Advanced Urothelial Carcinoma Research Articles

Synergistic antitumor activity of METTL3 peptide degrader and immune checkpoint inhibitor in advanced urothelial cancer.

e14623 Background: In patients afflicted with advanced urothelial carcinoma (aUC), the durable response rate to immune checkpoint inhibitor (ICI) is approximately 20%. Recent study showed the pivotal role of N6-methyladenosine (m6A) methyltransferase-like 3 (METTL3) in immune escape and the progression of aUC. This study aimed to develop a novel METTL3 peptide degrader RKL and investigate its synergistic effects and underlying mechanisms in combination with ICI for aUC. Methods: Methyltransferase expression profiles were scrutinized using The Cancer Genome Atlas database; while the prognostic implications of METTL3 expression in response to ICI were analyzed in the IMvigor210 cohort study. Single-cell RNA sequencing (scRNA-seq) was employed to elucidate the mechanistic insights. The METTL3 peptide degrader RKL was synthesized using Fmoc solid-phase peptide synthesis and purified with high-performance liquid chromatography. In vivo and in vitro experiments were conducted to assess the impact of RKL, ICI, and their combination on aUC inhibition. Results: In aUC, METTL3 exhibited the most significant up-regulation among m6A methyltransferases, while METTL14 and WTAP showed down-regulated expression. In the IMvigor210 cohort study, aUC patients with elevated METTL3 expression and treated with ICI demonstrated a poorer prognosis. scRNA-seq revealed that METTL3 upregulation promoted the expression of genes regulating cancer-associated fibroblast proliferation, contributing to enhanced tumor resistance to immunotherapy. RKL demonstrated high toxicity to urothelial carcinoma cell lines, inhibiting their proliferative, migratory, and invasive capacities in vitro. The combined treatment of RKL and ICI significantly reduced tumor volume (P<0.001), with a complete response achieved in 87.5% (7/8) of mice in the combination group, 12.5% (1/8) in the RKL group, and 25.0% (2/8) in the ICI group. Conclusions: METTL3 overexpression in aUC is associated with immune escape and resistance to ICI therapy. The METTL3 peptide degrader RKL, when combined with ICI, demonstrates synergistic antitumor effects in aUC, warranting further exploration in clinical research.

Avelumab first-line maintenance in advanced urothelial carcinoma: Complete screening for prognostic and predictive factors using machine learning in the JAVELIN Bladder 100 phase 3 trial.

Avelumab first-line (1 L) maintenance is a standard of care for advanced urothelial carcinoma (aUC) based on the JAVELIN Bladder 100 phase 3 trial, which showed that avelumab 1 L maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) vs BSC alone in patients who were progression free after receiving 1 L platinum-containing chemotherapy. Here, we comprehensively screened JAVELIN Bladder 100 trial datasets to identify prognostic factors that define subpopulations of patients with longer or shorter OS irrespective of treatment, and predictive factors that select patients who could obtain a greater OS benefit from avelumab 1 L maintenance treatment. We performed machine learning analyses to screen a large set of baseline covariates, including patient demographics, disease characteristics, laboratory values, molecular biomarkers, and patient-reported outcomes. Covariates were identified from previously reported analyses and established prognostic and predictive markers. Variables selected from random survival forest models were processed further in univariate Cox models with treatment interaction and visually inspected using correlation analysis and Kaplan-Meier curves. Results were summarized in a multivariable Cox model. Prognostic baseline covariates associated with OS included in the final model were assignment to avelumab 1 L maintenance treatment, Eastern Cooperative Oncology Group performance status, site of metastasis, sum of longest target lesion diameters, levels of C-reactive protein and alkaline phosphatase in blood, lymphocyte proportion in intratumoral stroma, tumor mutational burden, and tumor CD8+ T-cell infiltration. Potential predictive factors included site of metastasis, tumor mutation burden, and tumor CD8+ T-cell infiltration. An analysis in patients with PD-L1+ tumors had similar findings to those in the overall population. Machine learning analyses of data from the JAVELIN Bladder 100 trial identified potential prognostic and predictive factors for avelumab 1 L maintenance treatment in patients with aUC, which warrant further evaluation in other clinical datasets.

Prognostic analysis of disitamab vedotin combined with PD-1 inhibitor first-line treatment in advanced urothelial carcinoma: A propensity score analysis.

Prognostic analysis of disitamab vedotin combined with PD-1 inhibitor first-line treatment in advanced urothelial carcinoma: A propensity score analysis.

Enfortumab vedotin (EV) with pembrolizumab (P) versus chemotherapy (chemo) in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC): Analysis of cisplatin (cis)-eligible population from EV-302/KEYNOTE-A39.

