bluuebunny/crossref_metadata_2025 huggingface dataset:
A single-arm, phase II trial assessing the combination of AK105 and anlotinib in first-line treatment for persistent, recurrent, or metastatic cervical cancer.
Authors: Guo Ruixia , Qiu Haifeng , Wang Qian , Su Ke , Chang Lei , Cai Mingbo , Mao Meng , Bian Aiping
Published: June 2024

5530

Background: Anlotinib, a small molecule antiangiogenic drug, which can inhibit multiple tyrosine kinase receptor activity, had been proven effective and well-tolerant in patients with recurrent or metastatic cervical cancer who had received two or more lines of prior treatments. AK105 is a novel human immunoglobulin G1 (IgG1) anti-programmed cell death-1 (PD-1) antibody. This single-arm, phase Ⅱ clinical trial aimed to assess the efficacy and safety of AK105 plus anlotinib as fist-line therapy for persistent, recurrent, or metastatic cervical cancer. Methods: Patients with pathologically diagnosed persistent, recurrent, or metastatic cervical cancer were eligible for this study. They should have previously received platinum-based systemic chemotherapy and currently not suitable for local treatment like radiotherapy or surgery, with ECOG PS 0-1. Prior use of immune checkpoint inhibitors or antiangiogenic agents was excluded. The designed doses were: AK105, 200mg, IV, Q3W; anlotinib, 12mg, PO, QD, 2 weeks on/1 week off, Q3W. The treatment will last as long as two years, while should be halted by disease progression, or unacceptable toxicities. The primary endpoint was the objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression free survival (PFS), duration of response (DoR), overall survival (OS) and safety. Results: From Apr 2022 to Dec 2023, 15 patients were recruited with a median age of 50 years (range: 31-74). 9 patients were PD-L1 expression positive (CPS≥1), 1 negative and 5 NA. 73.3% patients were confirmed as squamous cell carcinoma. At the data cutoff date (Dec 29, 2023), 10 patients had received at least once tumor efficacy evaluation. 6 (6/10, 60.0%) patients achieved PR, 2 (2/10, 20.0%) patients achieved SD, and 2(2/10, 20.0%) patient PD. The ORR was 60.0% (95% IC, 26.2%-87.8%) and DCR was 80.0% (95% IC, 44.4%-97.5%). Incidence of any grades TRAEs was 86.7%. Grade 3 TRAEs incidence was 33.3% including hypertension (1/15, 6.7%), thrombocytopenia (1/15, 6.7%), elevated alanine aminotransferase (1/15, 6.7%), adrenal insufficiency (1/15, 6.7%), and rash (1/15, 6.7%), pulmonary infection (1/15, 6.7%). No Grade 4 or death occurred. Conclusions: This chemo-free therapy of AK105 plus anlotinib in the first-line treatment with persistent, recurrent, or metastatic cervical cancer showed promising efficacy with favorable toxicity profile. More data will be reported in the future. Clinical trial information: NCT05137171 .
Prognostic analysis of nimotuzumab combined with concurrent chemoradiotherapy in locally advanced cervical cancer: A multicenter real-world study.
Authors: Li Jiwei , Wu Tao , Cai Manbo , Xie Changjun , Ding Sijuan , Zou Wen , Wang Jingjing
Published: June 2024

