Bibi, Arifa

ABSTRACTBackgroundThe treatment landscape for multiple myeloma continues to evolve. Recently, the addition of anti‐CD38 monoclonal antibodies (mAbs) to the triplet regimen, comprising a proteasome inhibitor, an immunomodulatory agent, and a steroid, for transplant‐eligible newly diagnosed multiple myeloma (TENDMM) has shown promising results.AimsTo evaluate the overall efficacy and safety of quadruplet therapy with an anti‐CD38 mAb compared to a triplet regimen.MethodsA systematic search of Medline, Scopus, and EMBASE databases from inception to July 2024 identified relevant randomized controlled trials (RCTs). Efficacy and safety outcomes were derived using random‐effects meta‐analysis. Summarized outcomes include hazard ratios (HR) for progression‐free survival (PFS) and overall survival (OS), odds ratios (OR) for response rates, measurable residual disease (MRD) negativity rate, and grade 3 or higher adverse events (G ≥ 3 AEs).ResultsFive RCTs involving 2963 patients were included. A statistically significant PFS was observed for quadruplet therapy when compared to the triplet regimen (HR 0.44; 95% Confidence Interval [CI] 0.35–0.56). PFS benefit was consistent for the standard risk (SR) group (HR 0.38; 95% CI 0.27–0.52) and high risk (HiR) group (HR 0.62; 95% CI 0.41–0.92). No statistically significant benefit was observed for OS (HR 0.55; 95% CI 0.28–1.08). A statistically significant benefit was observed for the overall response rate (OR 1.77; 95% CI 1.02–3.06) and MRD negativity rate (OR 2.67; 95% CI 1.79–3.99). No significant differences were observed for G ≥ 3 AE (OR 1.21; 95% CI 0.92–1.58), lymphopenia (OR 1.09; 95% CI 0.62–1.89), and anemia (OR 1.06; 95% CI 0.83–1.37). However, a significantly increased risk was observed for all‐grade thrombocytopenia (OR 1.64; 95% CI 1.37–1.97), neutropenia (OR 2.24; 95% CI 1.67–3.02) and infections (OR 1.88; 95% CI 1.07–3.31).ConclusionQuadruplet therapy demonstrated a favorable efficacy and safety profile, with consistent benefit across subgroups. The findings support its potential as the new standard of care for TENDMM.

e19534 Background: Immunomodulatory drugs, proteasome inhibitors plus dexamethasone are the standard triplet induction regimen for TENDMM. We analyzed the efficacy of adding either anti-CD38 monoclonal antibodies (mAbs) or anti-SLAMF7 antibody to the triplet therapy. Methods: Ovid MEDLINE, EMBASE and published abstracts were systematically searched from each database’s inception through 01-31-2024 to identify II/III trials assessing quadruplet therapy versus triplet therapy in TENDMM patients. Hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS), odds ratios (OR) for overall response rates (ORR), measurable residual disease (MRD) negativity rate (with sensitivity of 10 -5) and grade 3 or higher treatment-related adverse events (G≥3 TRAE) were summarized using random effects meta-analysis via inverse variance approach. Additional subgroup analyses based on the cytogenetic risk were performed. P-value of interaction (Pint ) < 0.1 was pre-specified as statistically significant for the difference between the two groups. Results: 3806 studies were screened and seven trials were included with a total of 3546 patients. Four trials (2303 patients) assessed the addition of anti-CD-38 mAbs and three (1243 patients) assessed anti-SLAMF7 mAb, elotuzumab to the triplet regimen. Quadruplet therapy significantly improved PFS as compared to triplet (HR: 0.63; 95% CI: 0.43-0.92), and the PFS benefit was also observed in standard risk group (HR 0.5; 95% CI 0.2-0.9); however, results were insignificant for high-risk group (HR 0.8; 95% CI 0.62-1.93). No significant OS benefit was observed (HR: 0.79; 95% CI 0.49–1.26); however, data for three trials (CASSIOPEIA, DSMM XVII, PERSEUS) is immature, with longer-term follow-up ongoing. Quadruplet therapy showed significant results for very good partial response or better (OR: 1.7; 95% CI 1.2-2.36), stringent complete response (OR: 1.74; 95% CI 1.27-2.07) and complete response or better (OR: 1.91; 95% CI 1.19-3.06). MRD rate shows benefit with quadruplet therapy (OR: 2.59; 95% CI 2.22-3.01). Improved MRD rate was also observed for high-risk (OR 2.13; 95% CI 1.4-3.2) and standard-risk group (OR 2.58; 95% CI 1.68-3.94). Secondary analysis for efficacy of anti-CD38 mAbs showed benefit for PFS (HR: 0.44; 95% CI: 0.35-0.56), ORR (OR: 1.77;95% CI: 1.02-3.06), and MRD (OR: 2.98; 95% CI 1.8-4.8). G ≥3 TRAE did not significantly differ between the groups (OR: 1.05; 95% CI 0.97-1.12). However, quadruplet therapy showed significant risk of infection (OR: 1.2; 95% 1.05-1.35) and thrombocytopenia (OR: 1.41; 95% CI 1.24-1.59). Conclusions: Quadruplet therapy improved PFS, ORR, and MRD rates compared to triplet regimen and has demonstrated promising benefits to be considered the new standard of care for TENDMM patients.