4562 Background: EV-302/KEYNOTE-A39 (NCT04223856) is a phase 3, randomized, open-label, global study comparing EV+P with platinum-based chemo (PBC) for first-line (1L) treatment (tx) of patients (pts) with la/mUC regardless of cis eligibility. In EV-302, EV+P demonstrated a statistically significant and clinically meaningful benefit compared with PBC for the dual primary endpoints of progression-free survival (PFS) (hazard ratio [HR]: 0.45; P<0.00001) and overall survival (OS) (HR: 0.47; P<0.00001) in the overall pt population (Powles ESMO 2023), reducing the risk of progression and/or death by more than 50%. EV+P was FDA-approved in Dec 2023 for tx of adults with la/mUC. As cis eligibility status has long defined 1L tx, here we present results for pts who were eligible for cis at randomization. Methods: Pts with previously untreated la/mUC were randomized 1:1 to receive 3-week cycles of EV (1.25 mg/kg IV; Days 1 and 8) and P (200 mg IV; Day 1) or PBC (gemcitabine with cis or carboplatin). Select secondary endpoints included confirmed objective response rate (ORR), duration of response (DOR), and safety. Pts were deemed eligible/ineligible for cis by protocol-defined criteria and were stratified accordingly. Results: 478 pts (EV+P: 244, PBC: 234) were cis-eligible at randomization. 220 (94.0%) pts in the PBC arm received cis at Cycle 1. mPFS was 14.6 mo for EV+P; 6.5 mo for PBC (HR: 0.48, 95% CI, 0.38, 0.62). mOS was 31.5 mo for EV+P; 18.4 mo for PBC (HR: 0.53, 95% CI, 0.39, 0.72). ORR for EV+P was 70.8% with 32.5% complete response (CR) rate; mDOR (95% CI) was not reached (18.2 mo, NR). ORR for PBC was 53.0% with 15.5% CR rate; mDOR (95% CI) was 8.3 mo (5.9, 10.9). In EV+P arm, 82 pts (33.6%) remained on tx at data cutoff (DCO). 85 pts (34.8%) received subsequent therapy. 72 pts (29.5%) received any platinum-based therapy as first subsequent therapy; 43 pts (17.6%) received cis. In PBC arm, all pts were off study tx at DCO. 146 pts (62.4%) received any PD-1/L1 therapy following PBC. 83 pts received maintenance avelumab; 59 pts received PD-1/L1 therapy as 2L tx. Grade ≥3 TRAEs occurred in 53.9% of pts with EV+P and 62.7% of pts with PBC. Most common grade ≥3 TRAEs of special interest for EV were skin reactions (14.8%), hyperglycemia (7.8%), and peripheral neuropathy (5.8%). Most common grade ≥3 tx-emergent AEs of special interest for P were severe skin reactions (9.5%), pneumonitis (4.9%), and colitis (2.9%). Conclusions: EV+P improved clinical outcomes in pts who were eligible for cis with previously untreated la/mUC, reducing the risk of death by 47% compared with PBC. Results were consistent with the overall population. The AE profile of EV+P was generally manageable with no new safety signals. The results of EV-302 support EV+P as a new SOC for la/mUC, including pts who are eligible for cis. Clinical trial information: NCT04223856 .

Efficacy and safety of erdafitinib in pediatric patients with advanced solid tumors and FGFR alterations in the phase 2 RAGNAR trial.

10002 Background: Erdafitinib is an oral selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor approved in the US for adult patients (pts) with locally advanced or metastatic urothelial carcinoma with susceptible FGFR3 genetic alterations, as determined by an FDA-approved companion diagnostic test, whose disease has progressed on or after ≥1 line of prior systemic therapy. Primary analysis of the RAGNAR study Broad Panel Cohort demonstrated tumor agnostic efficacy in pts with solid tumors harboring predefined FGFR mutations or fusions (Pant 2023). Here we report on Final Analysis of efficacy and safety results from the Pediatric Cohort of the RAGNAR study. Methods: Pediatric pts ≥6 years with advanced solid tumors and any FGFR mutation, fusion, or tandem duplication received oral erdafitinib. Starting doses were 8 mg, 5 mg, and 3 mg daily for ages > 15 years, 12 to < 15 years, and 6 to < 12 years, respectively, in 21-day cycles with possible individualized up-titration based on serum phosphate and adverse events (AEs). The primary endpoint was objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 or Response Assessment in Neuro-Oncology [RANO]) by independent review committee (IRC). Secondary endpoints included ORR by investigator, duration of response (DOR), disease control rate (DCR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). Results: 11 pts (median age 13 years; range, 6-16; 64% female) received erdafitinib. Median follow-up was 9.7 months at data cutoff. Histologies included low-grade glioma (LGG-6 pts); high-grade glioma (HGG-3 pts); soft tissue sarcoma (1 pt), and temporal neurocytoma (TNEURO-1 pt). 7, 1, and 3 pts had FGFR1, FGFR2, and FGFR3 alterations, respectively. 6, 4, and 1 pts had FGFR fusions, mutations, and tandem duplication, respectively. Pts had a median of 1 prior line of systemic treatment; 6 (55%) had prior radiotherapy. At data cutoff, 1 of 3 pts (33%) with HGG and an FGFR1-TACC1 fusion achieved a partial response based on investigator assessment with a response duration of 19.8 months. Investigator-assessed objective responses were not observed in the other tumor types. DCR and CBR were 100% in pts with LGG and 67% in pts with HGG. Most common treatment-emergent adverse events (TEAEs) included hyperphosphatemia (64%), diarrhea (64%), pain in extremity (45%), alanine transaminase increased (36%), nausea (36%), and onycholysis (27%). No central serous retinopathy events occurred; related serious adverse events (SAEs) occurred in 4 (36%) pts, including 1 SAE of epiphysiolysis; there were no related TEAEs leading to death. Conclusions: In this small pediatric population comprising primarily refractory HGG and LGG with any FGFR alteration, erdafitinib demonstrated limited objective responses but promising disease control with acceptable safety. Clinical trial information: NCT04083976 .

Enfortumab vedotin and pembrolizumab as first-line treatment in recurrent or metastatic head and neck squamous cell carcinoma: A cohort of the EV-202 trial.