5532

Background: Nimotuzumab is a monoclonal antibody against EGFR, which can improve the radiotherapy efficacy of nasopharyngeal carcinoma with EGFR positive. Most cervical cancers are induced by virus and express EGFR. Therefore, this study explores the efficacy and safety of Nimotuzumab combined with concurrent chemoradiotherapy (CCRT) in locally advanced cervical cancer (LACC). Methods: Information on patients with stage IIB-IVa cervical cancer who received CCRT combined with Nimotuzumab or CCRT alone at five cancer centers from January 2021 to December 2022 were collected. Nimotuzumab was administered 200mg once a week for a total of 6 weeks, starting on the same day as CCRT. The imaging examination was carried out 2 months after the end of radiotherapy. The reduction rate of lesions = (pre-treatment diameter - post-treatment diameter)/pre-treatment diameter. Patients were classified into the Nimotuzumab group and No-Nimotuzumab group. Categorical variables were compared using the χ2 test or Fisher’s exact test. Clinical outcomes were analyzed using the Kaplan–Meier method with log-rank test. Results: There are 224 patients enrolled, median age 57 years (32–90 years). The median follow-up time was 20 months (12–36months). The 2-year overall survival (OS) and progression-free survival (PFS) rates were 93% and 89.5%, respectively. The objective response rate (ORR) was 91.96%. There were 64 patients in Nimotuzumab group and 160 patients in No-Nimotuzumab group. The number of patients in Nimotuzumab group with stage IIIC and IVa, as well as those without chemotherapy, is higher than that in No-Nimotuzumab group. There was no significant difference between the Nimotuzumab and No-Nimotuzumab groups in terms of 2-year OS rate (93.2% vs.93%, p = 0.895), and PFS rate (96.2% vs.90.4%, p = 0.645). However, The Nimotuzumab group has a better CR rate (53.13% vs. 35%, P=0.012), ORR (98.44% vs. 89.38%, p=0.024), and reduction rate of cervical lesions (79.26% vs.70.94%, p=0.046) compared to the No-Nimotuzumab group (Table). Also, there was no significant difference between the Nimotuzumab and No-Nimotuzumab groups in terms of hematological toxicity (89.83% vs. 94.48%, p=0.730), nausea and vomiting (35.59% vs. 38.19, p=0.865), radiation proctitis (45% vs. 33.1%, p=0.371), radiation cystitis (8.47% vs. 7.64%, p=0.761), and grade 3-4 toxicities. Conclusions: The combination of Nimotuzumab and CCRT for LACC has a better reduction rate of lesions and ORR, without increasing side effects. [Table: see text]
Clinico-molecular predictors of exceptional response to immune checkpoint inhibitors (ICI) in metastatic cervical cancer (mCC).
Authors: Barraud Solenn , Roussel-Simonin Cyril , Leary Alexandra
Published: June 2024

5539

Background: Metastatic cervical cancer (mCC) constitutes a global health challenge, despite preventive efforts like HPV vaccination, with imputable 342,000 deaths in 2020. Immunotherapies with Immune checkpoint inhibitors (ICI) have been assessed in the context of recurrent or mCC. Only 15% of patients with PDL1+ mCC respond to ICI, however responses can be prolonged. We aimed to describe outcomes for long-term responders (LTR) versus non long-term responders (NLTR) to ICI, and identify clinico-molecular predictors for LTR. Methods: We conducted a retrospective review of all patients with mCC treated with an ICI at Institut Gustave Roussy (IGR). Patients were classified as LTR if they had a complete response (CR) / partial response (PR) / stable disease (SD) maintained for ≥12 months (mo) and as NLTR if progressed <12mo after ICI initiation. Cox regression analysis was performed to identify factors significantly associated with LTR (vs NLTR) and expressed as an odds ratio (OR). For a subset (43/106 patients), genomic analyses were performed using large panel next generation sequencing done at IGR within specific trials: STARTRK (NCT02097810) and STING (NCT04932525) on a tumor sample. Results: Between 01/2015 and 09/2023, 106 patients with mCC were treated with an ICI at the IGR. 20 patients (19%) were classified as LTR and 86 as NLTR (81%). 93% of patients received ICI without chemotherapy (2 LTR and 6 NLTR). After a median follow-up of 42mo, median PFS was not-reached in LTR versus 3.5mo for NLTR. Among the 20 LTR, 11 pts were in sustained complete response with a median of 22mo (range 2-55mo) since ICI discontinuation. Neither body mass index, performance status, LDH, neutrophil/lymphocyte ratio nor number of prior lines were predictive of LTR vs NLTR. A multivariate regression analysis identified 3 clinical factors significantly associated with LTR: oligo-metastatic (OR=11.4; p 0.006), lymph node metastases only (OR=8.2; p 0.02) and progression outside of irradiated fields (OR=5.9; p 0.03). With regards to molecular features, neither TMB nor MMR status were predictive, however PIK3CA mutations were significantly more frequent in LTR, found in 90% (vs 27% of NLTR) and PBMR1 mutations found exclusively in LTR, while NLTR presented with higher rates of STK11 alterations. Conclusions: Although responses to ICI in mCC remain rare (<20% patients), they are associated with impressive outcomes (median PFS>3.5 years) with a significant proportion disease-free months to years after ICI discontinuation suggesting some may be cured. Certain clinico-molecular features are strongly associated with LTR and may allow the selection of patients for ICI.
Safety and tolerability of durvalumab + carboplatin/paclitaxel followed by durvalumab ± olaparib in patients with newly diagnosed advanced or recurrent endometrial cancer (EC) in the DUO-E/GOG-3041/ENGOT-EN10 trial.
Authors: Thomes Pepin Jessica , Chon Hye Sook , Sundborg Michael J. , Gold Michael A. , Kim Byoung-Gie , Blank Stephanie V. , Liu Ji-Hong , McCollum Michael , Mori Masahiko , Moore Kathleen N. , Rivera Diaz Julian , de Padua Charles Andreé Joseph , Martínez-García Jerónimo , Papadimitriou Christos , Gri an Karin , Póka Róbert , Kowgier Matthew , Oscroft Emma , Van Nieuwenhuysen Els , Westin Shannon Neville
Published: June 2024