e17059 Background: It is unclear if patients with different HRR gene-mutated mCRPC derive consistent benefit from treatment with PARPi and API combination. Approval labels for PARPi+API are inconsistent across regulatory bodies in the US (Food and Drug Administration, FDA) and Europe (European Medical Agency, EMA), adding to confusion among practicing clinicians. Therefore, we aimed to assess the differential efficacy of PARP+API therapy by different genes using up-to-date trial evidence. Methods: We maintain a living meta-analysis on mCRPC treatments that is updated when new data becomes available. Here, we report data from phase III randomized control trials (RCTs) assessing PARPi+API in 1L mCRPC. The outcomes of interest included radiographic progression-free survival (rPFS) and overall survival (OS). Hazard ratios (HR) for rPFS and OS by different genes were summarized using random effects meta-analysis via inverse variance approach. Results: We have screened 27376 references since the inception of this living review. Here, we report data from three trials (15 references) with a total of 1618 patients. Frequently reported HRR gene mutations in the included trials were BRCA2 (35%), ATM (21%), CDK12 (12.2%), CHEK2 (12.2%), BRCA1 (4.6%), and PALB2 (3.4%). In terms of rPFS, statistical benefit was observed in BRCA (0.28; 95% CI: 0.13-0.59) and CDK12 (0.58; 95% CI: 0.35-0.95) subgroups, whereas no statistically significant benefit was seen in PALB2 (0.53; 95% CI: 0.21-1.32), ATM (0.93; 95% CI, 0.57-1.53), and CHEK2 (0.92; 95% CI: 0.53-1.61) subgroups. For OS, benefit was observed in BRCA (0.47; 95%CI: 0.31-0.71) subgroup. While not statistically significant, a signal of meaningful OS benefit was observed in PALB2 (0.33; 95%CI: 0.10-1.16) but no OS benefit was observed in ATM (0.97; 95% CI: 0.57-1.67), CDK12 (0.80; 95% CI: 0.36-1.78), and CHEK2 (0.81; 95% CI: 0.37-1.75) subgroups. Conclusions: Current results show that mCRPC patients with BRCA and CDK12 alterations had delayed disease progression with PARPi+API as 1L therapy. BRCA mutations are also associated with improved OS, while patients with CHEK2 and ATM derived no significant benefit with PARPi+API combination. [Table: see text]

e16619 Background: Should patients (pts) with MIBC receive aIO given the DFS benefit seen in AMBASSADOR and CheckMate 274 trials is an important clinical question. Thus, we aimed to quantify the magnitude of absolute benefit across different subgroups to aid clinicians in shared decision-making with their patients. Methods: Phase III trials evaluating aIO as compared to observation or placebo (obs/plac) in pts with MIBC were considered eligible. Outcomes of interest included DFS and OS. Pre-specified subgroups included disease location, PDL1 status, neoadjuvant chemotherapy (NAC) receipt, and tumor and nodal (TN) staging. Pairwise comparisons were made using a DerSimonian-Lairds (DL) random-effects meta-analysis. Stratified baseline risks (obtained from clinical trials) and relative effect estimates were used to estimate corresponding intervention risks (CIRs). The difference in CIRs and baseline risk was calculated to present absolute risk differences (ARDs) in each subgroup category. Results: Analysis included three trials with 2220 pts (pembrolizumab, nivolumab, and atezolizumab assessed in each). No significant difference was observed in OS with aIO compared to obs/plac (hazard ratio: 0.91; 0.76-1.09). However, aIO significantly improved DFS compared to obs/plac (0.76; 0.64-0.91) in the overall population. In pts with bladder/lower tract disease, aIO improved DFS compared to obs/plac (0.72; 0.56-0.92); however, no significant difference was observed in DFS in pts with upper tract disease. There was a statistically significant effect modification by disease location (p: 0.01). Adjuvant IO significantly improved DFS in PDL1- (0.78; 0.64-0.94) but not in PDL1+ pts (0.75; 