (EV) for muscle-invasive bladder cancer (MIBC).

TPS4601 Background: Standard of care for MIBC is neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy + pelvic lymph node dissection (RC + PLND), but many patients with MIBC are ineligible for cisplatin-based chemotherapy. In the phase 1b/2 KEYNOTE-869/EV-103 study, combination therapy with the PD-1 inhibitor pembrolizumab and the Nectin-4–directed antibody-drug conjugate EV showed promising antitumor activity in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma. KEYNOTE-905/EV-303 (NCT03924895) is a multicenter, randomized, open-label, phase 3 study to evaluate efficacy and safety of perioperative pembrolizumab alone or combined with EV versus RC + PLND alone in patients with MIBC who are ineligible for or decline cisplatin-based treatment. Methods: Patients with treatment-naive MIBC (T2-T4aN0M0 or T1-T4aN1M0) and predominantly (≥50%) urothelial histology who are cisplatin ineligible or decline cisplatin-based treatment and have an ECOG PS score of 0-2 are eligible. Cisplatin ineligibility will be defined as meeting ≥1 of the following criteria: impaired renal function with calculated creatinine clearance 30-59 mL/min; ECOG PS 2; grade ≥2 audiometric hearing loss per CTCAE v4.0; or NYHA class III heart failure. Patients will receive neoadjuvant pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) for ≤3 cycles followed by RC + PLND and adjuvant pembrolizumab 200 mg IV Q3W for ≤14 cycles (arm A); RC + PLND followed by observation (adjuvant nivolumab permitted based on clinical indication and regulatory approval [arm B]); or neoadjuvant EV 1.25 mg/kg + pembrolizumab 200 mg IV Q3W for ≤3 cycles followed by RC + PLND and adjuvant EV + pembrolizumab for ≤6 cycles and adjuvant pembrolizumab 200 mg IV Q3W for ≤8 cycles (arm C). In the neoadjuvant and adjuvant phases of arm C, pembrolizumab will be administered on day 1 and EV will be administered on days 1 and 8 of each cycle. Enrollment is complete for arm A; patients will continue to be randomly assigned 1:1 to arm B or arm C. Stratification factors are tumor stage (T2N0 vs T3/T4aN0 vs T1-T4aN1), geographic region (United States vs Europe vs most of world), and cisplatin eligibility (cisplatin ineligible or cisplatin eligible but declines treatment). The primary end point is event-free survival between arm B and arm C. Secondary end points are event-free survival (arm A vs arm B) pathologic complete response, overall survival, disease-free survival, pathologic downstaging rates, and safety. Enrollment is planned for 308 patients, and recruitment is ongoing in Africa, Asia, Australia, Europe, North America, and South America. © 2023 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2023 ASCO-GU Annual Meeting. All rights reserved. Clinical trial information: NCT03924895 .

EE154 Budget Impact Analysis of Pembrolizumab Plus Enfortumab Vedotin As First-Line Treatment of Cisplatin-Ineligible Locally Advanced or Metastatic Urothelial Carcinoma in USA

Pembrolizumab plus enfortumab vedotin (Pem+EV) showed encouraging activity in first-line (1L) cisplatin-ineligible (cis-IE) patients with locally advanced or metastatic urothelial cancer (la/mUC) in the KEYNOTE-869/EV-103 trial. The objective is to estimate the budget impact of including Pem+EV to a US health plan formulary as a 1L therapy in cis-IE la/mUC.

A phase III randomized trial of eribulin (E) with or without gemcitabine vs standard of care (SOC) for metastatic urothelial carcinoma (UC) refractory to or ineligible for PD/PDL1 antibody (Ab): SWOG S1937.

TPS4608 Background: UC is 2nd most common genitourinary cancer. Current SOC offers platinum-based (PB) first line chemotherapy (chemo) with ddMVAC or gemcitabine-cisplatin (GC) regimens. For cisplatin ineligible patients (pts), SOC includes gemcitabine-carboplatin (GCa), and in select pts pembrolizumab. Erdafitinib is approved for pts with FGFR alterations and Enfortumab vedotin (EV) is approved for previously treated pts. A phase I/II CTEP study of eribulin (E) for metastatic UC (mUC) established the activity of E in UC with objective response rate (ORR) of 37.5% and a median progression free survival (PFS) of 4.1 months (mo) and median overall survival (OS) of 9.5 mo (N=150). A phase II CTEP study of gemcitabine-eribulin (GE) in cisplatin ineligible mUC showed an ORR of 50%, median OS of 11.9 mo and median PFS of 5.3 mo (N=24). The most common Grade 3-4 toxicities included: neutropenia 63%, anemia and fatigue 29%. Pts with liver metastases benefited from therapy with 5 responders in 7 pts for GE vs 12 out 49 E. Methods: This is a phase III, randomized 3 arm study comparing E vs. GE vs. SOC (docetaxel, paclitaxel, or gemcitabine). E is given at 1.4mg/m2 on day (D) 1 and 8 of a 21 D cycle. In the GE arm, gemcitabine is added to E at 1000 mg/m2 dose to D1 and D8. SOC follows standard dosing of the agents. There is no limit to the number/sequence of prior regimens. A simplified summary of eligibility criteria is presented here. All pts must have: received frontline systemic treatment such as PB chemo or a non-platinum regimen; received PD1/PDL1 Ab or be deemed ineligible for PD1/PDL1 Ab; received EV. Assuming a median OS for the SOC arm of 7 mo the study seeks to find at least a 50% increase in median OS to 10.5 mo (Hazard Ratio (HR) = 0.667). One-sided 0.0125 type I error to account for testing of two primary hypotheses (Each arm vs. SOC). 87% power to detect a 3.5 mo improvement in OS. We require 140 eligible (155 total) pts in each arm for a total of 465. The study was activated in Feb 2021 and accrual is ongoing. Clinical trial information: NCT04579224 .