TPS6116 Background: Novel treatment strategies are needed to treat recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) given the poor durability of response and prognosis with standard therapy. In KEYNOTE-048, among patients with R/M HNSCC and PD-L1 combined positive score (CPS) ≥1, first-line (1L) treatment with pembrolizumab demonstrated a median overall survival (OS) of 12.3 months. Nectin-4 is widely expressed in a variety of solid tumors, including bladder cancers and HNSCC. Enfortumab vedotin (EV) is a Nectin-4–directed antibody–drug conjugate approved for use in previously treated (EV monotherapy) or 1L (EV + pembrolizumab) locally advanced or metastatic urothelial carcinoma (la/mUC). EV + pembrolizumab showed superior OS and progression-free survival (PFS) vs chemotherapy in 1L la/mUC. EV-202 is a multicenter, open-label, phase 2 study (NCT04225117) evaluating the efficacy and safety of EV in multiple tumor-specific cohorts. In the previously treated R/M head and neck cancer cohort, 11 of 46 patients (23.9%) had a confirmed objective response with EV monotherapy; median PFS was 3.9 months (Swiecicki P, et al. ASCO 2023. Poster #6017). We hypothesize that EV + pembrolizumab may demonstrate benefit as a 1L therapy in patients with R/M HNSCC and CPS ≥1. Methods: Patients in the R/M HNSCC cohort of EV-202 have histologically or cytologically confirmed HNSCC, an ECOG performance status 0 or 1, no prior systemic therapy administered in the R/M setting (with the exception of systemic therapy completed >6 months prior if given as part of treatment for locally advanced disease), and CPS ≥1. A total of 40 patients are expected to be enrolled. An interim analysis will be conducted when 20 patients are evaluable for tumor response; 5 responders will be needed to proceed. Of 40 total patients, 14 must demonstrate response to claim promising antitumor activity. Patients will receive EV 1.25 mg/kg intravenously on days 1 and 8 and 200 mg of pembrolizumab intravenously on day 1 of each 21-day cycle until discontinuation, for reasons including disease progression or toxicity. Disease assessments will be performed 9 weeks from the first dose and every 6 weeks thereafter until disease progression, start of subsequent anticancer therapy, death, consent withdrawal, loss to follow-up, or study end, whichever occurs first. The primary endpoint is investigator-assessed, confirmed ORR per RECIST v1.1. Secondary endpoints include investigator-assessed duration of response, disease control rate, PFS, OS, and safety/tolerability. Analyses will also be evaluated per iRECIST. Exploratory analyses will include pharmacokinetics, immunogenicity, quality of life, and assessment of biomarkers that may correlate with treatment outcome, including Nectin-4 expression. Recruitment for this cohort began in November 2023 and is ongoing. Clinical trial information: NCT04225117 .

Dose escalation of KY-0118, PD-1, and IL-2v due-target fusion protein in patients with advanced renal clear cell carcinoma, urothelial carcinoma, and malignant melanoma.

e14505 Background: KY-0118 is an anti-PD1 and IL-2v(variant) fusion protein for advanced solid tumors. The non-α biased design reduces the binding to IL2-Raβγ and enhanced binding to PD-1 & IL2-Rβγ positive TILs to drive increased proliferation and activation of NK and CD8+ T cells without unwanted expansion of Tregs. KY-0118 adopts specific single design, only 67kDa MW thus obtains excellent tumor penetration activity. The preclinical data shows higher antitumor activity in several CDX models compared with nivolumab and IL2wt. KY-0118 monotherapy is currently in Phase I escalation. Methods: The phase I dose escalation is a traditional 3+3 design, KY-0118 on Days 1, 8 and 15, 21-day treatment cycle, 9 dose levels (0.3μg/kg-64μg/kg) or higher doses of 3 to 6 patients are planned. The dose expansion cohort is currently enrolling. The primary endpoint was to evaluate the safety, tolerability, and determine the DLT, MTD, RP2D of KY 0118 when given alone. Secondary objectives are PK/PD characteristics and preliminary evidence of efficacy via ORR per RECIST v1.1 and iRECIST. Results: Up to Jan 31, 2024, 21 patients have been treated, the median number of prior lines of systemic therapy was 2. The dose level 8 (48µg/kg) of DLT observation period is ongoing, no DLT was observed in the administered dose groups. Most of TEAEs are transient grade 1-2, no TEAE led to withdrawal from this study. The most common nonhematologic TRAEs were pyrexia, flu-like symptoms, nausea, fatigue. 2 patients had grade 3 hematologic toxicity. Treatment-related sAEs were observed in one patient (include nausea, vomiting, and pulmonary embolism, now recovered and continuing treatment). No patients experienced complete or partial response, but several showed evidence of antitumor activity, at the dose of 36 ug/kg, 21% shrinkage of target lesions in a patient with RCC, the DCR for the 12, 24, and 36μg/kg dose levels are 33%, 75%, and 67%, respectively. Conclusions: These preliminary data suggest that KY-0118 demonstrated a manageable safety profile and encouraging early evidence of activity has been observed in locally advanced and/or metastatic solid tumors. Enrollment is ongoing, further results are forthcoming. Pts: 21; AEs: 399; TEAEs: 289 (100%); AESI: 13; sAEs: 8. Clinical trial information: NCT06175780 .

Improving the efficacy of immunotherapy in patients with advanced or metastatic urothelial carcinoma: a new role for tyrosine kinase inhibitors in the treatment paradigm?

Improving the efficacy of immunotherapy in patients with advanced or metastatic urothelial carcinoma: a new role for tyrosine kinase inhibitors in the treatment paradigm?

Efficacy and safety of erdafitinib in adults with breast cancer and prespecified fibroblast growth factor receptor alterations in the phase 2 open-label, single-arm RAGNAR trial.