0.52-1.08). Likewise, aIO significantly improved DFS in pts who received NAC (0.69; 0.53-0.90) but not in pts who did not receive NAC (0.89; 0.75-1.05). In terms of TN staging, aIO improved DFS in T2-3N0 (0.73; 0.57-0.94), T4N0 (0.76; 0.61-0.95), and in T2-4N1 patients (0.75; 0.59-0.95). No statistically significant modifications were observed among these subgroups. Stratified ARDs for DFS by each subgroup are outlined (Table). Conclusions: When delayed disease progression is a vital consideration, a risk-adapted strategy for the optimal patient selection to receive aIO should be considered. Disease location (lower tract/bladder), node positivity, and receipt of NAC emerged as groups likely to derive greater benefit with aIO. [Table: see text]

e16579 Background: Recent results from EV 302 and CheckMate 901 have transformed the treatment landscape of untreated locally advanced/metastatic urothelial cancer (Ia/mUC). Here, we present the most up-to-date evidence of comparative efficacy and safety of first line (1L) treatment options in Ia/mUC with emphasis on Enfortumab vedotin (EV)-pembrolizumab (P) and gemcitabine (Gem)-cisplatin (Cis)-nivolumab (N). Methods: This living systematic review used the living interactive evidence (LIvE) synthesis framework. Full-text and abstract publications of phase II/III randomized clinical trials comparing 1L immunotherapy combined with chemotherapy (IO+C) or immunotherapy alone (IO) regimens with platinum-based chemotherapy (Plat) in Ia/mUC were included. Outcomes of interest included overall survival (OS), progression-free survival (PFS) and treatment-related grade 3 or greater adverse events (≥G3 TRAE). Mixed treatment comparisons were made using network meta-analysis. P-scores were computed to assess relative treatment rankings. Results: A total of 5 trials (8 references) with 4,749 patients and 9 unique treatments were included. EV-P and Gem-Cis-N were ranked first and second in terms of OS and PFS improvement. EV-P improved OS compared to Gem-Cis-N (HR: 0.60; 0.45-0.81), Gem-Plat-atezolizumab(A) (0.55; 0.42-0.72), durvalumab(D)- tremelimumab(T) (0.55; 0.42-0.72), Gem-Plat-P (0.55; 0.42-0.72), P (0.51; 0.39-0.68), D (0.47; 0.36-0.63), A (0.48; 0.36-0.63) and Gem-Plat (0.47; 0.38-0.58). EV-P also improved PFS compared to Gem-Cis-N (0.63; 0.48-0.82), Gem-Plat-A (0.55; 0.43-0.69), D-T (0.42; 0.33-0.53), Gem-Plat-P (0.58; 0.45-0.74), P (0.34; 0.26-0.44), D (0.35; 0.27-0.44) and Gem-Plat (0.45; 0.38- 0.54). For ≥G3 TRAE, A was ranked first with the lowest adverse events compared to others. EV-P (rank 5) had significantly fewer events compared to Gem-Plat, Gem-Plat-A, Gem-Cis-N and Gem-Plat-P. Gem-Cis-N was ranked last with significantly greater events compared to A, P, D, D-T, Gem-Plat, EV-P, and Gem-Plat-A (Table with ranks [p-scores]). Conclusions: Current evidence suggests that patients with untreated la/mUC experience improved survival and slower disease progression with EV-P when compared to other contemporary options. Gem-Cis-N may be a reasonable alternative in patients who are cisplatin-eligible. Cost and access to these treatments are crucial and should be considered to facilitate shared decision making. [Table: see text]

98 Background: The risk of secondary primary malignancies (SPM) among the survivors of GU cancer is not well-established. In this study, we attempt to describe the patterns of SPMs in patients diagnosed with GU cancers. Methods: The Surveillance, Epidemiology, and End Results (SEER) database (SEER*Stat 8.4.2) was searched to obtain data on the incidence of SPM in adult patients (age >18 years) diagnosed with GU cancers, including prostate, renal, and bladder cancer. Standardized incidence ratios (SIRs) with a 95% confidence interval (CI) were calculated. SIR was defined as the observed SPMS from each category divided by the expected number of SPMs in the age-matched US population for the same