5599

Background: DUO-E (NCT04269200) showed statistically significant and clinically meaningful progression-free survival improvement with addition of durvalumab (D) to carboplatin/paclitaxel (CP) followed by D ± olaparib (O) vs CP alone for patients (pts) with EC (Westin SN et al. J Clin Oncol 2024;42:283–99). We describe safety and tolerability, focusing on the most common adverse events (AEs). Methods: Pts with newly diagnosed FIGO Stage III/IV or recurrent EC and naïve to systemic treatment were randomized 1:1:1 to CP (CP + D placebo [pbo; 6 cycles] followed by D pbo + O pbo), CP+D (CP + D [1120 mg IV q3w; 6 cycles] followed by D [1500 mg IV q4w] + O pbo), or CP+D+O (CP + D [6 cycles] followed by D + O [300 mg tablets bid]). Safety was assessed through AEs. Results: 709 pts (19.3% mismatch repair deficient [dMMR], 80.7% MMR proficient [pMMR]) received treatment (CP: n=236; CP+D: n=235; CP+D+O: n=238). Total median treatment duration with D/pbo was 9.0, 9.9 and 13.1 months in the CP, CP+D and CP+D+O arms and 5.7, 7.6 and 9.2 months withO/pbo, respectively. 18.6%, 20.9% and 24.4% of pts in the CP, CP+D and CP+D+O arm, respectively, had AEs leading to treatment discontinuations, 50.0%, 54.5% and 68.9% had AEs leading to dose interruptions, and 56.4%, 54.9% and 67.2% had grade ≥3 AEs. There was no increase in immune-mediated AEs or AEs of special interest for O with CP+D+O. There were 3 cases of pure red-cell aplasia with CP+D+O (all grade 3) and 3 of autoimmune hemolytic anemia (1 with CP+D, 2 with CP+D+O; all grade 3). The most common AEs were mostly low grade, with grade 3/4 in few pts (anemia [14%, 16%, 24% in the CP, CP+D, CP+D+O arms, respectively], alopecia [0%, 0%, 0%], nausea [1%, <1%, 3%], fatigue [2%, 2%, 2%]), and led to few treatment discontinuations and interruptions (Table). AE profiles were generally consistent across MMR subgroups. Conclusions: In DUO-E, safety findings were generally consistent with the known safety profiles of CP, D and O. The addition of D to CP followed by D or by D + O resulted in expected and manageable safety profiles compared with CP alone, with the most common AEs being low grade and leading to few discontinuations or dose modifications/interruptions of D/pbo or O/pbo. Clinical trial information: NCT04269200 . [Table: see text]
Real-world treatment patterns and outcomes by mismatch repair/microsatellite instability (MMR/MSI) status in patients (pts) with advanced endometrial cancer (aEC), 2018-2023.
Authors: Pothuri Bhavana , Thaker Premal H. , Tymejczyk Olga , Reiss Samantha , Nitti Giovanni , Cain Theresa , Hada Manila
Published: June 2024

