bluuebunny/crossref_metadata_2025 huggingface dataset:
Preventing adverse events in patients with renal cell carcinoma treated with doublet immunotherapy using fecal microbiota transplantation (FMT): Initial results from perform a phase I study.
Authors: Fernandes Ricardo , Parvathy Seema Nair , Ernst D. Scott , Haeryfar Mansour , Burton Jeremy , Silverman Michael , Maleki Saman
Published: June 2022

4553

Background: The treatment landscape of metastatic renal cell carcinoma (mRCC) has evolved with the advent of either dual immune checkpoint inhibition (ICI) or in combination with Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor. Gut microbiota plays a central role in developing local and systemic immunity, with potential influence in controlling anti-tumor immune response in cancer patients treated with ICI. We hypothesize that FMT from healthy donors given before immunotherapy will establish a more resilient gut microbiota, reducing the treatment toxicity and improving response to therapy. PERFORM is an ongoing phase I study evaluating the safety of FMT and immunotherapy combination in first-line (1L) mRCC, and assessing whether FMT will prevent or mitigate immune-related adverse events (irAE). Methods: Eligible patients with untreated mRCC received a full dose and 2 supportive FMT procedures prior to the first 3 cycles of doublet ICI or in combination with VEGF-TKI. Primary endpoint is the feasibility and safety of combining FMT using intestinal bacteria existing in the stool of healthy donors with immunotherapy. Secondary endpoints include incidence of irAEs, objective response rate (ORR; RECIST v1.1), and changes in pts microbiome and immune profile post-FMT. We included a preliminary analysis of the first 10 patients. Results: 10 patients received FMT and doublet ICI therapy (10 ongoing). 8/10 (80%) patients were male. Median Age: 59.5 (53-71) years-old. Most common histology was clear cell RCC (90%) and all patients had an intermediate or poor-risk disease. 93.3% of planned FMT were administered. No dose-limiting toxicities due to FMT were observed. Median (range) follow-up was 5.5 (1–22) months. 4 patients (40%) discontinued treatment due to irAEs: colitis (n = 3), arthritis (n = 1). IrAEs were reported in 8 (80%) patients, including diarrhea (n = 6; 60%) and skin rash (n = 2, 20%). Grade 3/4 AEs were experienced by 6 (60%) patients, including colitis (n = 4, 40%). ORR was confirmed in 4/9 patients (44%; 95% CI, 30–60); 1 (11%) partial response. Microbiota and immune analysis data to be presented. Conclusions: The role of microbiome modification in preventing immune-related toxicities by adding FMT to ICI therapy was associated with a safety profile in unselected 1L mRCC and promising clinical efficacy data. Further prospective studies to examine the changes in the immune and microbiota profiles to determine biomarkers related to healthy outcomes/less frequent toxicities in patients receiving immunotherapy are warranted. Clinical trial information: NCT04163289.
Distinct outcomes in Hispanic/Latinx and non-Hispanic/Latinx patients with metastatic renal cell carcinoma (mRCC) treated with first-line ipilimumab plus nivolumab (ipi/nivo).
Authors: Ali Sana , Leong Sally , Meza Luis A , Dizman Nazli , Zengin Zeynep Busra , Kim Tane , Pak Youngju , Onyshchenko Mykola , Pal Sumanta K. , Chehrazi-Raffle Alex
Published: June 2022

4554

Background: Subgroup analyses have reported differences in clinical outcomes by ethnicity in patients (pts) receiving immune checkpoint inhibitors (Cheng et al Ann Oncol 2019; Peravali et al World J Clin Oncol 2021). We sought to compare real-world outcomes between Hispanic/Latinx and non-Hispanic/Latinx mRCC pts treated with first-line ipi/nivo within a safety-net healthcare system and at a tertiary care center in Southern California. Methods: We performed a retrospective analysis of mRCC pts who received ipi/nivo within the Los Angeles County Department of Health Services (a safety-net healthcare system) and the City of Hope Comprehensive Cancer Center (a tertiary oncology center) between Jan 1, 2015 and Dec 31, 2021. Pts were identified using institutional databases and clinical data were compiled from electronic health records. Pts with pathologic diagnosis of stage IV mRCC, age > 18 years and receipt of ipi/nivo as first-line therapy were included. Progression-free survival (PFS) was analyzed using the Kaplan-Meier method and covariates were adjusted using multivariate Cox proportional hazards regression. Results: Of 96 pts, 67 (70%) were male, 90 (94%) had clear-cell histology, and 89 (93%) had intermediate/poor IMDC risk. Forty-two pts (44%) were Hispanic/Latinx while the remainder were non-Hispanic/Latinx (44 pts [46%] White, 7 pts [7%] Asian, and 3 pts [3%] Other). Fifty (52%) and 46 (48%) pts received their care at a tertiary care center and within a safety-net healthcare system, respectively. Median age, IMDC risk classification, BMI, and number of comorbidities were similar between both groups. Pooled analysis by ethnicity revealed significantly shorter PFS in Hispanic/Latinx vs non-Hispanic/Latinx pts (HR 1.60, 95% CI 1.04-2.48, p = 0.03). At 12 months, 19% of Hispanic/Latinx pts (95% CI, 9-32) and 35% of non-Hispanic/Latinx pts (95% CI, 23-48) were alive and progression-free. There was no difference in PFS between pts at the safety-net hospital system vs tertiary care center (HR 1.32, 95% CI 0.87-2.02, p = 0.19). Conclusions: Our real-world analysis of mRCC pts demonstrated poorer outcomes with ipi/nivo in Hispanic/Latinx pts. We are currently interrogating multiple social determinants of health that may contribute to these concerning disparities.
A robust, trial-agnostic gene signature for response to tyrosine kinase inhibition in ccRRCC.
Authors: Khaleel Sari Safaa , Liu Minwei , Kuo Fengshen , Kotecha Ritesh , Lee Chung-Han , Voss Martin H , Motzer Robert J. , Hakimi A. Ari , Reznik Eduard
Published: June 2022