period. The data was further stratified by age (<50y, 50-70y, >70y), race (White, Black, Asian/Pacific Islander), ethnicity (Hispanic, non-Hispanic), chemotherapy, and radiotherapy exposure. Results: A total of 1,041,217 patients were included in this analysis. In patients diagnosed with GU cancer, the incidence of overall SPM was 11%. Particularly, patients with GU cancers were observed to have a high incidence of Endocrine system SPM (1.52; 1.45-1.59), and urinary system SPM (1.51; 1.49-1.53) These results were consistent by different sociodemographic groups. In patients diagnosed with prostate cancer, the incidence of thyroid SPM was increased (1.31; 1.23-1.39). Particularly, prostate cancer patients treated with radiation therapy had increased incidence rates of SPM in the peritoneum, omentum and mesentery (1.57; 0.79-2.81) and urinary bladder (1.36;1.32-1.40) was higher as compared to those with no exposure to radiation therapy (1.11;1.08-1.13 and 1.03;1-1.06 respectively). Bladder cancer patients had an overall increased incidence of SPM in the esophagus (1.21; 1.08-1.35), lung, bronchus, trachea, and other respiratory organs (1.97;1.92-2.01), prostate (3.50;3.4-3.6) and kidney (1.86;1.76-1.97). A higher incidence of renal pelvis, ureter and other urinary organ SPM (11.08;10.48-11.07) was also notable in this population. Similarly, kidney cancer patients had a higher incidence of the endocrine system (3.00;2.74-3.27), prostate (1.24;1.2-1.29) and bladder 1.78;1.68-1.79 SPMs. Conclusions: This population-based study shows an increased risk of SPM development in GU cancer survivors compared to the general population. Clinicians should keep a high index of suspicion for SPMs and initiate appropriate workups at early warning signs.

643 Background: The FDA approval of enfortumab (EV) and pembrolizumab (Pembro) combination therapy as a first-line treatment for cisplatin-ineligible patients with locally advanced/metastatic urothelial carcinoma (la/mUC) was based on the EV-103 trial. We aim to assess the clinical response rate of this combination therapy in our institution's patients with locally advanced and metastatic UC. Methods: This retrospective cohort study included 20 patients diagnosed with locally advanced/metastatic UC(la/mUC) who were treated with EV-Pembro combination for at least 2 cycles, from June 2022 to August 2023 at the Mayo Clinic. Patients who were treatment naïve or who progressed one or more lines of therapy were included in the study cohort. Main outcome of interest included imaging-based best overall response rate in terms of complete (CR) and partial (PR) response, stable disease (SD), and progressive disease (PD). Results: Out of 20 patients, the number of males and females were 16 (80%) and 4 (20%) respectively; the median age was 77 years (IQR: 51-92). 3 (15%) of patients had involvement of upper urinary tract disease along with bladder cancer. The common sites of visceral metastasis at the time of initial presentation include liver 2(10%), lung 6(30%) and lymph nodes12(60%). Common toxicities of this regimen included rash, pruritis, peripheral neuropathy, fatigue, transaminitis, dysgeusia, and diarrhea. The treatment was stopped in 10 (50%) patients due to completion of planned therapy (achieved CR or proceeded with resection of residual disease) (30%), 5 patients due to progression (50%), 1 patient due to therapy side effects (10%) and in 1 patient due to death (10%). The objective response was 45% (N =9); 5 (25%) had PR, and 4 (20%) had CR. A total of 2 (10%) had SD while 2 (10%) experienced PD. Histological correlation with clinical benefit is shown in the table. Conclusions: EV-Pembro combination therapy shows promising responses in patients who have progressed after previous lines of therapy, consistent with previously published data on EV 201 in small cohorts. However, ongoing expansion of this cohort and data from larger studies will help further elucidate survival benefits and their correlation with genetic testing. [Table: see text]