Study EV-103 dose escalation/cohort A: Long-term outcome of enfortumab vedotin + pembrolizumab in first-line (1L) cisplatin-ineligible locally advanced or metastatic urothelial carcinoma (la/mUC) with nearly 4 years of follow-up.

4505 Background: Despite available therapeutic options, which include carboplatin-based chemotherapy, PD-1/PD-L1 inhibitor monotherapies, and avelumab maintenance, there is an urgent unmet need for effective and durable 1L therapies for cisplatin-ineligible patients (pts) with la/mUC. Both enfortumab vedotin (EV) and pembrolizumab (P) show survival benefits as monotherapies for pts with previously treated la/mUC. The combination of EV+P previously showed a manageable safety profile and promising antitumor activity in Study EV-103 Dose Escalation/Cohort A (DE/A) and Cohort K. Here, we report updated safety, efficacy per RECIST v1.1 by BICR, survival data, and subsequent therapies for DE/A after nearly 4 years of follow-up. Methods: In DE/A of this ongoing phase 1b/2 study, 1L cisplatin-ineligible pts with la/mUC received 3-week cycles of EV 1.25 mg/kg (Days 1, 8) in combination with P (Day 1). The primary endpoint was safety/tolerability. Key secondary endpoints included confirmed ORR (cORR), DOR, PFS (all per RECIST v1.1 by BICR and investigator), and OS. Safety and subsequent therapy results are also presented. Results: As of 16 Sep 2022, 45 pts with 1L la/mUC (median age 69 yrs [51-90]) received treatment. All pts discontinued treatment and 18 pts remain on study (median follow-up of 47 months). The cORR by BICR after a median of 9 cycles was 73.3% (95% CI: 58.1, 85.4), with a DCR of 84.4% (95% CI: 70.5, 93.5) and CR rate of 15.6%. The median DOR was 22.1 months (95% CI: 8.38, -), with a 12-month DOR of 63.9% (95% CI: 44.19, 78.17). The median PFS was 12.7 months (95% CI: 6.11, -), with a 12-month PFS of 55.0% (95% CI: 38.84, 68.58). The median OS was 26.1 months (95% CI: 15.51, -), with a 12-month OS rate of 83.4% (95% CI: 68.25, 91.72). The most common treatment-related adverse events of special interest for EV were skin reactions (66.7%), peripheral neuropathy (62.2%), and ocular disorders (40.0%). The most common treatment-emergent adverse events of special interest for P were severe skin reactions (24.4%), pneumonitis (8.9%), colitis (6.7%), and hypothyroidism (6.7%). Sixty percent of pts received subsequent cancer-related therapies, including systemic therapy (48.9%), surgery (8.9%), and palliative radiotherapy (8.9%). The most common 2L systemic anti-cancer therapies were P (17.8%), carboplatin-based therapy (11.1%), and EV (6.7%). Conclusions: EV+P, continues to demonstrate promising survival trends with rapid and durable responses in 1L cisplatin-ineligible pts with la/mUC. The safety profile of the combination is manageable and stable with a longer follow-up, and no new safety concerns have emerged. These results are concordant with previously reported DE/A data by investigator assessment and support the evaluation of EV+P in ongoing phase 3 studies in UC. Clinical trial information: NCT03288545 .

Real-world effectiveness of pembrolizumab as first-line therapy for cisplatin-ineligible patients with advanced urothelial carcinoma: the ARON-2 study.

The advent of immune-checkpoint inhibitors has challenged previous treatment paradigms for advanced urothelial carcinoma (UC) in the post-platinum setting as well as in the first-line setting for cisplatin-ineligible patients. In this study, we investigated the effectiveness of pembrolizumab as first-line treatment for cisplatin-ineligible UC. Data from patients aged ≥ 18years with cisplatin-ineligible UC and receiving first-line pembrolizumab from January 1st 2017 to September 1st 2022 were collected. Cisplatin ineligibility was defined according to the Galsky criteria. Thirty-three Institutions from 18 countries were involved in the ARON-2 study. Our analysis included 162 patients. The median follow-up time was 18.9months (95%CI 15.3-76.9). In the overall study population, the median OS was 15.8months (95%CI 11.3-32.4). The median OS was significantly longer in males versus females while no statistically significant differences were observed between patients aged < 65y versus ≥ 65y and between smokers and non-smokers. According to Recist 1.1 criteria, 26 patients (16%) experienced CR, 32 (20%) PR, 39 (24%) SD and 55 (34%) PD. Our data confirm the role of pembrolizumab as first-line therapy for cisplatin-unfit patients. Further studies investigating the biological and immunological characteristics of UC patients are warranted in order to optimize the outcome of patients receiving immunotherapy in this setting.