4558

Background: Combination systemic therapies (ST) including immunotherapy (IO) and Tyrosine Kinase Inhibitors (TKI) have become the standard of care for management of metastatic clear cell carcinoma (ccRCC). Several expression (GE) signatures have been reported to predict TKI response with the aim of identifying the optimal ST regimen (IO/IO or IO/TKI) per patient. However, these gene signatures were developed and evaluated using data from individual trials with clinically distinct patient cohorts, fundamentally impeding their general application to diverse and heterogeneous patient populations. We therefore sought to identify genes consistently and directly associated with progression-free survival (PFS) with TKI ST across several trials. Methods: We applied a stratified, weighted concordance model to identify genes consistently demonstrating statistically significant association with PFS in the sunitinib TKI arm in four large randomized controlled trials (RCTs) of ST in ST-naïve ccRCC patients: COMPARZ (Motzer et al, 2013), Checkmate 214 (Motzer et al, 2018), IMmotion 151 (Rini et al, 2019), and Javelin 101 (Motzer et al, 2019). Concordant genes with Benjamini-Hochberg adjusted p-value (pAdj) ≤ 0.01 were selected. Of these, genes significantly associated with PFS on Cox proportional hazard regression (pAdj ≤ 0.05) in at least 3 of the 4 datasets were selected. Ontologic process and pathway enrichment analyses (OPPEA) against several ontologic databases were peformed using Metascape (Zhou et al, 2019). Results: We identified 2,794 statistically significant genes demonstrating concordant association with PFS across all 4 datasets (1087 patients); 71 genes were significantly associated with PFS on univariate post-hoc analysis in ≥3 of the datasets. OPPEA of these results identified significant enrichment in genes associated with cell cycle, cell division, and VEGFA-VEGFR2 pathways (Table 1). Although 5 genes in our set overlapped with published angiogenesis GES, the majority of these genes constitute entirely novel transcriptomic correlates of response to sunitinib. Conclusions: We developed a robust meta-gene signature consisting of genes directly and consistently associated with TKI response using data from several clinical trials. This gene signature is readily applicable to heterogeneous patient populations treated with anti-VEGF therapies. [Table: see text]
A prospective exploratory clinical study of penpulimab plus anlotinib as first-line treatment for locally advanced or metastatic urothelial carcinoma.
Authors: Yang Bo , Xiong Qi , Song Qi , Long Yaping , Guo Gang , Li Hongzhao
Published: June 2022

4567

Background: A high unmet need remains for first-line cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma (la/mUC).Immune checkpoint inhibitors have been implemented in the management of cisplatin-ineligible la/mUC. Penpulimab is a programmed death 1 (PD-1) inhibitor which had approved by the Chinese National Medical Products Administration (NMPA) on August 2021. Anlotinib is a novel oral multi-target tyrosine kinase inhibitor and primary targeted to VEGFR, FGFR, PDGFR and c-Kit. The current prospective single-arm phase Ⅱ clinical trial (ChiCTR1900028022) aimed to assess the efficacy and safety of penpulimab plus anlotinib as first-line therapy for la/mUC. Methods: Patients (pts) who had no prior systemic therapy and at least one measurable lesion according to RECIST v1.1 with histologically or cytologically confirmed locally advanced unresectable or metastatic urothelial carcinoma (including unresectable or metastatic urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis), 18-75 years, ECOG 0-2, were considered eligible for enrollment. Patients received 200 mg penpulimab intravenously on day 1 plus anlotinib, 8 mg oral daily for days 1-14 of a 21-day cycle until confirmed disease progression, intolerable toxicity, physician/patient decision to withdraw, or completion of 24 months of treatment. The primary endpoint was objective response rate (ORR), and the secondary endpoints included disease control rate (DCR), progression-free survival (PFS) and safety. Results: As of Dec. 2021, 10 pts were enrolled, 9 pts had the best overall response assessments which inferred the ORR of 66.7%（95% CI, 29.9-92.5）and the DCR of 88.9% (PR in 6 pts and SD in 2 pts; 95% CI, 51.8-99.7). The median PFS was 8.2 months（(95% CI, 8.0-8.4). Any grades of adverse events (AEs) were observed in 90% (9/10) of pts, containing hyperthyroidism (33%), Creatinine increased (33%),haematuria (22%), anaemia (22%), hypertension (11%), fatigue (11%). High grade AEs of grade Ⅳ liver dysfunction were observed in one patient (11%). Conclusions: An effective treatment strategy for cisplatin-ineligible patients and for patients unable to receive chemotherapy is an important unmet clinical need. Penpulimab in combination with anlotinib in pts with la/mUC showed encouraging efficacy and satisfactory safety. Clinical trial information: ChiCTR1900028022.
Benchmarking maintenance therapy survival in first-line advanced urothelial carcinoma using disease modeling.
Authors: Galsky Matt D. , Wirtz Heidi , Bloudek Brian , Hepp Zsolt , Timmons Jack , Lenero Enrique , Powles Thomas
Published: June 2022