5601

Background: Over the past decade, progress has been made in treating aEC, with newer therapies introduced in the first-line (1L) and second-line (2L) setting. Molecular profiling of MMR/MSI has emerged as a valuable tool for guiding treatment decisions, but real-world evidence on the shifting treatment paradigm is limited. Thus, this study aims to assess molecular profiling uptake, treatment patterns, and outcomes among aEC pts. Methods: This retrospective study included pts from the nationwide Flatiron Health electronic health record-derived deidentified database who were diagnosed with aEC (stage III/IV or recurrent) and initiated 1L therapy between 1/1/2018 and 6/30/2023. Patient characteristics, treatment patterns, and real-world time to next treatment (rwTTNT) were examined across MMR/MSI status: deficient (dMMR), proficient (pMMR), and never tested (NT). Kaplan-Meier methods were used to generate unadjusted time to event estimates. Results: A total of 1,441 pts met study criteria. Median age at aEC diagnosis was 68 years (range: 26-85), 1,056 (73%) were treated in the community setting, and 1,199 (83%) received MMR/MSI testing. Endometrioid carcinoma occurred in 619 (43%) overall and was the predominant histology (231/293; 79%) in dMMR. Approximately 15% had record of another cancer diagnosis at any point. NT pts were more likely than those tested to be Black or African American (26% vs 18%) and diagnosed with stage IV disease (55% vs 48%). The table presents select therapies and rwTTNT estimates. pMMR pts often received platinum-based chemotherapy (PBCtx) in 1L (67%) and immune checkpoint inhibitor (CPI) + vascular endothelial growth factor (VEGF) inhibitor therapies in 2L (23%), while dMMR pts were more likely than others to receive other CPI regimens (mono, combo + chemo) in 1L (23%) and 2L (44%). Median rwTTNT was similar across subgroups in 1L but was markedly longer among dMMR pts (10.8 vs 5-6 months) in 2L. Conclusions: While MMR/MSI testing was common, use of 2L immunotherapy for dMMR (51%) and CPI + VEGF for pMMR (23%) was lower than expected and may reflect slow uptake of recently approved, molecular profile-specific therapies. MMR/MSI testing gaps remain, especially in underrepresented pts, and may be a barrier to adoption of new therapies. Future analyses will be critical to assess changes in outcomes over a longer timeframe. Continued education is needed to increase access to newer FDA approved treatments. [Table: see text]
Prognostic value of PORTEC-3 molecular markers by disease risk in a real-world early endometrial cancer cohort.
Authors: Dow Jessica , Kolli Sahiti , Karalius Brad , Shami Jessica , Khosla Sajan , Roy David , Mayer Ingrid A. , Dempster Sara
Published: June 2024

5604

Background: Molecular classification of endometrial cancer (EC) proposed by The Cancer Genome Atlas in 2013 has improved prognostic assessment of patients. PORTEC-3 assessed these molecular markers in early-stage high risk patients. We examine the prognostic value of these markers in a real-world data (RWD) cohort of early-stage high risk patients and extend the analysis to intermediate and low risk patients to inform treatment decisions across disease risk levels. Methods: We performed a retrospective study (2016-2022) of EC patients from the Tempus de-identified, multimodal RW database. Stage I-III patients who received total hysterectomy with bilateral salpingo-oophorectomy and next generation sequencing (NGS) Tempus xT assays were stratified into high, intermediate, and low risk disease levels based on tumor characterization and categorized into POLE mutated (POLEm), mismatch repair-deficient (dMMR), p53-abnormal (p53abn), or no specific molecular profile (NSMP) PORTEC-3 subtypes. Recurrence-free survival (RFS), defined as time from surgery to earliest disease recurrence, progression, metastasis or death, was assessed using Kaplan-Meier methods for the combination of risk level and molecular subtype. We compared RFS trends across molecular subtypes at 5-years in PORTEC-3 and 18-months in RWD due to limited follow-up. Results: Of the 740 eligible RWD patients, 546 (74%), 110 (15%) and 84 (11%) were high, intermediate, and low risk and 286 (39%), 250 (34%), 180 (24%) and 24 (3%) were P53abn, NSMP, dMMR and POLEm, respectively. Similar to RFS trends at 5 years in PORTEC-3, the p53abn subtype consistently had the lowest 18-month RFS, although the degree of separation from other subtypes varied across risk levels. NSMP and dMMR subtypes had 18-month RFS within 4% of each other for high and low risk levels, consistent with PORTEC-3. The POLEm subtype had 100% 18-month RFS across risk levels, but low prevalence. Conclusions: Marker prognostic ranking was consistent between the PORTEC-3 high risk cohort and all risk levels in RWD despite absolute RFS differences likely due to differences in baseline characteristics and outcome assessments. The consistent poor prognosis of p53abn patients, good prognosis of POLEm albeit with limited power, and moderate prognosis of NSMP and dMMR patients in RWD support use of these markers to inform treatment decisions across disease risk levels in an early EC setting. [Table: see text]
HER2 expression in a molecularly characterized cohort of patients with endometrial cancer (EC): SPECTRUM study.
Authors: Cortés Salgado Alfonso , Moreno Esther , Palacios José , Guerra Eva , del Campo-Albendea Laura , Carretero-Barrio Irene , Rosas Marta , Saavedra Serrano Cristina , Gion Maria , Caniego-Casas Tamara , Fernández-Abad María , Lopez Miranda Elena , Martinez-Jañez Noelia , Vida Navas Elena , Pérez Míes Belén
Published: June 2024