A phase II open-label trial of avelumab plus axitinib in previously treated non-small-cell lung cancer or treatment-naïve, cisplatin-ineligible urothelial cancer

We hypothesized that avelumab plus axitinib could improve clinical outcomes in patients with advanced non-small-cell lung cancer (NSCLC) or urothelial carcinoma (UC). We enrolled previously treated patients with advanced or metastatic NSCLC, or untreated, cisplatin-ineligible patients with advanced or metastatic UC. Patients received avelumab 800 mg every 2 weeks (Q2W) and axitinib 5 mg orally two times daily. The primary endpoint was objective response rate (ORR). Immunohistochemistry was used to assess programmed death-ligand 1 (PD-L1) expression (SP263 assay) and the presence of CD8+ T cells (clone C8/144B). Tumor mutational burden (TMB) was assessed by whole-exome sequencing. A total of 61 patients were enrolled and treated (NSCLC, n= 41; UC, n= 20); 5 remained on treatment at data cut-off (26 February 2021). The confirmed ORR was 31.7% in the NSCLC cohort and 10.0% in the UC cohort (all partial responses). Antitumor activity was observed irrespective of PD-L1 expression. In exploratory subgroups, ORRs were higher in patients with higher (≥median) CD8+ T cells in the tumor. ORRs were higher in patients with lower TMB (<median) in the NSCLC cohort and higher TMB (≥median) in the UC cohort. Treatment-related adverse events (TRAEs) occurred in 93.4% of patients, including grade ≥3 TRAEs in 55.7%. Avelumab exposures with 800 mg Q2W dosing were similar to those observed with 10 mg/kg Q2W dosing. In previously treated patients with advanced/metastatic NSCLC, ORR appeared to be superior to anti-PD-L1 or anti-programmed cell death protein 1 monotherapy, irrespective of PD-L1 status, whereas in untreated, cisplatin-ineligible patients with advanced/metastatic UC, ORR was lower than expected, potentially limited by small patient numbers. Clinicaltrial.gov NCT03472560; https://clinicaltrials.gov/ct2/show/NCT03472560.

Current State and Future Directions of EGFR-Directed Therapy in Head and Neck Cancer.

Epidermal growth factor receptor (EGFR) is commonly overexpressed in many head and neck squamous cell carcinomas (HNSCC). With the success of EGFR inhibition in other cancer types, there was optimism for efficacy in HNSCC. Unfortunately, the clinical outcomes of EGFR-directed therapy have not provided overwhelming benefit. In the curative-intent setting, cisplatin has proven superior over cetuximab, an EGFR monoclonal antibody, in multiple large trials, and cisplatin should continue to be the treatment of choice when administered with definitive or adjuvant radiation. For cisplatin-ineligible patients, we prefer carboplatin-based treatment over cetuximab. We reserve cetuximab for a small group of patients who are eligible for radiation and systemic treatment but have contraindications to any platinum therapy. The role of EGFR inhibitors in the recurrent/metastatic setting is more robust. Although supplanted by immunotherapy as front-line treatment, cetuximab remains a meaningful second-line option for patients who have progressed on immune checkpoint inhibitors. Overall, EGFR-directed therapies have been of modest value in the treatment of both locally advanced and metastatic HNSCC. The future of EGFR-directed therapies will likely develop from exploring combination therapies, especially with immunotherapy. Early evidence suggests synergistic effects allowing for a more robust immune response, which holds promise for novel regimens in the treatment of HNSCC.

Abstract 2119: Intravenous vitamin C therapy for cisplatin ineligible bladder cancer patients (CI-MIBC): Early investigation into potential pharmacodynamic biomarkers