4575

Background: First-line (1L) maintenance avelumab (maintA) in patients with advanced urothelial carcinoma (aUC) prolonged overall survival (OS) in the JAVELIN Bladder 100 trial. JAVELIN measured OS from the initiation of maintA among a subgroup of the overall aUC 1L treated population, including only patients who did not progress with 1L platinum-based therapy (PBT) and remained progression free during a 4-10 week treatment-free interval following completion of 1L PBT. As such, patients who progressed on or immediately following PBT were not included in the trial. To address this, we used disease modeling to estimate maintA OS measured from initiation of 1L PBT to align maintA OS with the common initiation point to benchmark with other 1L clinical trials. Methods: We developed a simulated cohort to estimate OS from initiation of 1L PBT in all aUC patients including those who received maintA. Eligibility for maintA (PBT progressed vs not progressed) was assessed at 5.6 months post-initiation of 1L PBT, accounting for 6 PBT cycles and a nominal 6-week treatment-free interval. Median OS of 14.3 months from the 1L PBT arm of a recent 1L trial, KEYNOTE-361, was used to represent the OS of the simulated cohort of 1L aUC patients. The simulated cohort was stratified by eligibility for maintA. Among the 1L treated population, 57% were projected to be progression-free and eligible for maintA based on progression-free survival (PFS) from KEYNOTE-361. Among those eligible, 85% were assumed to receive maintA based on expert clinical input. OS of maintA eligible patients was 21.4 months from JAVELIN. Our disease model estimated OS among a maintA ineligible simulated cohort, which was combined with the maintA eligible cohort to yield an estimated OS in the overall aUC population measured from initiation of 1L PBT. Results: Approximately 50% of the 1L modeled population receive maintA (i.e., 57% eligible x 85% treated). Our approach estimated a median OS of 9.9 months for the maintA ineligible cohort and 27.0 months for the maintA eligible cohort. Combined, the estimated median OS with maintA, measured from initiation of 1L PBT, in all 1L-treated aUC patients was 15.8 months (vs 14.3 months with PBT only in 1L). Conclusions: MaintA improves OS for eligible patients, however our simulation model suggests a significant proportion of patients will not receive MaintA. The estimated OS of 15.8 months for the population-level impact of maintA, accounting for patients ineligible for 1L maintA, demonstrates remaining unmet need in the overall 1L aUC population.
Phase Ib study of avelumab and novel AXL inhibitor avb-S6-500 in patients with metastatic urothelial carcinoma (mUC).
Authors: Tripathi Abhishek , Clingerman Melissa , Fabreo Riza Celine , Ayanambakkam Adanma , Cross Brian , Stratton Kelly Lynn , Cookson Michael , Pal Sumanta K. , Agarwal Neeraj
Published: June 2022

4579

Background: AXL is a member of the mammalian Tyro3/AXL/Mer (TAM) receptor tyrosine kinase family, which upon binding to its ligand Gas6 promotes immunosuppression in the tumor microenvironment. AVB-S6-500 (AVB) is a novel AXL pathway inhibitor which binds to circulating Gas6 and inhibits ligand-dependent AXL signaling. In this phase Ib investigator-initiated trial (NCT04004442), we evaluated the safety, tolerability, pharmacodynamics, and preliminary antitumor efficacy of AVB with the anti-PD-L1 antibody avelumab in mUC. Methods: Patients with PD-1/L1 inhibitor naïve locally advanced unresectable or mUC with measurable disease were eligible if they were either in-eligible for, refractory to, or declined platinum-based chemotherapy. Employing a 3+3 dose escalation design, patients were treated with AVB 5mg/kg weekly (dose level; DL1), or 10 (DL2), 15 (DL3), or 20 (DL4) mg/kg every two weeks along with avelumab 800 mg every 2 weeks administered intravenously. The safety and tolerability of the combination as measured by the incidence of dose limiting toxicities (DLTs) was the primary endpoint while objective response rate (ORR) per RECIST 1.1 was key secondary endpoint. Pharmacodynamic studies evaluated baseline and on therapy (C2D1) Gas6 levels. Results: To date, a total of 15 patients have been enrolled (DL1: n = 3, DL2: n = 7, DL3: n = 3 and DL4: n = 2). Among the 13 evaluable patients, DLT was observed in 1 patient (grade 3 fatigue; DL2). Grade ≥3 adverse events irrespective of attribution were seen in 6 patients which included UTI (n = 3), hyponatremia (n = 1), elevated creatinine (n = 1), and anemia, thrombocytopenia, hematuria, anorexia and sepsis (n = 1 each; all in same patient). No treatment related deaths were noted. While enrollment on DL4 is ongoing, the maximum tolerated dose for AVB has not been reached. Treatment with AVB effectively suppressed circulating Gas6 levels from baseline (median: 28.4 ng/mL; range: 20.4-54.0 ng/mL) to below threshold of detection in 85% (n = 11/13) of patients. Median follow up was 10 months (95% CI: 3.9, 18.55). Confirmed ORR was 38% (n = 5/13) while 1 patient had stable disease as best response. Durable responses lasting > 6 months were seen in 3 patients (7, 19 and 21 mos) who continue to be on treatment without disease progression. Additional correlative studies investigating AXL, Gas6, PD-L1 expression and gene expression signatures are currently underway. Conclusions: Concurrent avelumab and AVB was safe and AVB effectively neutralized circulating Gas6 across DLs. Albeit small sample size, the efficacy of the combination was encouraging and ORR compares favorably to that previously reported with PD-1/L1 inhibitor monotherapy. Updated safety, efficacy and biomarker data will be presented. Clinical trial information: NCT04004442.
S1314 correlative analysis of ATM, RB1, ERCC2, and FANCC mutations and pathologic complete response (pT0) at cystectomy after neoadjuvant chemotherapy (NAC) in patients with muscle invasive bladder cancer (MIBC): Implications for bladder preservation.
Authors: Plimack Elizabeth R. , Tangen Catherine , Plets Melissa , Kokate Rutika , Xiu Joanne , Nabhan Chadi , Ross Eric A. , Grundy Erin , Choi Woonyoung , Dinney Colin P.N. , Lee I-Ling C. , Lucia Scott , Flaig Thomas W. , McConkey David James
Published: June 2022