1088 Background: Erdafitinib is an oral selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor approved in the US for adult patients (pts) with locally advanced or metastatic urothelial carcinoma with susceptible FGFR3 genetic alterations, as determined by an FDA-approved companion diagnostic test, whose disease has progressed on or after ≥1 line of prior systemic therapy. The primary analysis results from the RAGNAR study demonstrated tumor agnostic efficacy in patients with advanced solid tumors with predefined FGFR alterations after failure of standard therapies (Pant 2023). Here, we report results on patients with breast cancer in the RAGNAR study. Methods: Patients with breast cancer and prespecified FGFR1-4 alterations (mutations or fusions) who had documented disease progression after exhausting standard therapies received oral erdafitinib 8 mg daily with optional up-titration until disease progression or intolerable toxicity. The primary end point was objective response rate by Independent Review Committee (IRC). Secondary endpoints include duration of response, disease control rate, progression-free survival, overall survival, and safety. Results: At data cutoff (median follow up, 30.3 months), 16 patients with breast cancer received erdafitinib. Median age was 54 y (range 37-74); all (100%) patients were female and had visceral metastases. Patients had a median of 5 prior lines of systemic therapies (range 2-12); one (6%) patient had responded to the last line of therapy. Ten (63%) patients had FGFR fusions, and 6 (38%) had FGFR mutations. Mutations of TP53 and PIK3CA were found in 6/16 patients. Objective response rate and disease control rate by IRC were 31% (95% CI 11-59) and 69% (95% CI 41-89); objective response rate and disease control rate by investigator were 38% (95% CI 15-65) and 69% (95% CI 41-89), respectively. Median time to onset of response was 1.4 months. Responses were observed in patients with both FGFR2 fusions and with FGFR2/3 mutations. Median duration of response, progression free survival, and overall survival were 6.9 months, 5.7 months, and 8.9 months, respectively. Common adverse events (AEs) included stomatitis (81%), diarrhea (69%), and hyperphosphatemia (69%), dry mouth (63%), and palmar-plantar erythrodysesthesia (44%). Six (38%) patients had serious AEs. No patients discontinued erdafitinib due to AEs. No treatment-related deaths were observed. Conclusions: Erdafitinib demonstrated clinically meaningful activity in heavily pretreated patients with breast cancer and prespecified FGFR alterations. Safety data were consistent with the erdafitinib safety profile. Clinical trial information: NCT04083976 .

Costs associated with novel first-line (1L) treatments in patients (pts) with locally advanced or metastatic urothelial carcinoma (la/mUC) from a United States (US) Medicare and commercial payer perspective.

e16552 Background: Recent drug approvals in the 1L treatment (tx) setting have expanded options for pts with la/mUC. It is important to understand the economic burden of these novel therapies within the current tx landscape. This study estimated first-year cost of care in the US from a Medicare and commercial payer perspective for pts with la/mUC treated with the following 1L tx: enfortumab vedotin (EV) + pembrolizumab (PEM) in platinum-eligible pts, nivolumab (NIV) + platinum-based chemotherapy (PBC) in cisplatin-eligible pts, and 1L PBC with or without avelumab (AVE) 1L maintenance (1LM). Methods: A cost of care model was developed to estimate direct medical care costs in the first year of tx with EV + PEM, NIV + PBC, and PBC with and without AVE 1LM in pts with la/mUC who are eligible for 1L PBC; pts treated with NIV + PBC were eligible for cisplatin. The latest available costs (2023 USD)—including drug acquisition and administration, disease management, adverse event (AE) management, and subsequent therapy (second-line or later line) costs—were calculated based on tx duration, progression-free survival, overall survival, and AE incidence with various therapies. Efficacy and safety data were sourced from key published trials (EV-302, CheckMate-901, JAVELIN Bladder 100) and product prescribing information. Results: Estimated first-year costs per treated pt are shown in the Table. Cost per treated pt was estimated to range between $56,952 to $438,660 and $90,918 to $457,390 for Medicare and commercial payers, respectively, with the highest cost for EV+PEM and the lowest for PBC only. Drug acquisition costs in the 1L represented the majority of the costs except PBC, for which subsequent tx and administration costs represented the largest cost component. Conclusions: Costs per treated pt were lower for PBC with AVE 1LM than for EV+PEM and NIV+PBC. As value-based oncology care is becoming increasingly important in the US, comprehensive understanding of costs across different tx options and sequences can facilitate informed tx choice. [Table: see text]

Evorpacept plus enfortumab vedotin in patients (Pts) with locally advanced or metastatic urothelial carcinoma (la/mUC): Phase 1a dose escalation results.

4575 Background: Maximizing antibody dependent cellular phagocytosis (ADCP) in the tumor microenvironment requires both the inhibition of the myeloid CD47/SIRPα checkpoint and activation of the macrophage’s FcyR by an anti-cancer specific antibody (Lakhani et al. Lancet Oncol 2021). Evorpacept (EVO) is a CD47 inhibitor with an inactivated Fc effector domain that blocks the CD47-SIRPα interaction. Enfortumab vedotin (EV) is a nectin-4-directed antibody drug conjugate (ADC) which engages the FcyR on the macrophage. We evaluated whether EVO plus EV would be safe, tolerable and active in pts with la/mUC. Methods: 20 pts with la/mUC who had received prior platinum-based chemotherapy and progressed during or after treatment with a PD-1/L1 inhibitor were administered study drug in this phase 1 study (NCT05524545). Dose escalation (DE) cohorts were administered intravenous (IV) EVO 20 mg/kg or 30 mg/kg Q2W plus standard EV 1.25 mg/kg IV on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was first cycle dose limiting toxicity (DLT) using a Bayesian Optimal Interval design. Additional pts were enrolled in both dose levels as backfill cohorts to further characterize safety, PK, PD, and preliminary antitumor activity. Investigator response was based on RECIST v1.1, and data cut off was 18Jan(safety)/24Jan(efficacy) 2024. Results: Fourteen pts were administered EVO 20 mg/kg Q2W (DE n= 3; backfill n=11) and 6 pts EVO 30 mg/kg Q2W (DE n=6) plus standard EV. No DLTs were observed, and the maximum tolerated dose (MTD) of the combination was not reached. The maximum administered dose (MAD) of EVO was 30 mg/kg Q2W combined with EV. There were no treatment-related deaths on study. Treatment emergent adverse events (TEAEs) occurring in > 25% of subjects included fatigue, diarrhea, abnormal loss of weight, dysgeusia, decrease appetite, hyperglycemia, constipation, hypomagnesemia, lacrimation increased, nausea, peripheral sensory neuropathy, rash maculo-papular and urinary tract infection (UTI). There were 3 serious adverse events that were related to EVO plus EV (G3 UTI [1 pt]; G4 neutrophil count decreased and G3 UTI [1 pt]). Sixteen patients were response evaluable. The overall response rate (ORR) was 63% (1CR, 9PR). Accrual is ongoing and updated data will be provided at the time of presentation. Conclusions: This is the first study, to our knowledge, reporting data on the combination of a CD47 blocking agent in combination with an ADC in la/mUC. EVO plus EV is well tolerated at doses evaluated with no MTD reached and a MAD of 30 mg/kg Q2W. The combination shows early promising clinical activity compared to an ORR of 41% with EV alone in pts with la/mUC who had previously received platinum-based chemotherapy and a PD-1/L1 inhibitor (Powles et al. N Engl J Med 2021). Further investigation in this refractory population, including patients with prior EV exposure, is warranted. Clinical trial information: NCT05524545 .