Abstract Neoadjuvant cisplatin based chemotherapy is considered standard of care for patients with locally advanced bladder cancer (BCa). However, upwards of 50% of patients are ineligible due to poor performance status, underlying kidney disease, peripheral neuropathy, hearing loss and/or cardiac disease. There are currently no accepted alternative regimens with significant activity, and many cisplatin ineligible patients usually proceed directly to surgery. Prior research in other cancers has indicated intravenous vitamin C (IVC), or ascorbate, may serve as a beneficial adjuvant to less toxic therapeutic regimens. We initiated a single arm, Simon 2-stage, Window of Opportunity trial using high dose IVC with single cycle gemcitabine/carboplatin (GCa) (NCT04046094). The primary outcome was pathologic downstaging. Twelve patients with newly diagnosed CI-MIBC were enrolled. Patients received single cycle GCa and IVC titrated to 350-400 mg/dL for ~21 days followed by cystectomy after ~4-6 weeks. As reported, pathological downstaging (&amp;lt;ypT2N0Mx) was present in 4 (33%) of patients. Three of the four patients had a complete response (ypT0NoMx) including one patient with plasmacytoid variant histology. Treatment was well tolerated with no attributable AE/SAEs. Given the discrepancy in response levels, we began identifying potential markers of pharmacodynamic efficacy to inform future trials. Novel data evaluating Ki67+ cells by immunohistochemistry indicate widespread proliferation in non-responders to IVC/GCa, whereas responding patients had visibly fewer positive cells, suggesting a direct effect on cell death and proliferation. TUNEL staining was present in all samples, although often minimally, and thus TUNEL may not yield enough signal to reliably make determinations about treatment outcomes. Urinary cytokine values were assessed using multiplex ELISA and reported as pg/mL urine. Multiple cytokines including IL-1RA, CCL2, IL-8, CXCL10 were present at markedly high concentrations in patients with BCa. Cytokine levels generally increased between diagnostic resection and radical cystectomy indicating potential immune activation by the IVC/GCa treatment. Cytokine levels generally fell between radical cystectomy and follow-up samples suggesting resolution of inflammation after cystectomy. In conclusion, IVC/GCa may be a viable alternative neoadjuvant treatment strategy for patients with BCa that are ineligible for cisplatin-based chemotherapy. Identifying biomarkers of response remains a major area of interest to refine study designs and identify patients most likely to benefit from therapy. Citation Format: Benjamin L. Woolbright, Ganeshkumar Rajendran, Erika Abbott, Zeb Zacharias, Jon Houtman, Rahul Parikh, Qi Chen, Ameer Hamza, Elizabeth Wulff-Burchfield, Jeffrey M. Holzbeierlein, Jeanne Drisko, Michael D. Henry, John A. Taylor. Intravenous vitamin C therapy for cisplatin ineligible bladder cancer patients (CI-MIBC): Early investigation into potential pharmacodynamic biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2119.

In-Field Toxicity Analysis of a Phase 1 Clinical Trial of Nivolumab and Ipilimumab With Definitive Radiation Therapy in Locally Advanced Squamous Cell Carcinoma of the Head and Neck

Combined modality therapy for locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) is associated with increased toxicities. Immunotherapy has a documented benefit in the recurrent/metastatic setting with a favorable toxicity profile. We evaluated in-field toxicities in the context of a single-institution clinical trial with combined nivolumab, a PD-1 inhibitor, and ipilimumab, a CTLA-4 inhibitor, and concurrent radiation therapy (RT) in patients with LA SCCHN. We analyzed in-field toxicity events in 24 cisplatin-eligible patients with newly-diagnosed LA SCCHN (14 HPV-positive oropharyngeal) treated with nivolumab (3 mg/kg every two weeks for 17 doses) and ipilimumab (1 mg/kg every six weeks for 6 doses) starting two weeks prior to intensity-modulated radiation therapy (IMRT; 70 Gy in 2 Gy fractions). All patients completed RT with no treatment delays. 16/24 patients experienced at least one grade 3 in-field toxicity during radiation treatment including radiation dermatitis (5), dysphagia (6), oral mucositis (10), odynophagia (3), oropharyngeal pain (1), and hoarseness (1). There were no grade 4 or 5 AEs during ICI-RT. Five patients (22%) developed soft tissue ulcers (STU) at the primary tumor site during the consolidation phase, one of which led to a fatal carotid rupture. STUs developed at a median of 91 (range 50-107) days post RT and were negative for viable tumor. Three-year locoregional control rate was 94.7% (95% CI, 85.2%-100%). Concurrent radioimmunotherapy with nivolumab and ipilimumab resulted in excellent locoregional control, but may have an increased the risk of STU. Patients treated with such an approach should be closely monitored for in-field toxicity events, including soft tissue ulceration.

MP56-09 NEOADJUVANT PEMBROLIZUMAB SHOWS PROMISE AS EFFECTIVE SYSTEMIC THERAPY PRIOR TO RADICAL CYSTECTOMY FOR CISPLATIN-INELIGIBLE MUSCLE INVASIVE BLADDER CANCER