4581

Background: SWOG S1314 (NCT02177695) was designed to validate the CoXEN classifier as a predictive biomarker in pts undergoing cystectomy after NAC. We repurposed banked DNA samples and prospective trial data from S1314 to further validate the predictive ability of the Philadelphia 4 gene signature (P4GS: any mutation in ATM, RB1, FANCC, ERCC2) to predict pT0 as previously reported (PMID: 26238431) and used in the RETAIN trial (NCT02710734). The RETAIN trial prospectively enrolled pts to receive NAC (DDMVAC) followed by allocation to bladder observation vs. intervention (cystectomy or RT) based on clinical evaluation and presence vs absence of P4GS. The primary objective of this correlative investigation was to determine whether presence of P4GS is predictive of pT0 at surgery. Methods: Eligibility for S1314 included cT2-T4a N0 M0 MIBC, cisplatin eligible, with plan for cystectomy; 237 pts were randomized between ddMVAC and gem/cis (GC) using standard dose/schedule. Of 167 pts who were evaluable for the original COXEN analysis (received 3+ cycles of chemo and evaluable for path response) adequate banked DNA was available for 105. Next-generation sequencing using the CARIS 592 Gene Panel (Caris Life Sciences, Phoenix, AZ) was performed. Pathogenic mutation or VUS of ATM, RB1, FANCC or ERCC2 was noted as present or absent for each pt and correlated with pT0 using logistic regression, adjusting for clinical stage. Results: Among the 105 pts, 51% ddMVAC, 49% GC. 15% female, 95% white, 15% clinical stage T3/T4a Prevalence of mutations: ATM (24%), ERCC2 (17%), FANCC (4%), RB1 (24%) and any variant 53%. Presence of any mutation correlated with pT0 (p = 0.0006), sensitivity 79%, specificity 59%. This association did not vary by treatment arm (MVAC vs. GC). The table below shows the contributions of each of the 4 genes with the greatest contribution from ATM and ERCC2. FANCC was non-contributory due to low prevalence. Conclusions: Patients with a mutation in ATM, RB1, FANCC or ERCC2 (P4GS) have a statistically significantly higher odds of a pT0 with GC or MVAC compared to those who do not have any variant. This signature was used to prospectively allocate patients to bladder observation as part of the RETAIN trial previously reported (ASCO GU 2021). RETAIN completed enrollment, final analysis of the primary endpoint – 2-year metastasis free survival – is expected later in 2022. Clinical trial information: NCT02177695.
Study EV-103 Cohort H: Antitumor activity of neoadjuvant treatment with enfortumab vedotin monotherapy in patients with muscle-invasive bladder cancer who are cisplatin-ineligible.
Authors: Petrylak Daniel P. , Flaig Thomas W. , Mar Nataliya , Gourdin Theodore Stewart , Srinivas Sandy , Rosenberg Jonathan E. , Guseva Maria , Yu Yao , Narayanan Sujata , Hoimes Christopher J.
Published: June 2022

4582

Background: Up to 25% of all patients (pts) diagnosed with urothelial cancer present with muscle-invasive disease for whom the risk of progression or metastasis is substantial. Neoadjuvant chemotherapy prior to radical cystectomy and pelvic lymph node dissection (RC+PLND) has been shown to prolong overall survival for patients who are cisplatin (cis) eligible. The standard of care for cis-ineligible pts undergoing surgery does not include neoadjuvant therapy. Therefore, safe and effective neoadjuvant therapies are an unmet need for cis-ineligible pts with muscle invasive bladder cancer (MIBC). Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in urothelial cancer, and has been shown to benefit previously treated locally advanced or metastatic urothelial cancer pts in phase 2 and 3 trials, including cis-ineligible pts. Methods: Cohort H of the EV-103 phase 1b/2 trial (NCT03288545) enrolled pts with cis-ineligible cT2-T4aN0M0 MIBC who were eligible for RC+PLND and had an ECOG of 0-2. Pts received 3 cycles of neoadjuvant EV (1.25 mg/kg) on Days 1 and 8 of every 3-week cycle prior to RC+PLND. The primary endpoint of the study was pathological complete response rate (pCRR; ypT0N0) by central review. Key secondary endpoints included pathological downstaging (pDS) rate (ypT0,Tis,Ta,T1,N0) and safety. Results from a preliminary analysis are presented. Results: 22 pts were treated. Pts had cT2 (68.2%), cT3 (27.3%), and cT4 (4.5%) tumors. 68.2% pts had predominant urothelial cancer; 31.8% had a mixed histology. 19 pts completed all 3 cycles of EV. 21 underwent RC+PLND, and 1 had a partial cystectomy. 36.4% pts had a pCR. pDS was seen in 50.0% pts. The most common EV treatment-related adverse events (TRAEs) were fatigue (45.5%), alopecia (36.4%), and dysgeusia (36.4%). 18.2% pts had Grade ≥3 EV TRAEs. No surgeries were delayed due to EV administration. 3 pts had Grade 5 AEs while on study that were unrelated to EV; in 2 pts these AEs occurred > 30 days after RC+PLND. Conclusions: Observed pCRR after neoadjuvant EV showed promising activity in cis-ineligible pts with MIBC who have a high unmet need. Adverse events were consistent with the known safety profile of EV. This first disclosure of data supports the ongoing phase 2 and 3 programs evaluating EV in MIBC. Clinical trial information: NCT03288545.
Clinical utility of urine DNA for noninvasive detection and minimal residual disease monitoring in urothelial carcinoma.
Authors: He Zhisong , Hu Hailong , Niu Yuanjie , Guo Zhaoxia , Ding Feng , Wang Yunkai , Wang Wang , Zhou Tao , Cao Shanbo , Lou Feng , Wang Huina
Published: June 2022