639 Background: Immunotherapy combined with chemotherapy (IO/C) as the first-line management of locally advanced or metastatic urothelial carcinoma (LA/mUC) has been investigated in multiple trials with conflicting outcomes. Therefore, we conducted a meta-analysis of available trials to compare objective response rates (ORR) of this combination regimen, both in overall and in cisplatin-ineligible populations. Methods: EMABSE and MEDLINE were searched from 2000 through July 20th, 2023, to identify phase II and III clinical trials assessing IO, C or both in LA/mUC. Main outcome of interest was objective response rates (ORR) as defined in the included trials. An inverse variance random-effects meta-analysis was performed to estimate pooled ORR using the restricted maximum likelihood estimation method. Subgroup differences were assessed among IO/C, IO alone, and C alone. The threshold for statistical significance was established at 0.1. Results: Of 5975 citations identified, a total of 26 trials with a total of 4,628 participants were included in this systematic review. In the overall group, the ORR in IO/C trials (5 trials, 1,236 patients) was 44.70% (95% CI: 21.88%- 70.0%). In IO trials (7 trials, 2,189 patients), ORR was 23.68% (19.55%- 28.36%) and in C trials (26 trials, 4,628 patients) was 43.46% (37.43%-49.68%]). In the cisplatin-ineligible group, the ORR in IO/C trials (2 trials, 240 patients) was 60.06% (33.38%-81.86%), in IO trials (6 trials, 1,103 patients) was 26.15% (23.01%; 29.56%), and in C trials (8 trials, 767 patients) was 42.45% (35.67%-49.52%). In terms of subgroup differences, the difference in ORR was statistically significant between IO/C and IO trials (p= 0.0844) and between IO and chemotherapy trials (p< 0.0001) in the overall population. Similarly, we found a statistically significant difference in ORR between IO/C and IO (p= 0.0108) and between IO and chemotherapy trials (p< 0.0001) in the cisplatin-ineligible population. No statistically significant differences were observed between IO/C and C alone. Conclusions: First-line IO/C may achieve a better objective response compared to IO alone in patients diagnosed with locally advanced/metastatic UC. Although, there appears to be a trend of greater benefit with IO/C compared to C alone, the difference was not statistically significant. The results will be updated as soon data from new trials (CheckMate 901 and EV 302) becomes available which could offer new insights. [Table: see text]

627 Background: Enfortumab vedotin (EV) is an antibody-drug conjugate recently approved to treat locally advanced or metastatic bladder cancer (la/mUC). Initial trials have shown promising response to EV in advanced urothelial cancers (UC), where prognosis is currently poor. Here, we report real-world experience using EV at a tertiary center. Methods: This study reports treatment details and outcomes in 92 patients (pts) that received at least one complete cycle of EV monotherapy in treatment of la/mUC. Treatment details include intent of cycle duration, 21 days (treatment on days 1 and 8) or 28 days (treatment on days 1, 8 and 15), dose reductions, and median number of cycles completed. Interruptions in treatment are reported as intentional (i.e. holding EV after achieving positive response) or unintentional (i.e. secondary to drug toxicity or other delay). Image-based best clinical response consists of progressive disease (PD), stable (SD), partial (PR), complete response (CR), and not evaluable (NE). Clinical benefit rate (CBR) is defined as either SD, PR, and CR outcomes. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Results: Patients mean age was 71.1 years (IQR: 66.8 - 78), 72 (79.2%) are male and 20 (20.8%) female, 89 (96.7%) pts received EV in the setting of metastatic UC, 3 (3.3%) in locally advanced UC. 13 (13.5%) pts were previously chemotherapy exposed, 9 (9.8%) were immunotherapy exposed, 60 (65.2%) were both chemo and immunotherapy exposed, and 11 (12.0%) received EV first line. 46 (50%) pts underwent 21-day treatment cycles, and 46 underwent 28-day treatment cycles. The median number of EV cycles was 3 (range 1-16) in the overall cohort, 3 in the 21-day cycle group, and 4 in the 28-day cycle group. 50 (54.3%) pts required dose reductions secondary to toxicity. 11 (12.0%) pts had planned interruptions, and 33 (35.9%) had unplanned interruptions. Best clinical response consisted of 24 (26.0%) pts with PD, 12 (13.0%) with SD, 25 (27.2%) with PR, 17 (18.5%) with CR, and 14 (15.2%) NE. CBR was 54 (58.7%) in the overall sample. CBR in the 21-day and 28-day cycle groups was identical at 27 (29.3%). EV therapy was discontinued most for cancer progression (34, 37.0%), therapy toxicity (18, 19.6%), and pt death (12, 13.0%). In 13 (14.1%) pts therapy is still ongoing. 73 (76.0%) pts had mild to moderate toxicities, and 19 (19.7%) reported severe toxicities that required hospitalization. Median OS in the total cohort was 11.01 months (95% CI: 8.51-14.6). Median PFS is 5.49 months (95% CI: 4.60-8.19). Conclusions: Real-world utilization of EV showed significant heterogeneity in administration patterns (21 days vs 28 days) and across a range of settings (first line, chemo exposed, IO exposed, chemo and IO exposed). Although EV has high response rates, more than 3/4th of patients suffered mild to moderate toxicities and 1/5th required hospitalization.

229 Background: We aim to investigate non-cancer cause of death in adults within 2 years after initial diagnosis of mGU cancers including bladder cancer (BC), kidney cancer (KC), and prostate cancer (PC). Methods: Surveillance, Epidemiology, and End Results (SEER) database (2004-2020) was searched to obtain data on death caused by cardiovascular diseases (CVD), kidney diseases (KD), respiratory diseases (RD), liver diseases (LD), diabetes mellitus (DM), and sepsis in adults (>20y of age) diagnosed with mGU cancers. Standardized mortality ratios (SMRs) with 95% confidence interval (CI) were calculated within 2y of initial diagnosis. SMR was defined as the observed deaths from each category divided by the expected number of deaths in the age-matched US population for the same period. SMR >1 indicated increased while <1 indicated decreased mortality. Stratification factors included age (<50y, 50-70y, >70y), race (White, Black, Asian/Pacific Islander), ethnicity (Hispanic, non-Hispanic), chemotherapy, and radiotherapy. Results: This study including 77,246 mGU cancer patients showed that the greatest risk of early death was observed to be caused by sepsis (SMR: 4.21, 95% CI: 3.64-4.84) followed by CVD (1.70, 1.62-1.80), KD (1.58, 1.31-1.90), LD (1.58, 1.16-2.09), DM (1.56, 1.32-1.82), and RD (1.38, 1.22-1.56). Patients aged <50y observed the highest risk of mortality caused by sepsis (61.76, 30.83-110.5) followed by KD (28.06, 9.11-65.48) and CVD (5.63, 3.60- 8.84). However, patients aged 50-70y were more likely to die by RD (2.47, 1.94-3.09) and LD (2.01, 1.38-2.82). The results were consistent for Black patients; sepsis (6.59, 5.04-8.46) followed by RD (2.01, 1.41-2.78) and KD (1.64, 1.04-2.46). Asian/Pacific Islanders were more likely to die from CVD (2.52, 2.13- 3.00) and DM (2.21, 1.21-3.71). Hispanics were more likely to die from LD (3.11, 1.66-5.32) and non-Hispanics from sepsis (4.28, 3.68-4.96). This risk of death due to sepsis was increased with chemotherapy (7.06, 5.22-9.33) and radiotherapy (4.92, 3.58-6.61). Detailed results are available in Table. Conclusions: Sepsis remained the leading cause of early non-cancer-deaths in mGU cancers consistently across all subgroups. Younger adults were more likely to die from CVD and KD, Black patients from RD, and Hispanics from LD. [Table: see text]