Age and other criteria influencing nontreatment of patients (pts) with locally advanced or metastatic urothelial carcinoma (la/mUC): Results of a physician survey in five European countries (Eu5).

4570 Background: Real-world studies have shown that a majority of pts with la/mUC do not receive first-line (1L) systemic therapy (tx), despite guideline recommendations. This cross-sectional study assessed the criteria that Eu5 physicians consider when making decisions about 1L tx for pts with la/mUC. Methods: A quantitative online survey of Eu5 physicians was performed in Aug-Sep 2022. Respondents answered questions related to demographics, practice patterns, and criteria considered in 1L decision-making. Descriptive statistics were used to analyze demographics and responses. Logistic regression was used to analyze physician characteristics associated with reporting no age threshold vs any age threshold when defining platinum ineligibility. Results: 503 physicians (69% oncologists and 31% urologists) completed the quota-based survey. Most respondents had been in practice for >10 years (69%) and treated 5-19 pts with la/mUC per month (58%) in public teaching hospitals (40%), public nonteaching hospitals (24%), and private hospitals (20%). Physicians estimated that they do not prescribe 1L tx for ≈25% of their pts. The majority of physicians selected advanced age (62.0%) and poor performance status (PS; 54.7%) as their top reasons for not prescribing 1L tx, followed by pt refusal (45.9%) and poor renal function (43.1%). Most physicians (78.1%) reported having an age threshold above which they recommend against 1L systemic tx (mean, 74.7 years old [Table]). After adjusting for baseline characteristics, physicians were more likely to have an age threshold if they were from Italy vs Germany (odds ratio [OR] 0.22 [95% CI 0.06-0.73]), practiced in a public nonteaching hospital (OR 0.28 [95% CI 0.10-0.73]) or public/private office settings (OR 0.14 [95% CI 0.03-0.57]) vs private hospital, and if they treated <20 pts/month (2-10 pts: OR 0.36 [95% CI, 0.17-0.74]; 11-19 pts: OR 0.25 [95% CI 0.09-0.62]). Conclusions: 1L systemic tx rates self-reported by Eu5 physicians were higher than those previously published. Many physicians reported having an age threshold for not offering systemic tx, which was relatively low compared with the senior age profile of the la/mUC population. Physicians who reported an explicit age threshold may be inappropriately excluding pts from tx; this could be a driver for systemic tx underutilization in la/mUC. [Table: see text]

Estimated impact of novel immune checkpoint inhibitors on reducing cancer mortality in patients with locally advanced or metastatic urothelial carcinoma in Russia.

Estimated impact of novel immune checkpoint inhibitors on reducing cancer mortality in patients with locally advanced or metastatic urothelial carcinoma in Russia.

Enfortumab vedotin (EV) with pembrolizumab (P) versus chemotherapy (chemo) in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC): Analysis of the cisplatin (cis)-ineligible population from EV-302/KEYNOTE-A39.

4563 Background: EV-302/KEYNOTE-A39 (NCT04223856) is a phase 3, randomized, open-label, global study comparing EV+P with platinum-based chemo (PBC) for first-line (1L) treatment (tx) of patients (pts) with la/mUC regardless of cis eligibility. In EV-302, EV+P demonstrated a statistically significant and clinically meaningful benefit compared with PBC for the dual primary endpoints of PFS (hazard ratio [HR]: 0.45; P<0.00001) and OS (HR: 0.47; P<0.00001) in the overall pt population (Powles ESMO 2023), reducing the risk of progression and/or death by more than 50%. EV+P was FDA-approved in Dec 2023 for tx of adults with la/mUC. As cis eligibility status has long defined 1L tx, here we present results of an analysis for pts who were ineligible for cis at randomization. Methods: Pts with previously untreated la/mUC were randomized 1:1 to receive 3-week cycles of EV (1.25 mg/kg IV; Days 1 and 8) and P (200 mg IV; Day 1) or PBC (gemcitabine with cis or carboplatin [carbo]). Select secondary endpoints included confirmed objective response rate (ORR), duration of response (DOR), and safety. Pts were deemed eligible/ineligible for cis following protocol-defined criteria and stratified accordingly. Results: 408 pts (EV+P: 198, PBC: 210) were cis-ineligible at randomization. 205 (97.6%) pts in the PBC arm received carbo at Cyle 1. mPFS was 10.6 months for EV+P; 6.1 months for PBC (HR: 0.43, 95% CI, 0.33, 0.55). mOS was not reached for EV+P and was 12.7 months for PBC (HR: 0.43, 95% CI, 0.31, 0.59). ORR for EV+P was 63.9% with 24.7% complete response (CR) rate; mDOR (95% CI) was not reached (16.3 months, NR). ORR for PBC was 34.9% with 9.1% CR rate; mDOR (95% CI) was 6.6 months (5.6, 10.2). In EV+P arm, 62 pts (31.3%) remained on tx at data cutoff (DCO). 55 pts (27.8%) received subsequent therapy. 10 pts received cis and 27 pts received carbo as first subsequent therapy. In PBC arm, all were off study tx at DCO. 114 pts (54.3%) received any PD-1/L1 therapy following PBC. 52 pts received maintenance avelumab; 58 pts received PD-1/L1 therapy as second-line tx. Grade ≥3 TRAEs occurred in 58.4% of pts with EV+P and 77.1% of pts with PBC. Most common grade ≥3 TRAEs of special interest for EV were skin reactions (16.2%), peripheral neuropathy (8.1%), and hyperglycemia (4.1%). Most common grade ≥3 tx-emergent AEs of special interest for P were severe skin reaction (14.7%), hepatitis (2.0%), and pneumonitis (2.0%). Conclusions: In this pt population with historically poor prognosis, EV+P improved clinical outcomes in pts who were ineligible for cis; results were consistent with the overall population. The risk of death was reduced by more than 50%. The AE profile of EV+P was generally manageable with no new safety signals. The results of EV-302 support EV+P as a new SOC for la/mUC, including pts who are ineligible for cis. Clinical trial information: NCT04223856 .