4583

Background: Current methods for the early detection and minimal residual disease (MRD) of urothelial carcinoma (UC) are often invasive and/or possess sub-optimal sensitivity, especially in upper tract urothelial carcinoma (UTUC). Methods: We developed an efficient workflow named the urine tumor DNA multidimensional bioinformatic predictor, utLIFE, by using low-coverage whole-genome sequencing and targeted deep sequencing. We identified the UC specific mutations and large CNV in the discovery cohort. The utLIFE-UC model was trained in a bladder cancer retrospective cohort (n = 150) and validated in an bladder cohort(n = 674) and UTUC cohort(n = 22). 31 patients established diagnosis of BC who are on neoadjuvant were also enrolled, including a MRD training cohort (n = 16) with serial urine samples at baseline, during treatment and before surgery; a independent MRD validation cohort (n = 15) with urine samples before surgery. Results: The utLIFE-UC model could discriminate UC with high accuracy (94.3%), sensitivity (92.8%), and specificity (96.0%). Furthermore, compared to cytology, the assay achieved a great improvement in sensitivity in the detection of non–muscle-invasive bladder cancer (NMIBC, 94.7% vs. 31.6%,p = 0.0002), and muscle-invasive bladder cancer(MIBC, 82.6% vs. 69.6%, p = 0.4894). The utLIFE-UC model was also validated in independent BC cohort (sensitivity 94.3%, specificity 92.6%) and UTUC cohort (sensitivity 90.9%, specificity 90.9%). utLIFE-UC score also showed outstanding potential on dynamic surveillance of residual disease in UC as the score showed dramatically decreased in pCR patients. As expected, utLIFE-UC score could classify pCR and non-pCR(PR, SD, PD) with NPV 100% in MRD training and validation cohorts, which showed superior sensitivity over that of urine cytology (100% vs.37.5%, p = 0.0070) and FISH (100 vs. 42.9%, p = 0.0125). Conclusions: utLIFE-UC diagnostic model for early diagnosis, residual disease detection in UC is a cost-effective, rapid, high-throughput, noninvasive, and promising approach, which may reduce the burden of cystoscopy and blind surgery.
Chemotherapy with significant mortality benefit in patients with bladder cancer with variant and non-urothelial histologies (NUVH).
Authors: Perimbeti Stuthi , Jiang Changchuan , Deng Lei , Roy Arya Mariam , Gupta Shilpi , Kambam Greeshma , Chatta Gurkamal S. , George Saby , Gopalakrishnan Dharmesh
Published: June 2022

4586

Background: Non urothelial cancers and urothelial cancers with variant histologies(NUVH) have a more aggressive natural history and are at a higher risk of progression to muscle invasive disease(MIBC) when compared to their urothelial counterparts. Although surgical resection is the treatment of choice in localized disease, radiation(RT) is commonly used in patients who are not surgical candidates. The use of chemotherapy has shown modest benefit in some retrospective studies. Considering the low incidence of NUVH, there are no large-scale studies examining the benefits of chemoradiation(CRT) in MIBC with NUVH. Methods: The National Cancer Database was queried to identify MIBC patients with NUVH from the years 2004-2018.Inclusion criteria for the study are age > 18 years, Non urothelial or variant histologies and receipt of RT. Patients who underwent cystectomy or had metastatic disease were excluded. The population was divided into two cohorts if they received chemoradiation. Chi-Square test and Mann Whitney U tests were used to compare frequency distributions. Cox proportional Hazard regression was employed to control for confounding factors associated with overall survival. Covariates for confounding included age, race, sex, income, insurance status, charlson-deyo comorbidity index, education. Results: Among 1773 observations in the final analysis, 63.05%(n = 1118) received CRT. Small cell, large cell and neuroendocrine cancers composed of the majority of NUVH. 38.01% (n = 641). Other histologies composed of squamous cell cancer 30.34%(n = 538), spindle cell/sarcomatoid cancers10.15%(180), adenocarcinoma 11.44%(203). Patients who received CRT were found to be significantly younger (76 vs 82 years P: < 0.0001) with higher male predominance74.73%. 5 year overall mortality was significaantly lower in the CRT vs RT group ( 66.47% vs 81.55%, p < 0.001). After controlling for confounding factors, CRT was associated with lower risk of mortality Hazard Ratio(HR)of 0.41(0.36-0.47) p < 0.0001. Added, the survival benefit of CRT continued in the non small cell variant cohort HR: 0.43(0.37-0.51) P < 0.0001. Conclusions: In this large retrospective study, CRT was associated with reduced overall mortality among patients with non-urothelial MIBC. The findings suggest the importance of systemic therapy in providing a survival advantage to non-urothelial MIBC, including the non-small cell variants. [Table: see text]
Efficacy of hyperthermic-intra-vesical chemotherapy in patients with BCG-refractory nonmuscle-invasive bladder cancer.
Authors: Pignot Geraldine , Lorusso Vito , Doisy Laure , Guerin Mathilde , Vicier Cecile , Dermeche Slimane , Branger Nicolas , Maubon Thomas , Rybikowski Stanislas , Walz Jochen , Gravis Gwenaelle
Published: June 2022

4592

Background: In Bacillus Calmette-Guérin (BCG) refractory non-muscle-invasive bladder cancer (NMIBC), radical cystectomy is the standard of care. For patients unwilling or unable to undergo cystectomy, alternative intravesical therapies are currently being investigated to minimize the risk of recurrence and progression. Chemohyperthermia by HIVEC (Hyperthermic-Intra-Vesical Chemotherapy) is a therapeutic option in BCG-refractory patients. The objective of our study was to evaluate the 2-year oncological results of HIVEC in BCG-refractory patients. Methods: Between June 2016 and September 2021, patients treated with HIVEC (6 weekly instillations) for BCG-refractory NMIBC were prospectively included in our study. These patients had a theoretical indication for cystectomy but were ineligible for surgery or refused it. The primary endpoint was 1-year recurrence-free survival (RFS) rate. Secondary endpoints were 6-month complete response rate for Cis, 1-year overall and cancer-specific survival rates and bladder preservation rate. Results: Seventy patients, mean age 70 [42-89] years, were treated consecutively. After a mean follow-up of 20.9 months, 32 patients recurred (mean time of 10.6 months) and 7 patients finally had a cystectomy. The recurrence-free survival rate was 53.1% at 1 year and 20.5% at 2 years. Six patients progressed to a muscle-invasive disease, after a mean delay of 6.7 months. Four of them experienced metastatic progression and died from bladder cancer. Cancer-specific and overall survival rates were 95.1% and 92.9% at 1 year, and 87.5% and 77.8% at 2 years. The bladder preservation rate was 90%. For patients with Cis (34% of the entire series), the 6-month complete response rate was 75%. The presence of Cis was not a predictive factor of response to HIVEC. Tolerance was excellent with 38.2% grade 1-2 adverse events and no grade 3-4 adverse events. Conclusions: Chemohyperthermia using the HIVEC device achieved a RFS rate of 53.1% at 1 year and enabled a bladder preservation rate of 90%. While cystectomy remains the standard of care, HIVEC may be discussed cautiously for patients who are not eligible for surgery and well informed of the risk of progression to muscle-invasive disease.
[68Ga]Ga-PSMA-11 PET baseline imaging as a prognostic tool for clinical outcomes to [177Lu]Lu-PSMA-617 in patients with mCRPC: A VISION substudy.
Authors: Kuo Phillip , Hesterman Jacob , Rahbar Kambiz , Kendi Ayse T. , Wei Xiao X. , Fang Bruno , Adra Nabil , Armstrong Andrew J. , Garje Rohan , Michalski Jeff M. , Ghebremariam Samson , Brackman Marcia , Wong Connie , Benson Taylor , Vogelzang Nicholas J.
Published: June 2022