5610

Background: Human epidermal growth factor receptor 2 (HER2)-low is a new category defined by HER2 1+ or 2+ by immunohistochemistry (IHC) and lack of HER2 amplification by in situ hybridization (ISH). Trastuzumab deruxtecan demonstrated antitumor activity in HER2-expressing gynecologic tumors. Little is known about HER2-low frequency in EC subtypes, the heterogeneity of the expression, the best scoring criteria or the prognostic value. Methods: This is a single center, retrospective study including patients diagnosed with EC amenable to curative treatment from 2003 to 2019. Two tissue cores of each sample were selected for the creation of 5 tissue microarrays (TMA). Molecular subrogated (MS) classification (WHO 5ed) was performed: polymerase epsilonmutated (POLEmut), mismatch repair deficient (dMMR), TP53 abnormal (p53abn) or non-specific molecular profile (NSMP). HER2 was assessed by IHC (4B5) and ISH on TMAs. HER2 scoring was done according to ASCO/CAP guidelines for breast and the proposed endometrial criteria. HER2 heterogeneity was defined as a difference in HER2 IHC ≥2+ or discrepancy in HER2 ISH between cores. Primary objective was to describe the frequency of HER2-low in MS. Secondary objectives included to assess heterogeneity, concordance between breast and endometrial criteria and the impact of HER2-low on recurrence-free (RFS) and overall survival (OS). Results: 193 patients were analyzed. Median age was 66.4 years (31-90). According to FIGO 2009 classification, stage I, II and III-IV corresponded to 71.5%, 14% and 14.5% of patients. Most cases (57.5%) were low-grade endometrioid followed by 14% serous, 11.9% high-grade endometrioid, 5.2% clear cell, 2.6% carcinosarcoma and 8.7% other histology. Regarding MS, 3.1% were POLEmut, 25.4% dMMR, 28% p53abn, 40.9% NSMP and 2.6% unclassifiable. Considering the entire cohort, 69.9% were HER2-negative (0+), 25.8% HER2-low and 4.3% HER2-positive (3+ or ISH+). The frequency of HER2-low was highest for POLEmut (66.7%) followed by p53abn (42.6%) (Table). Low heterogeneity in HER2 expression was demonstrated, with an agreement between cores in 84.5% of cases. Breast and endometrial criteria showed concordance in 85.5% of patients, with a kappa of 0,624 (p<0,05). HER2-low nor HER2-positive versus HER2-negative had an impact on RFS or OS. Conclusions: This is the first study showing the spectrum of HER2 expression in a MS cohort of EC. HER2-low is more frequent in POLEmut and p53abn subtypes. HER2-low had no prognostic significance. [Table: see text]
Analysis of healthcare provider treatment of advanced endometrial cancer and concordance with expert recommendations in 2023 vs 2022.
Authors: Rosenthal Kristen M. , Cartwright Megan , Constanzo Jerfiz D. , Chon Hye Sook , Duska Linda R. , Hoskins Ebony R. , Salani Ritu
Published: June 2024