Disitamab vedotin (DV, RC48-ADC) combined with cadonilimab (anti-PD-1/CTLA-4 bispecific antibody) in patients with locally advanced or metastatic urothelial carcinoma (la/mUC): An open-label, single-arm, phase II study.

e16572 Background: The first-line regimens for locally advanced or metastatic urothelial carcinoma(la/mUC)remain an unmet need. RC48-ADC has been approved in China for platinum-refractory la/mUC with HER2 overexpression (IHC 2+ or 3+). Cadonilimab (AK104, PD-1/CTLA-4 bsAb) showed encouraging antitumor activity in gynecologic cancer, urological tumors, etc. The aim of this study is to evaluate the efficacy and safety characteristics of RC-48 ADC combined with cadonilimab in the treatment of la/mUC with HER2 expression. Methods: This is an open-label, multicenter, prospective, phase 2 trial to evaluate RC48-ADC combined with cadonilimab in mUC. The study set a safe introduction period, 6 patients were included and received the initial dose of RC48-ADC at 2 mg/kg combined with cadonilimab at 6 mg/kg every two weeks. If no DLT event occurred in the 6 patients, then continued to expand 30 patients, with an expected sample size of 36 cases; If DLT safety event occurred in 6 cases, the RC48-ADC dose reduced to 1.5 mg/kg and cadonilimab dose reduced to 4 mg/kg for Q2W; Treatment continued until disease progression, intolerable toxicity, death, etc. Primary endpoint was ORR and safety, Secondary endpoints included DOR, PFS, OS, and exploration of tumor biomarkers. Results: By the cutoff date of 4 February 2024, Thirteen la/mUC patients were enrolled who have not received systematic treatment or intolerant to cisplatin or refuse chemotherapy {8 males; median age 72 y [61-83]; 77%(10/13) of patients had distant metastasis. HER2 expression IHC 2+ or 3+ was in 85% patients (11/13), and PD-L1 low expression was 100% (6/6)}. Dose-limiting toxicity was observed (Bullous rash, ALT/AST elevated) among first 6 patients, therefore reduced cadonilimab from 6mg/kg to 4mg/kg Q2W, RC48-ADC remained. 8 patients have efficacy evaluation, ORR was 75.0% (6/8), including 12.5% CR (1/8). DCR was 100%. Median progression-free survival (PFS) and overall survival (OS) were not reached. 69.2% (9/13) Pts experienced treatment-related adverse events (TRAEs). The most common TRAEs were AST/ALT increase (30.8%), fever (23.1%), anemia (23.1%), rash (15.4%), and pruritus (15.4%), etc. TRAEs ≥G3 were occurred in 15.4%(2/13) patients, one patient died due to a cerebrovascular event. 30.8% had immune-related AEs(≥G3 irAE 15.4%), including immune-related skin reactions, hepatitis, and colitis. Conclusions: This was the first study to evaluate RC48-ADC in combination with cadonilimab (anti-PD-1/CTLA-4 bispecific antibody) in urothelial carcinoma. Preliminary results showed that the combination have promising efficacy in first-line treatment of la/mUC and a manageable safety profile, it may potentially provide a new option for la/mUC treatment, especially for those who cannot tolerate cisplatin-based chemotherapy. Clinical trial information: NCT06178601 .

Informing optimal treatment (tx) sequences for platinum-eligible patients with locally advanced or metastatic urothelial carcinoma (la/mUC) in the United States: Results of a clinical simulation modeling exercise.