5002

Background: In the phase 3 VISION study, gallium (68Ga) gozetotide (68Ga-PSMA-11) PET/CT imaging was used to determine eligibility for lutetium (177Lu) vipivotide tetraxetan (177Lu-PSMA-617). Given that 177Lu-PSMA-617 targets PSMA, we assessed the association between quantitative PSMA imaging parameters and treatment outcomes. Methods: In VISION, adults with mCRPC with ≥ 1 PSMA-positive (+) and no PSMA-negative lesions meeting the exclusion criteria were enrolled. In this sub-study, the association between imaging data from pre-enrollment 68Ga-PSMA-11 PET/CT scans of pts in the 177Lu-PSMA-617 group and clinical outcomes was assessed. Imaging data meeting quality requirements were analyzed for 548/551 pts. PSMA expression was quantified by 5 PET parameters: PSMA+ lesions by region, mean standardized uptake value (SUVmean), maximum SUV (SUVmax), PSMA+ tumor volume, and tumor load (PSMA+ tumor volume × SUVmean). Parameters were extracted from the whole body and 4 regions. Association between PET parameters and radiographic progression-free survival (rPFS; primary objective), overall survival (OS), objective response rate (ORR), and prostate–specific antigen 50 (PSA50) response was assessed. Results: Most pts (92.7%) had PSMA uptake in bone. In both the whole-body and regional analyses, statistically significant associations of PSMA PET parameters to clinical outcomes were observed (whole-body data shown in Table). Higher whole-body SUVmean was associated with improved clinical outcomes; pts in the highest quartile (SUVmean: rPFS, ≥ 10.2; OS, ≥ 9.9) had a median rPFS and OS of 14.1 and 21.4 months, vs 5.8 and 14.5 months for those in the lowest quartile (< 6.0; < 5.7), respectively. Absence of PSMA+ lesions in bone, liver, and lymph node, and lower PSMA+ tumor load, were indicators of good prognosis. Conclusions: Higher SUVmean is strongly associated with improved outcomes with 177Lu-PSMA-617; clinical efficacy for different SUV levels vs the SoC arm is being assessed. Data support use of 68Ga-PSMA-11 PET/CT scan to identify pts who will benefit from PSMA-targeted radioligand therapy.[Table: see text]
Prognostic significance of raised serum tumor markers (STM) after 2 cycles of chemotherapy in men with intermediate- and poor-risk non-seminomatous testicular germ cell tumors (NSGCT) treated at a single-centre in India.
Authors: VARSHNEY ANKUR NANDAN , Raj Abhishek , Sahoo Ranjit Kumar , KP Haresh , Singh Prabhjot , Shamim Shamim Ahmed , Seth Amlesh , Ray M D INDIA INSTITUTE OF MEDICAL , Kaushal Seema , Das Chandan Krushna , Batra Atul
Published: June 2022

5036

Background: Testicular GCT is a rare malignancy, with excellent outcomes. However, approximately one-fourth of intermediate risk and half of the patients with poor risk disease succumb to recurrent GCT. We looked at the prognostic significance of raised serum tumor markers after 2 cycles of chemotherapy in patients with poor risk GCT. Methods: This is a chart-review based retrospective analysis of patients with intermediate and poor risk NSGCT diagnosed and treated at a tertiary care centre in New Delhi, India from 2015-2021. Risk categories were defined as per the International Germ Cell Cancer Collaborative Group. Multivariable Cox regression models were constructed to analyse the prognostic impact of normal STM at the end of second cycle of chemotherapy on overall survival (OS) and relapse free survival (RFS), while adjusted for measured confounders. Results: A total of 312 patients were identified with testicular NSGCT, of whom 109 were intermediate (n = 48, 44%) and poor risk (n = 61, 56%). The median age at diagnosis was 27 (interquartile range, 21-34) years. ECOG PS of patients was 0-1 in 51% and 2-4 in 49%, and poor risk patients were more likely to have a poor ECOG PS at diagnosis (70% vs 30%, P < 0.001). First-line chemotherapy was BEP in 86% patients and VIP in the remaining 14%, and surgery for residual disease was performed in 22%. Overall, 35% patients had normal STM after 2 cycles of chemotherapy, and patients with intermediate risk were likely to achieve normal STM at this time-point (50% vs 23%). At a median follow-up of 62 months, the 5-year RFS rate was 62% (poor risk 52% and intermediate risk 78%), and OS rate was 68% (58% and 80%, respectively). Men with normal STM after 2 cycles chemotherapy had a better RFS (hazard ratio [HR], 0.70; 95% confidence interval 0.48-0.81; P < 0.001) and OS (HR,0.82; 95% CI 0.61-0.99; P = 0.04). After adjusting for risk category, and ECOG PS in a multivariable Cox regression model, patients with normal STM at the end of 2 cycles of chemo continued to have better outcomes (adjusted HR for RFS, 0.78; 95% CI, 0.77-0.89; P = 0.03, and adjusted HR for OS, 0.92; 95% CI,0.81-0.99; P = 0.05). Intermediate risk NSGCT and good ECOG PS also predicted better RFS and OS. Conclusions: Patients with NSGCT whose STMs do not normalize after 2 cycles of chemotherapy have worse RFS and OS compared to those with normal STM at this time-point. Further clinical trials will be needed to study the role of escalation or switch of chemotherapy in this subset of population.
Candidate surrogate endpoints in advanced prostate cancer: Aggregate meta-analysis of 143 randomized trials.
Authors: Gharzai Laila A , Jiang Ralph , Jaworski Elizabeth , Morales Krystal A , Dess Robert Timothy , Jackson William C. , Hartman Holly , Mehra Rohit , Kishan Amar Upadhyaya , Solanki Abhishek A , Schaeffer Edward M. , Feng Felix Y , Zaorsky Nicholas George , Berlin Alejandro , Ponsky Lee Evan , Shoag Jonathan Evan , Sun Yilun , Schipper Matthew J. , Garcia Jorge A. , Spratt Daniel Eidelberg
Published: June 2022