You have accessJournal of UrologyCME1 Apr 2023MP56-09 NEOADJUVANT PEMBROLIZUMAB SHOWS PROMISE AS EFFECTIVE SYSTEMIC THERAPY PRIOR TO RADICAL CYSTECTOMY FOR CISPLATIN-INELIGIBLE MUSCLE INVASIVE BLADDER CANCER Kyle Rose, Marco Bandini, Heather Huelster, Giuseppe Basile, Shreyas Naidu, Philippe Spiess, Andrea Necchi, and Roger Li Kyle RoseKyle Rose More articles by this author , Marco BandiniMarco Bandini More articles by this author , Heather HuelsterHeather Huelster More articles by this author , Giuseppe BasileGiuseppe Basile More articles by this author , Shreyas NaiduShreyas Naidu More articles by this author , Philippe SpiessPhilippe Spiess More articles by this author , Andrea NecchiAndrea Necchi More articles by this author , and Roger LiRoger Li More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003309.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: There is an unmet clinical need for systemic treatment in patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based neoadjuvant chemotherapy. We aimed to compare pathologic response and survival outcomes in cisplatin-ineligible patients receiving neoadjuvant pembrolizumab (NAP) vs. immediate radical cystectomy (IRC). METHODS: Cisplatin-ineligible patients with cT2-4N0M0 MIBC were identified from the PURE-01 trial and compared against cisplatin-ineligible MIBC patients treated with immediate radical cystectomy (IRC). Overall survival (OS) analysis was performed using the Kaplan-Meier method and Log-Rank functions. Cox-proportional hazards modelling was used to determine variable contribution to survival. Propensity score matching was performed for IRC and NAP patients based on pre-cystectomy ECOG status, GFR, age, sex, and clinical T stage. An exploratory analysis also matched patients by pathologic T stage. Statistical analysis was performed using R. RESULTS: Thirty-nine cisplatin-ineligible patients treated with NAP were identified from PURE-01, and compared against 313 cisplatin-ineligible patients undergoing IRC (Figure 1A). OS was prolonged in the NAP patients, with median survival of 19 months in the IRC vs. not reached (NR) in the NAP group (p<0.01). Thirty-nine patients were identified from the IRC cohort after propensity matching, with comparable baseline clinicopathologic data. Patients receiving NAP experienced a higher complete response rate on final pathology (pT0: 33% vs. 13%, p=0.03). Median OS was prolonged in the NAP group (NR vs. 21.0 mo, p<0.01), specifically at 12 mo (89% vs. 57%), 24mo (64% vs. 28%), and 36 months after surgery (33% vs. 13% ) (p<0.01). On Cox Proportional Hazards Modelling, patients undergoing IRC demonstrated worse OS with a hazard ratio of 2.0 (95% CI 1.1 - 3.89). CONCLUSIONS: Cisplatin-ineligible patients receiving NAP for muscle invasive bladder cancer had a higher rate of downstaging and a survival advantage over patients who underwent IRC. Results of ongoing prospective randomized trials will help validate these findings and provide therapeutic options to cisplatin-ineligible patients. Source of Funding: NA © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e777 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kyle Rose More articles by this author Marco Bandini More articles by this author Heather Huelster More articles by this author Giuseppe Basile More articles by this author Shreyas Naidu More articles by this author Philippe Spiess More articles by this author Andrea Necchi More articles by this author Roger Li More articles by this author Expand All Advertisement PDF downloadLoading ...

Carboplatin Induction Chemotherapy in Clinically Lymph Node–positive Bladder Cancer

BackgroundThere are currently no guideline recommendations regarding the treatment of cisplatin-ineligible, clinically lymph node–positive (cN+) bladder cancer (BCa). ObjectiveTo investigate the oncological efficacy of gemcitabine/carboplatin induction chemotherapy (IC) in comparison to cisplatin-based regimens in cN+ BCa. Design, setting, and participantsThis was an observational study of 369 patients with cT2–4 N1–3 M0 BCa. InterventionIC followed by consolidative radical cystectomy (RC). Outcome measurements and statistical analysisThe primary endpoints were the pathological objective response (pOR; ypT0/Ta/Tis/T1 N0) rate and the pathological complete response (pCR; ypT0N0) rate. We applied 3:1 propensity score matching (PSM) to reduce selection bias. Overall survival (OS) and cancer-specific survival (CSS) were compared across groups using the Kaplan-Meier method. Associations between the treatment regimen and survival endpoints were tested in multivariable Cox regression analyses. Results and limitationsAfter PSM, a cohort of 216 patients was available for analysis, of whom 162 received cisplatin-based IC and 54 gemcitabine/carboplatin IC. At RC, 54 patients (25%) had a pOR and 36 (17%) had a pCR. The 2-yr CSS was 59.8% (95% confidence interval [CI] 51.9–69%) for patients who received cisplatin-based IC versus 38.8% (95% CI 26–57.9%) for those who received gemcitabine/carboplatin. For the pOR (p = 0.8), ypN0 status at RC (p = 0.5), and cN1 BCa subgroups (p = 0.7), there was no difference in CSS between cisplatin-based IC and gemcitabine/carboplatin. In the cN1 subgroup, treatment with gemcitabine/carboplatin was not associated with shorter OS (p = 0.2) or CSS (p = 0.1) on multivariable Cox regression analysis. ConclusionsCisplatin-based IC seems to be superior to gemcitabine/carboplatin and should be the standard for cisplatin-eligible patients with cN+ BCa. Gemcitabine/carboplatin may be an alternative treatment for selected cisplatin-ineligible patients with cN+ BCa. In particular, selected cisplatin-ineligible patients with cN1 disease may benefit from gemcitabine/carboplatin IC. Patient summaryIn this multicenter study, we found that selected patients with bladder cancer and clinical evidence of lymph node metastasis who cannot receive standard cisplatin-based chemotherapy before surgery to remove their bladder may benefit from chemotherapy with gemcitabine/carboplatin. Patients with a single lymph node metastasis may benefit the most.

Effectiveness and safety of immune checkpoint inhibitor monotherapy in advanced upper tract urothelial carcinoma: A multicenter, retrospective, real-world study.