5613

Background: Practice patterns are rapidly evolving for first-line (1L) treatment (tx) of advanced endometrial cancer (aEC). In 2022, we created an online interactive decision support tool [clinicaloptions.com/Endometrialtool] for healthcare professionals (HCPs) with case-specific recommendations from 5 gynecologic oncology experts for treating 1L and second-line (2L) aEC. In 2023, NCCN guidelines included a recommendation of carboplatin/paclitaxel plus an immune checkpoint inhibitor (ICI) for 1L tx of aEC. Working with the experts, we updated the tool to its current 2023 version. Here, we compare planned tx reported by HCPs using the 2023 tool vs expert recommendations and compare practice patterns for the 2023 vs 2022 tools. Methods: To use the 2023 tool, HCPs entered key characteristics, including the tx setting; tumor histology (1L only); actionable biomarker status (dMMR/MSI-H, HER2, ER/PgR); prior tx, response, and response duration (2L only); and planned tx. After HCPs reported their planned tx, the tool showed expert recommendations for that scenario and asked if the recommendations changed the planned tx. Results: From September 2023 to January 2024, 123 HCPs entered 181 cases into the tool, of which 45% were in the 1L setting. HCPs reported a biomarker status of "unknown” in 30% of 1L cases. In 2022, all experts recommended platinum-based chemotherapy (plt CT) ± bevacizumab for 1L HER2-negative cases, whereas all experts in 2023 recommended plt CT + ICI for 1L cases with dMMR/MSI-H (Table). There was less consensus on adding ICI to plt CT when 1L cases had no actionable biomarker. In 2023, the tx planned by HCPs matched ≥1 expert in 29/54 (54%) of 1L cases—a modest improvement from 2022, when matches occurred in 19/42 (45%) of 1L cases. In 2023, match rates were highest for dMMR/MSI-H cases (50%-86%), followed by cases without actionable biomarker (36%-50%) or HER2+ (33%-67%). Overall, 88% of HCPs indicated that the tool recommendations either changed or confirmed their tx plan. Conclusions: HCPs are challenged to optimally manage 1L aEC in concordance with expert recommendations and/or NCCN guidelines. Detailed analyses of HCP tx vs expert recommendations in the 1L and 2L settings and 2023 vs 2022 practice patterns will be presented. [Table: see text]
Understanding patient and provider preferences in management of metastatic renal cell carcinoma (mRCC).
Authors: Yazdanpanah Omid , Benjamin David Joseph , Vosoughi Elham , Raad Ali , Popal Medina , Kongtim Piyanuch , Mar Nataliya , Rezazadeh Arash
Published: June 2024

e16530

Background: First-line clear cell mRCC management has evolved to include doublet therapies containing either a tyrosine kinase inhibitor (TKI) with an immuno-oncology (IO) agent or two IO agents. Oncologists typically prescribe therapies based on guideline recommendations or their personal experience with various therapies. However, patient preferences may not be a major factor in this decision-making process. Previously published data on this topic is scarce. This study aimed to assess patient preferences in the treatment of mRCC and compare it with providers' perspectives. Methods: A single-arm, prospective study surveyed mRCC patients with a questionnaire containing descriptions of 5 possible treatment options in simple language: 1) single-agent TKI; 2) IO/IO; 3) IO/TKI; 4) phase 3 clinical trial (CT); and 5) phase 1/2 CT. Patients rated their preference for each option on a 1 (least preferred) to 10 (most preferred) scale. The same questionnaire plus de-identified patient characteristics were provided to 2 academic and 1 community oncologists. Ordinal logistic regression was used to analyze the impact of patient characteristics on each treatment ranking. Pearson’s correlation was used to calculate correlation coefficients of patients' and providers' responses. Results: A total of 48 patients were surveyed with an average age of 62. Patients' responses most frequently fell in the 7-10 category for all treatment options. Among patients, the most preferred treatment option was single-agent TKI (average score of 7.9), while the least popular one was IO/IO and early phase CTs (average score of 6.0 for both) ( p<0.01). Patient variables, including sex, race, language, insurance, employment and marital status, household income, and de novo versus recurrent mRCC, were not significantly associated with a greater likelihood of picking a particular treatment option. Among oncologists, the most preferred treatment option was early and late phase CTs (average score of 7.9 and 7.4, respectively), while single-agent TKI was the least preferred choice (average score of 5.7) ( p<0.01). Age and prior treatment history were independently correlated with oncologist therapy choices. Conclusions: This study highlights the differences between patient and oncologist mRCC treatment preferences. Patients appear to prefer single-agent TKIs, while clinical trial participation is the least favored. Socioeconomic factors had no impact on patient preferences, highlighting individuality. In contrast, oncologists prefer CTs and are influenced by patients’ age and prior therapies. Ultimately, this study underscores the importance of an individualized discussion with each patient, devoid of any assumptions, to evaluate their therapeutic objectives and make shared decisions. Patient education on clinical trials is also paramount.
Association of race with clinical outcomes in patients with advanced renal cell carcinoma (aRCC) treated with immune checkpoint inhibitors (ICIs).
Authors: Choi Yujin , Yildirim Ahmet , Wei Mengting , Liu Yuan , Goswamy Rohit Vivek , Brown Jacqueline T. , Nazha Bassel , Martini Dylan J. , Hartman Caitlin , McClintock Greta Russler , Zhuang Tony , Kissick Haydn , Harris Wayne B. , Carthon Bradley Curtis , Kucuk Omer , Master Viraj A. , Bilen Mehmet Asim
Published: June 2024