5039

Background: The Intermediate Clinical Endpoints (ICEs) in Cancer of the Prostate (ICECaP) working group identified metastasis-free survival as a valid surrogate endpoint for overall survival (OS) for patients with localized prostate cancer. No comparably validated surrogate endpoints for OS exist in advanced prostate cancer. Methods: In this meta-analysis, PubMed was searched for trials in advanced prostate cancer, defined as node positive (N1M0), metastatic castration-sensitive (mCSPC), non-metastatic (M0CRPC), or metastatic castration-resistant prostate cancer (mCRPC). Eligible randomized trials were required to report OS and ≥1 intermediate clinical endpoint (ICE). ICEs included biochemical-failure (BF), clinical failure (CF), BF-free survival (BFS), progression-free survival (PFS), radiographic PFS (radiographic +/- other study defined endpoints). Candidacy for surrogacy was assessed using the second condition of the meta-analytic approach, correlation of the treatment effect of the ICE and OS, using R2 weighted by the inverse variance of the log ICE hazard ratio and defined as an R2 > 0.70. Results: A total of 143 randomized trials (n = 75,601 patients) were included. No candidate endpoints met criteria for surrogacy; R2 BF (n = 28,922) 0.42 (95%CI 0.18-0.64), BFS (n = 25,741) 0.57 (95%CI 0.37-0.73), CF (n = 22,616) 0.31 (95%CI 0.0075-0.56), PFS (n = 52,639) 0.50 (95%CI 0.35-0.63), and radiographic PFS (n = 52,548) 0.50 (95%CI 0.35-0.63). Within preplanned subgroups by castration sensitive or resistant disease, or by treatment type, neither BFS nor PFS met criteria for surrogacy. When assessing radiographically-defined progression (exclusive or with clinical progression), PFS for the overall group and by castration status did not meet criteria for surrogacy. Sensitivity analyses demonstrated that candidacy for surrogacy of all endpoints tested did not change over time. Conclusions: Our aggregate screening method for surrogate endpoints in advanced prostate cancer demonstrated commonly used clinical endpoints are not valid surrogate endpoints for OS, and further composite endpoint construction is necessary.
Safety and survival outcomes in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with lutetium-177–prostate-specific membrane antigen (177Lu-PSMA) after radium-223 (223Ra): Interim analysis of the RALU study.
Authors: Rahbar Kambiz , Essler Markus , Eiber Matthias , la Fougère Christian , Prasad Vikas , Fendler Wolfgang P. , Rassek Philipp , Hasa Ergela , Dittmann Helmut , Bundschuh Ralph A. , Pabst Kim M. , Kurtinecz Milena , Sandstrom Per , Verholen Frank , Sartor A. Oliver
Published: June 2022

5040

Background: 223Ra and 177Lu-PSMA both prolong overall survival (OS) in different mCRPC settings. Previous data from the observational REASSURE (Sartor O, et al. 2021) and WARMTH (Ahmadzadehfar H, et al. 2021) studies suggested the feasibility of sequencing 223Ra and 177Lu-PSMA therapies. Here we used data from the observational, retrospective RALU study to further examine the safety and clinical outcomes of sequential 223Ra/177Lu-PSMA therapy in pts with mCRPC. Methods: This interim analysis investigated the baseline characteristics, safety (primary endpoint) and OS (secondary endpoint) in pts who received 177Lu-PSMA after 223Ra using retrospective data collected in German centers. Results: Data from 49 pts were available for this interim analysis. At baseline, before the start of 177Lu-PSMA, 73% of pts were Eastern Cooperative Oncology Group performance status (ECOG PS) 1 and 27% ECOG PS 2. Visceral metastases were present in 31% of pts. Median prostate-specific antigen (PSA) and alkaline phosphatase (ALP) were 287 ng/ml and 142 U/L, respectively (Table). 70% of pts received ≥4 life-prolonging therapies prior to 177Lu-PSMA, with abiraterone acetate (80%), enzalutamide (67%) and docetaxel (92%) being the most frequently used. 74% of pts received ≥5 223Ra injections. Pts received either PSMA-617 (67%) or PSMA I&T (33%): 65% of pts received 1–4 cycles and 33% received 5–6 cycles. Median duration of 177Lu-PSMA therapy was 4.9 months (m) (0–57.1). Median time from the last 223Ra dose to first 177Lu-PSMA dose was 9.3 m (0.9–41.9). Any grade treatment-emergent adverse events (TEAEs) from the start of 177Lu-PSMA therapy to 30 days of follow-up occurred in 91.8% of pts, and serious TEAEs in 20% of pts. Grade 3-4 hematologic laboratory abnormalities up to 90 days post-177Lu-PSMA occurred in 34.7% of pts for anemia, 12.8% for thrombocytopenia and 2.0% for neutropenia. No grade 5 toxicities occurred. 39% of pts had ≥30% decline in PSA during 177Lu-PSMA treatment. Median OS was 12.6 m (95% CI 8.8–16.1) from the start of 177Lu-PSMA therapy. Conclusions: In this real-world retrospective analysis of selected pts with advanced mCRPC, the 223Ra/177Lu-PSMA treatment sequence was clinically feasible and well tolerated. [Table: see text]
Alkaline phosphatase (ALP) decline and overall survival (OS) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223 (Ra-223) in the REASSURE study.
Authors: James Nicholas D. , Heinrich Daniel , Castro Elena , George Saby , Song Daniel Y. , Dizdarevic Sabina , Baldari Sergio , Essler Markus , de Jong Igle Jan , Lastoria Secondo , Hammerer Peter G. , Meltzer Jeffrey , Sandstrom Per , Verholen Frank , Tombal Bertrand F. , O'Sullivan Joe M. , Sartor A. Oliver
Published: June 2022