The effectiveness and safety of immune checkpoint inhibitor (ICI) monotherapy in advanced upper tract urothelial carcinoma (UTUC) is less reported. In total, 106 consecutive advanced UTUC patients receiving ICI monotherapy were collected from nine high volume centers. Clinical outcomes were analyzed according to multiple parameters (e.g., treatment line, metastatic sites). Objective response rate (ORR), overall survival (OS) and progression-free survival (PFS) were captured after ICI initiation. With a median follow-up of 12.0months, 25 patients in the first-line group and 15 patients in the second-line group died of UTUC. We reported a median OS of 18.0months, a median PFS of 5.0months, and an ORR of 38.6% for patients in the first-line group; a median OS of 10.0months, a median OS of 4.0months, and an ORR of 27.8% for patients in the second-line group. Complete response was observed in two patients in the first-line group and one patient in the second-line group with a total complete response rate of 2.8%. In the univariate and multivariate analysis, visceral metastasis with a hazard ratio of 2.4 was associate with poor OS. The most common treatment-related adverse events included fatigue (11.3%), pruritus (10.4%), and diarrhea (6.6%). This real-world study suggests that ICI monotherapy is active and has acceptable toxic effects for unresectable or metastatic UTUC as first-line therapy in cisplatin-ineligible patients or second-line therapy in platinum-refractory patients.

Current Status of Perioperative Therapy in Muscle-Invasive Bladder Cancer and Future Directions.

Cisplatin-based combination chemotherapy has been a standard of care in the perioperative management of muscle-invasive bladder cancer for years, but several novel therapies are under active investigation. This review aims to provide an update on recent relevant literature and a forward look at the future landscape of adjuvant and neoadjuvant therapy in muscle-invasive bladder cancer patients who opt for radical cystectomy. The recent approval of nivolumab as adjuvant therapy established a new treatment option for high-risk patients with muscle-invasive bladder cancer after radical cystectomy. Several phase II studies of chemo-immunotherapy combinations and immunotherapy alone have reported pathological complete responses in the 26-46% range, including studies in cisplatin-ineligible patients. Randomized studies of perioperative chemo-immunotherapy, immunotherapy alone, and enfortumab vedotin are ongoing. Muscle-invasive bladder cancer remains a challenging disease associated with significant morbidity and mortality; however, increasing options in systemic therapy and an increasingly personalized approach to cancer treatment suggest continued future improvements in patient care.

Neoadjuvant pembrolizumab for cisplatin-ineligible muscle-invasive bladder cancer prior to radical cystectomy.

513 Background: There is an unmet need for systemic treatment options in patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based neoadjuvant chemotherapy. The PURE-01 trial has also demonstrated preliminary efficacy when pembrolizumab is used in the neoadjuvant setting. We aimed to compare pathologic response and survival outcomes in cisplatin-ineligible patients receiving neoadjuvant pembrolizumab (NAP) vs. immediate radical cystectomy (IRC). Methods: Cisplatin-ineligible MIBC patients were identified from the PURE-01 trial and compared against cisplatin-ineligible MIBC patients treated with immediate radical cystectomy (IRC). Overall survival was analyzed using Kaplan-Meier and Cox Proportional Hazards Modelling. IRC patients were matched via nearest neighbor propensity technique to cisplatin-ineligible patients from PURE-01 by ECOG status, GFR, age, sex, and clinical T stage. Results: Thirty-nine cisplatin-ineligible patients treated with NAP were identified from PURE-01, and compared against 313 cisplatin-ineligible patients undergoing IRC (Figure 1A). OS was prolonged in the NAP patients, with median survival of 19 months in the IRC vs. not reached (NR) in the NAP group (p=&lt;0.01). Following nearest neighbor matching, 39 patients were identified from the IRC cohort, with comparable baseline clinicopathologic variables as listed in the table. Patients receiving NAP experienced a higher complete response rate on final pathology (pT0: 33% vs. 13%, p=0.03). Median OS was prolonged in the propensity score matched analysis (NAP NR vs. IRC 21.0mo, p&lt;0.01), specifically at 12mo (89% vs. 57%), 24mo (64% vs. 28%), and 36 months after surgery (33% vs. 13% ) (p&lt;0.01). Compared to NAP, cisplatin-ineligible patients undergoing IRC experienced worse OS, with a Hazard Ratio of 2.0 (95% CI 1.1 - 3.89). Conclusions: Cisplatin-ineligible patients receiving NAP for muscle invasive bladder cancer had a higher rate of downstaging and a survival advantage over patients who underwent IRC. Although this study suggests promising systemic options for cisplatin-ineligible patients in the neoadjuvant setting, results of ongoing prospective randomized trials will help validate these findings and provide therapeutic options to cisplatin-ineligible patients. [Table: see text]

Patient-reported outcomes (PROs) in cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC) treated with enfortumab vedotin (EV) alone or in combination with pembrolizumab (P) in the phase 1b/2 EV-103 Cohort K study.