e13514 Background: Platinum-based chemotherapy (PBT) followed by avelumab (AVE) as first-line (1L) maintenance for patients with nonprogressive disease (PBT ± AVE) is the standard of care in la/mUC. This study compared the overall survival (OS) and cost-effectiveness of the tx sequence of PBT ± AVE followed by enfortumab vedotin (EV) or other therapies, including immuno-oncology (IO), in second line (2L; ie, PBT + 2L EV/IO or PBT + AVE + 2L EV/IO) vs 1L EV + pembrolizumab (PEM) for PBT-eligible patients (PBTp) from a US commercial payer perspective. Methods: A partitioned survival model compared outcomes with PBT ± AVE and EV + PEM among PBTp. Inputs included progression-free survival and OS, time to tx discontinuation, adverse event (AE) incidence, and health utilities and costs. Efficacy inputs were sourced and extrapolated from patient data in JAVELIN Bladder 100 (data cut: Jun 4, 2021), AVENANCE real-world study (1), and published data (EV-302 trial). Safety data were sourced from US prescribing information. Drug, subsequent tx, disease management, and AE management costs (2023 USD) were calculated. The optimal tx sequencing scenario assumed 80% of patients starting PBT were eligible to receive AVE (2023 Flatiron data cut; (2)), 70% of patients progressing on PBT ± AVE would start 2L, and 70% of those would be eligible for EV. Outcomes included life-years (LYs), quality-adjusted LYs (QALYs), costs, and incremental cost-effectiveness ratio (ICER). Scenarios and probabilistic sensitivity analyses (PSAs) were conducted to assess uncertainty. Results: LY, QALY, costs, and ICER modeling outcomes are shown in the Table. Use of EV in 2L after PBT ± AVE is associated with 0.76 lower QALYs, but given the large cost saving, it represents a cost-effective use of resources at the $150,000/QALY willingness to pay (WTP) threshold. PSAs showed that PBT ± AVE is likely to be more cost-effective over a broad and relevant WTP threshold range ($0-500,000/QALY). Results were sensitive to drug acquisition costs and eligibility to receive AVE and 2L EV. Conclusions: Based on this simulation exercise, the use of 2L EV after PBT ± AVE achieves considerable survival benefit at substantially lower costs vs 1L EV + PEM in PBTp with la/mUC. Given the shift toward value-based care in oncology, such analyses are becoming increasingly relevant to guide clinical decision-making. There is a need to assess tx alternatives that balance healthcare costs while optimizing outcomes in patients with la/mUC. 1. Barthélémy et al, J Clin Oncol 2024;42[suppl 4]: Abstract 561. 2. Moon et al, J Clin Oncol 2023;41[suppl 16]: Abstract 4567. [Table: see text]

Efficacy and safety of erdafitinib in adults with NSCLC and prespecified fibroblast growth factor receptor alterations in the phase 2 open-label, single-arm RAGNAR trial.

8515 Background: Erdafitinib is an oral selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor approved in the US for treatment of locally advanced or metastatic urothelial carcinoma in adults with susceptible FGFR3 alterations, as determined by FDA-approved companion diagnostic test, who have progressed during or after ≥1 line of prior systemic therapy. Primary analysis results from the RAGNAR study demonstrated tumor agnostic efficacy in patients with advanced solid tumors with predefined FGFR alterations after failure of standard therapies (Pant 2023). Here we report results on patients with non-small-cell lung cancer (NSCLC) in the RAGNAR study. Methods: Patients with advanced or metastatic squamous or non-squamous NSCLC with prespecified FGFR1-4 alterations (mutations/fusions) and with documented disease progression after exhausting standard therapies were included. Patients with other targetable alterations (eg, EGFR, ALK, ROS1) were excluded. Patients received oral erdafitinib until disease progression or intolerable toxicity. The primary end point was objective response rate by independent review committee. Secondary endpoints include duration of response, disease control rate, progression-free survival, overall survival, and safety. Results: At data cutoff (median survival follow-up of 23.7 months), 23 patients with NSCLC received erdafitinib. Median age was 63 years (range 50-79); 22 (96%) had metastases. Patients had a median of 2 prior lines of systemic therapies (range 1-7; 48% had 3+ prior lines); only 2 (9%) patients had responded to their prior line of therapy. Fourteen patients (61%) had squamous and 9 (39%) non-squamous histology; 13 patients (57%) had FGFRfusions and 10 (43%) had FGFR mutations. Three patients had CDKN2Aand 3 patients had PIK3CA co-alterations. Objective response rate by independent review committee was 26% (95% CI 10-48); disease control rate was 74% (95% CI 52-90). Median time to onset of response was 1.5 months. Responses were observed in 21% (3/14) of patients with squamous; 33% (3/9) with non-squamous histology, 29% (2/7) of patients with FGFR2, 25% (4/16) with FGFR3alterations, and in 20% (2/10) of patients with FGFR mutations and 31% (4/13) with fusions. Median duration of response, progression-free survival and overall survival were 4.6 months, 4.1 months, and 10.5 months, respectively. Most common adverse events (AEs) were diarrhea (65%), stomatitis (61%), dry mouth (44%), hyperphosphatemia (65%), dry skin (30%), and fatigue (22%); 6 (26%) had serious AEs; 2 (9%) discontinued erdafitinib due to AEs. No treatment-related deaths were observed. Conclusions: Erdafitinib demonstrated clinically meaningful activity in pre-treated patients with NSCLC and pre-specified FGFR alterations. Safety data were consistent with erdafitinib safety profile. Clinical trial information: NCT04083976 .

Pembrolizumab for advanced urothelial carcinoma: exploratory ctDNA biomarker analyses of the KEYNOTE-361 phase 3 trial

Circulating tumor DNA (ctDNA) is emerging as a potential biomarker in early-stage urothelial cancer, but its utility in metastatic disease remains unknown. In the phase 3 KEYNOTE-361 study, pembrolizumab with and without chemotherapy was compared with chemotherapy alone in patients with metastatic urothelial cancer. The study did not meet prespecified efficacy thresholds for statistical significance. To identify potential biomarkers of response, we retrospectively evaluated the association of pre- and posttreatment ctDNA with clinical outcomes in a subset of patients who received pembrolizumab (n = 130) or chemotherapy (n = 130) in KEYNOTE-361. Baseline ctDNA was associated with best overall response (BOR; P = 0.009), progression-free survival (P < 0.001) and overall survival (OS; P < 0.001) for pembrolizumab but not for chemotherapy (all; P > 0.05). Chemotherapy induced larger ctDNA decreases from baseline to treatment cycle 2 than pembrolizumab; however, change with pembrolizumab (n = 87) was more associated with BOR (P = 4.39 × 10−5) and OS (P = 7.07 × 10−5) than chemotherapy (n = 102; BOR: P = 1.01 × 10−4; OS: P = 0.018). Tumor tissue-informed versions of ctDNA change metrics were most associated with clinical outcomes but did not show a statistically significant independent value for explaining OS beyond radiographic change by RECIST v.1.1 when jointly modeled (pembrolizumab P = 0.364; chemotherapy P = 0.823). These results suggest distinct patterns in early ctDNA changes with immunotherapy and chemotherapy and differences in their association with long-term outcomes, which provide preliminary insights into the utility of liquid biopsies for treatment monitoring in metastatic urothelial cancer. Clinical trial registration: NCT02853305.