5041

Background: Ra-223 extends OS in pts with mCRPC. Predictive markers of response to Ra-223 are needed to help select pts who would benefit most from Ra-223 therapy. The ALSYMPCA study suggested a correlation between ALP decline and longer OS. Here, we evaluated whether ALP decline is associated with OS in the global real-world REASSURE study. Methods: Pts treated with Ra-223 were grouped by baseline ALP ≤147 U/L vs >147 U/L and any ALP decline vs no decline at week 12 from the first Ra-223 dose. The 147 U/L cut-off was selected based on the highest upper limit of normal for ALP from literature. Pts with a trend of decreasing ALP at closest value to week 12 between weeks 8 and 16 were included in the any decline group. Association of ALP decline with OS was assessed in the ≤147 U/L and >147 U/L groups separately. Median OS is provided with an unadjusted hazard ratio (HR) (95% confidence interval [CI]). Multivariate Cox models provided adjusted HRs (95% CI) for the association of ALP decline with OS. Some baseline covariates were not included in the models due to missing data. Results: 785 of 1465 pts had baseline ALP measurements, of whom 779 had week 12 ALP measurements: 443 had ≤147 U/L and 336 >147 U/L. In the ≤147 U/L group, median OS was 23.0 months (m) (95% CI 20.9–25.7) in pts with ALP decline (n=329) and 16.4 m (95% CI 14.1–20.4) in pts with no decline (n=114). In the >147 U/L group, median OS was 12.9 m (95% CI 11.7–14.3) in pts with ALP decline (n=295) and 8.1 m (95% CI 5.6–10.3) in pts with no decline (n=41). Comparison of unadjusted and adjusted HRs is shown in the Table. Conclusions: Pts with an ALP decline in first 12 weeks of Ra-223 treatment had longer OS. The effect of other baseline variables, including age, PSA, Hgb and prior treatments, provided adjustment but did not change this outcome. [Table: see text]
Outcome of patients with PSMA PET/CT screen failure by VISION criteria and treated with 177Lu-PSMA therapy: A multicenter retrospective analysis.
Authors: Hotta Masatoshi , Czernin Johannes , Gafita Andrei , Calais Jeremie
Published: June 2022

5042

Background: The VISION trial showed that 177Lu-PSMA prolongs survival and improves the quality of life of patients with advanced mCRPC. It used PSMA-PET/CT to select patients for inclusion. The screen failure rate was “only” 12.6% (126/1003) and some have argued that the trial could have been positive even in an unselected population. It remains unknown whether the VISION-PET criteria were appropriate to stratify patients into likely responders versus non-responders to177Lu-PSMA. Here, we evaluated the outcome of patients who would have been excluded by the VISION-PET criteria and were nevertheless treated with 177Lu-PSMA. Methods: Patients treated with ≥1 cycle of 177Lu-PSMA between 11/2017 and 07/2021 (n = 74) who were registered in our institutional database and those enrolled in a multicenter dataset published previously (n = 230) (Gafita A, Lancet Oncol 2021) were retrospectively studied. One dual certified nuclear medicine and radiology reader reviewed baseline PSMA PET/CT studies and classified the patients as eligible (VISION-PET-E) or screen failure (VISION-PET-SF) based on the VISION-PET criteria: 1) absence of metastatic lesion(s) with uptake > liver background (i.e., low PSMA expression) or 2) presence of ≥ 1 metastatic lesion measurable by CT (≥ 1 cm for bone lesions with soft-tissue component (M1b) and solid/visceral organs lesions (M1c); ≥ 2.5 cm for lymph nodes lesions (N1-M1a)) with uptake ≤ liver background (i.e., PSMA-negative lesions). Outcome measures were PSA response rates (decline of ≥50% (PSA50RR), any decline (anyPSARR)), PSA-progression free-survival (PSA-PFS), and overall survival (OS). Results: 3/304 patients (1%) were excluded (lost to follow-up (n = 2), missing CT data (n = 1)). The median follow-up time was 22.5 (range: 2.1-62.3) months. 272/301 (90.4%) were VISION-PET-E, while 29/301 (9.6%) were VISION-PET-SF: 8/301 (2.7%) and 21/301 (7.0%) patients with low PSMA expression and PSMA-negative lesions, respectively. The VISION-PET-SF patients had worse PSA50RR (21% vs 50%; p = 0.005), anyPSARR (41% vs 71%; p = 0.003), median PSA PFS (2.1 months (95%CI: 1.1-3.3) vs. 4.1 (4.0-5.8); p = 0.023)), and tended to have a shorter OS (9.6 months (95%CI: 4.7-14.0) vs. 14.2 (12.6-15.9); p = 0.16) than the VISION-PET-E patients. Conclusions: VISION-PET-SF patients had worse outcomes than the VISION-PET-E patients. Our cohort only included patients who were eligible by each local site criteria. It did not include those 10-15% of patients who were excluded by local site assessment. Thus, 20-25% of the patients may be screen failures in unselected populations. Refinements in patient selection for 177Lu-PSMA are needed to optimize outcomes. Not characterizing target expression prior to PSMA-targeted treatment appears now non-ethical as a predictive whole-body imaging biomarker for response to PSMA-targeted therapies is available.