439 Background: The EV-103 Cohort K trial evaluated 1L EV+P or EV alone (NCT03288545) in pts with la/mUC who were cisplatin-ineligible. EV+P showed a clinically meaningful objective response rate (64.5%; 95% CI, 52.7–75.1) with a manageable safety profile. Because la/mUC is associated with symptoms with a frequent impact on quality of life (QOL) and functioning (Mamtani et al. JCO 2021), we describe the impact of EV+P or EV alone on QOL and symptoms. Methods: In this open-label, Phase 1b/2 trial, cisplatin-ineligible pts with la/mUC were randomized 1:1 to EV+P or EV alone. For exploratory PRO endpoints, pts completed EORTC QLQ-C30 and the BPI-SF at baseline, weekly for cycles 1–3, and once every cycle for the remainder of treatment period. The PRO analysis set included only pts who were treated and completed the questionnaire at baseline. Mixed effect models for repeated measures (MMRM; least squares [LS] mean, standard error [SE]) not adjusted for multiplicity, estimated change vs baseline until Week 24; established thresholds (EORTC QLQ-C30: 10-point change; BPI-SF: 2-point change) were applied to determine clinically meaningful change. Results: Of the 76 pts treated with EV+P, 65 were included in the PRO analysis set. EORTC QLQ-C30 and BPI-SF were completed by 100% and 95%, respectively, at baseline; compliance rates were ≥84% for both instruments through Week 24. In the EORTC QLQ-C30 MMRM analyses, QOL was maintained through Week 24 for EV+P; functioning and symptom scores remained stable over time, with improvements in emotional functioning, pain and sleep disturbance vs observed baseline. In the EV+P arm, clinically meaningful reductions in pain were seen at Week 12 (-12.64 [3.208]) vs baseline and persisted through Week 24 (-13.20 [3.406]). In the BPI-SF MMRM analyses, worst and average pain, pain interference and severity consistently showed improved scores from Week 4–24 for EV+P; clinically meaningful change in worst pain was seen at Week 21 (-2.08 [0.361]). Similar completion and compliance rates were seen for the EV alone PRO analysis set (n=63). EV alone demonstrated clinically meaningful improvements in pain at Week 24 in the EORTC QLQ-C30 (-10.63 [4.110]) and consistent small-to-moderate improvements in the BPI worst and average pain, and pain severity (0.5–1.0 points). Sleep disturbances demonstrated improvement, and other symptom scales, QOL and functional domains remained stable. Conclusions: PRO data showed that EV+P in cisplatin-ineligible pts with la/mUC was associated with preservation or improvement of QOL, functioning, and symptoms. Improvement in pain was demonstrated consistently in both PRO instruments and treatment arms. These PRO data complement the clinical outcomes of EV+P in 1L cisplatin-ineligible pts with la/mUC. Clinical trial information: NCT03288545 .

A phase III randomized trial of eribulin (E) with or without gemcitabine vs standard of care (SOC) for metastatic urothelial carcinoma (UC) refractory to or ineligible for PD/PDL1 antibody (Ab): SWOG S1937.

TPS581 Background: UC is 2nd most common genitourinary cancer. Current SOC offers platinum-based (PB) first line chemotherapy (chemo) with ddMVAC or gemcitabine-cisplatin (GC) regimens. For cisplatin ineligible patients (pts), SOC includes gemcitabine-carboplatin (GCa), and in select pts pembrolizumab. Erdafitinib is approved for pts with FGFR alterations and Enfortumab vedotin (EV) is approved for previously treated pts. A phase I/II CTEP study of eribulin (E) for metastatic UC (mUC) established the activity of E in UC with objective response rate (ORR) of 37.5% and a median progression free survival (PFS) of 4.1 months (mo) and median overall survival (OS) of 9.5 mo (N=150). A phase II CTEP study of gemcitabine-eribulin (GE) in cisplatin ineligible mUC showed an ORR of 50%, median OS of 11.9 mo and median PFS of 5.3 mo (N=24). The most common Grade 3-4 toxicities included: neutropenia 63%, anemia and fatigue 29%. Pts with liver metastases benefited from therapy with 5 responders in 7 pts for GE vs 12 out 49 E. Methods: This is a phase III, randomized 3 arm study comparing E vs. GE vs. SOC (docetaxel, paclitaxel, or gemcitabine). E is given at 1.4mg/m2 on day (D) 1 and 8 of a 21 D cycle. In the GE arm, gemcitabine is added to E at 1000 mg/m2 dose to D1 and D8. SOC follows standard dosing of the agents. There is no limit to the number/sequence of prior regimens. A simplified summary of eligibility criteria is presented here. All pts must have: received frontline systemic treatment such as PB chemo or a non-platinum regimen; received PD1/PDL1 Ab or be deemed ineligible for PD1/PDL1 Ab; received EV. Assuming a median OS for the SOC arm of 7 mo the study seeks to find at least a 50% increase in median OS to 10.5 mo (Hazard Ratio (HR) = 0.667). One-sided 0.0125 type I error to account for testing of two primary hypotheses (Each arm vs. SOC). 87% power to detect a 3.5 mo improvement in OS. We require 140 eligible (155 total) pts in each arm for a total of 465. The study was activated in Feb 2021 and accrual is ongoing. Funding: National Institutes of Health/National Cancer Institute grants U10CA180888, U10CA180819. Clinical trial information: NCT04579224 .

Enfortumab vedotin (EV) alone or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer (la/mUC): Subgroup analyses of confirmed objective response rate (cORR) from EV-103 cohort K.