INSIGHT-005: A new stratum of the explorative, open-labeled, phase I INSIGHT study to evaluate the feasibility and safety, as well as preliminary efficacy, of subcutaneous injections with IMP321 (eftilagimod alpha) in combination with PD-L1 inhibitor (avelumab) for metastatic or unresectable locally advanced urothelial carcinoma (UC)—IKF-s614.

TPS4620 Background: UCs are the 6th most common malignancies in the Western world being localized in the upper (5-10%) or the lower (90-95%) urinary tract. Metastatic UC (mUC), which accounts for 5% of all cases, is associated with a dismal prognosis and prompt progression. So far, the 1st line therapy for mUC encompassed platinum-based combination regimens. Recent data indicate beneficial patient treatment with immune checkpoint inhibitors. Thus, avelumab was approved for maintenance therapy after progression-free platinum-based chemotherapy for locally advanced (LA) or mUC. Further immune checkpoint inhibitors (e.g. pembrolizumab, atezolizumab, nivolumab) achieved approval or showed promising results for treatment of different patient populations. Eftilagimod alpha (efti) is a soluble LAG-3 fusion protein and a MHC class II agonist activating APCs followed by CD8 T-cell activation. The combination of efti with PD-1/PD-L1 blockade is not yet available and is proposed to enhance efficacy. Based on previous results from the INSIGHT trial and change in treatment landscape we hypothesize that combining avelumab and efti will display clinically relevant efficacy in unresectable LA UC or mUC subgroups with acceptable toxicity. Methods: INSIGHT-005 is a new stratum within the investigator-initiated INSIGHT phase I platform trial ongoing at multiple sites (n=9) in Germany. Patients with unresectable LA UC or mUC will receive efti in combination with avelumab. 30 patients will be enrolled in 3 subgroups: I) Previously untreated, eligible for platinum-based therapy, with PD-L1 CPS≥10; II) Previously untreated, not-eligible for platinum-based therapy, irrespective of the PD-L1 status; III) Suffered disease progression after platinum-based chemotherapy for metastatic disease and did not receive avelumab maintenance therapy, irrespective of the PD-L1 status. Enrolled patients will receive avelumab 800 mg i.v. and efti 30 mg s.c. on the same day Q2W for a maximum of 24 cycles. Tumor evaluation will be performed via CT or MRI every 8 weeks. The primary endpoint of this study is to explore feasibility, safety, and preliminary efficacy of efti when added to avelumab in unresectable LA UC or mUC. Secondary endpoints include safety and efficacy parameters as defined by objective response, time to and duration of response and PFS according to RECIST 1.1, OS and biomarker analyses. First patient was enrolled on 2023-11-29. Currently, recruitment is ongoing. ClinicalTrials.gov ID: NCT03252938 Clinical trial information: NCT03252938 .

Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (aUC): Long-term outcomes from the JAVELIN Bladder 100 trial in patients (pts) with histological subtypes.

4567 Background: Results from the phase 3 JAVELIN Bladder 100 trial (NCT02603432) led international treatment guidelines to recommend avelumab 1L maintenance as a standard-of-care treatment for pts with aUC without progression after 1L platinum-based chemotherapy (PBC). Around 20% of UCs are mixed with other histological subtypes/variants; these tumors do not have specific treatment guidelines and represent an unmet treatment need. In the large real-world AVENANCE study (NCT04822350; N=594) of avelumab 1L maintenance in pts with aUC in France, outcomes in pts with histological subtypes were consistent with those in the overall population. Here, we report a post hoc analysis of long-term outcomes from JAVELIN Bladder 100 in pts with predominantly UC mixed with &lt;50% histological subtype component. Methods: Eligible pts had unresectable locally advanced or metastatic UC without progression after 1L PBC and were randomized 1:1 to receive avelumab + best supportive care (BSC) or BSC alone. The primary endpoint was overall survival (OS) measured from randomization; secondary endpoints included progression-free survival (PFS) and safety. This post hoc analysis was conducted in all pts with histological subtypes. Results: In the avelumab + BSC and BSC alone arms, respectively, 44/350 and 57/350 pts had histological subtypes. At efficacy data cutoff (June 4, 2021), median follow-up in both arms was ≥38.0 mo. In pts with histological subtypes, OS and PFS measured from randomization were prolonged with avelumab + BSC vs BSC alone (Table). Long-term safety (cutoff, April 6, 2023) in treated pts with histological subtypes was generally consistent with the overall safety population. Treatment-related adverse events (TRAEs) of any grade occurred in 36 pts (83.7%) in the avelumab + BSC arm vs 1 pt (1.8%) in the BSC alone arm; grade ≥3 TRAEs occurred in 9 pts (20.9%) and 0 pts, respectively. Conclusions: This exploratory analysis shows the long-term efficacy and safety of avelumab 1L maintenance in pts with histological subtypes in JAVELIN Bladder 100. No new safety concerns were identified. These results were consistent with those in the overall population and support the use of avelumab 1L maintenance in pts with aUC without progression following 1L PBC, including pts with predominantly UC mixed with &lt;50% histological subtype component. Clinical trial information: NCT02603432 . [Table: see text]