499 Background: In EV-103 Cohort K (NCT03288545), EV and P in combination (EV+P) showed encouraging antitumor activity and a manageable safety profile when used as 1L therapy in patients (pts) w/ la/mUC who are ineligible for cisplatin, a population w/ high unmet need. Here we report results of an analysis of prespecified Cohort K subgroups known to be associated w/ poor outcomes. Methods: Pts who are cisplatin-ineligible w/ previously untreated la/mUC were randomized 1:1 to EV (1.25 mg/kg) as monotherapy on Days 1 and 8 or in combination w/ P (200 mg) on Day 1 of 3-week cycles. Primary endpoint is cORR per RECIST v1.1 by blinded independent central review w/ no formal statistical comparison between arms. Secondary endpoints included duration of response and safety (e.g. treatment-related adverse events, TRAEs). The cORR analysis was performed in prespecified subgroups including age, ECOG PS, liver metastasis, PD-L1 expression status, metastatic disease site at baseline, and primary disease site of origin. Results: 149 pts were treated: EV+P n=76; EV n=73; cORRs across key subgroups for both EV+P and EV monotherapy are shown in the table. For EV+P overall cohort, cORR (95%CI): 64.5% (52.7, 75.1); median DOR was not reached. cORRs were consistent across subgroups for EV+P including those w/ ECOG PS score of 1-2: 62.8% (46.7, 77.0) and presence of liver metastasis: 53.8% (25.1, 80.8). Among TRAEs of special interest in the EV+P arm, skin reactions occurred in n=51 (67.1%); peripheral neuropathy occurred in n=46 (60.5%). For EV+P, 68.4% of pts had TRAEs leading to interruption of either EV or P; 48.7% of pts had TRAEs leading to EV dose reduction. Median duration of EV+P treatment was 11 cycles. Conclusions: EV+P showed promising cORR in 1L cisplatin-ineligible pts w/ la/mUC; activity was consistently observed across a range of pre-specified subgroups including those with poor prognosis. EV+P TRAEs were manageable w/ close monitoring and appropriate dose modifications w/ a meaningful duration of treatment. EV+P has the potential to address high unmet needs in 1L la/mUC and MIBC and is being further evaluated in 3 Phase 3 trials (NCT04223856, NCT04700124, NCT03924895). Clinical trial information: NCT03288545 . [Table: see text]

Neoadjuvant nivolumab (N) + ipilimumab (I) in cisplatin-ineligible patients with upper tract urothelial cancer (UTUC).

511 Background: Perioperative platinum-based chemo for UTUC improves pathologic responses and disease-free survival (DFS) while anti-PD1 monotherapy has limited activity to date (PURE-02). Here, we report the results from stage 1 of a phase II neoadjuvant trial of N+I for cisplatin-ineligible patients (pts) with UTUC. Methods: Cisplatin-ineligible pts with histologically confirmed high-grade UTUC and/or radiographically invasive UTUC with positive selective urine cytology were eligible. Pts were treated with I 3mg/kg + N 1mg/kg (weeks [wk] 0, 6), and N 3mg/kg (wk 3) prior to radical nephroureterectomy (NU). The primary endpoint (EP) was pathologic complete response (pCR, ypT0pN0) and secondary EPs included &lt;ypT2pN0 rate, DFS, and toxicity. The study has a Simon optimal two-stage design: if ≥1/9 pts achieved pCR in stage 1, the trial would proceed to accrue 24 total pts. Next generation sequencing of pre-treatment tumors was correlated with pathologic response. Results: Nine pts were enrolled between 2/2021-7/2022 with median age 71 (range 62-86), 89% male. Primary sites included ureter, n=6; renal pelvis, n=2; and both, n=1. Four pts (44%) had hydronephrosis. Median tumor diameter was 3.0 cm, (range: not measurable to 4.2 cm). Six pts (67%) received all planned treatment; N+/-I was stopped early for CTCAE grade 2 hyperthryoidism, n = 1; grade 2 diarrhea, n = 1; and grade 3 pneumonitis, n = 1. Median time from last treatment to NU was 1.7 months (range 0.6-3.7). No progression was noted on systemic therapy and all pts underwent NU, with pCR in 3/9 pts (33%) and &lt;ypT2pN0 in 6/9 (67%). Two pts had metastatic recurrence at 10.3 and 15.6 months after treatment initiation, while 1 pt died of post-op complications related to bowel leak 7.2 months after N+I initiation (4.7 months after NU) and 1 died 9.2 months after N+I initiation (4.7 months after NU) from complications of a fall unrelated to disease, surgery or N+I. Median tumor mutational burden (TMB) in 7 pts with pre-treatment sequencing was 13.2 mutations/megabase (range 6.6-106.3); all 3 pts with TMB&lt;10 were &gt;ypT1 or node positive at NU and all 4 pts with TMB&gt;10 were &lt;ypT1pN0. Three pts (43%) had FGFR3 driver mutations. Three pts had confirmed pathogenic germline variants in mismatch repair genes (MSH2, n=2; MLH1, n=1), all of which achieved pCR (n=1) or ypTaN0 (n=2) and remained alive and disease-free at last follow-up. CTCAE grade ≥3 treatment-related adverse events occurred in 4 pts (1 myasthenia, 1 maculopapular rash, 1 pneumonitis, 1 hepatitis plus elevated lipase). Conclusions: In this cohort of cisplatin-ineligible pts with UTUC, neoadjuvant N+I showed clinical activity meeting the trial’s Simon optimal two-stage design’s criteria to proceed to the second stage. All pts with pathogenic germline variants in mismatch repair genes achieved &lt;ypT1pN0 and remain free of disease. Clinical trial information: NCT03520491 Clinical trial information: NCT03520491 .