e16539

Background: Race has been regarded to be associated with clinical outcome of aRCC patients undergoing therapy with ICIs, but larger data is still limited. Here, we evaluated race and clinical outcome in aRCC patients treated with ICI. Methods: A retrospective analysis was conducted on adult patients with aRCC treated with ICIs at Emory Winship Cancer Institute between 1/1/2018 and 8/31/23. Overall survival (OS) and progression-free survival (PFS) was calculated from the date of treatment initiation to death and progression, respectively. Progression was determined by RECIST v1.1 or clinical progression. Clinical benefit (CB), including stable disease, partial response, and complete response, was determined by RECIST v.1.1. Univariate (UVA) and multivariate (MVA) analyses were conducted for CB, OS, and PFS in patients to assess the association with race. Results: There was a total of 401 patients, consisted of 71.1% White patients, 21.2% African American patients, and 7.7% patients with other racial profiles. Median age was 66 (range = 18-95). Treatment plan involved 139 (34.6%) patients for single ICI therapy, 131 (32.6%) patients for ICI/ICI therapy, 108 (26.9%) patients for ICI/TKI (tyrosine kinase inhibitor) therapy, 6 (1.5%) patients for ICI/ICI/TKI therapy, and 17 (4.23%) patients for therapy with ICI plus an experimental drug. Race was significantly associated with the CB, OS, and PFS of the patients in the UVA. African American patients demonstrated worse clinical outcomes with hazard ratios (HR) significantly less than 1 for both OS and PFS and odds ratios (OR) significantly greater than 1 for CB. According to the Kaplan-Meier plots, the median OS for African American and White patients were 17.1 and 34.8 months, respectively. Similarly, median PFS for African American, White, and patients of other races were 3.6, 7.7, and 13.9, respectively. MVA also suggested greater clinical benefit for patients of White and other racial backgrounds when compared to African American patients. Conclusions: The significant difference in clinical outcomes between the racial profile of patients suggest that African American patients may have worse clinical outcomes in treatment involving ICIs. A more in-depth analysis of race’s association with clinical outcomes can be conducted to assist with treatment plan decisions in the future. [Table: see text]
Dietary interventions selectively target dysregulated metabolism and reveal metabolic vulnerabilities in preclinical models of advanced renal cell carcinoma.
Authors: Orsi Sabrina , Chang Musea , Delle Fontane Ilaria , Jawadwala Abbas , Colligan Sean , De Nigris Filomena , Pili Roberto
Published: June 2024

e16545

Background: Long-term toxicities and acquired resistance to targeted therapies represent a critical clinical challenge for the treatment of advanced clear cell and non-clear cell renal cell carcinoma (RCC), thus highlighting the need for novel therapeutic strategies. Large-scale metabolomic data have associated metabolic alterations with the pathogenesis and progression of RCC. As diet has been reported to alter the availability of circulating metabolites available to tumors, dietary interventions represent an innovative strategy to selectively target metabolically dysregulated tumors. Unfortunately, tumor cell plasticity, intratumor heterogeneity, and a lack of understanding regarding metabolic vulnerabilities in tumors are a critical roadblock in the use of dietary restrictions in patients. Therefore, the overall goals of the present study were to better understand nutrient utilization and metabolic dysfunction in RCC to provide biologic rationale for incorporating dietary interventions with standard cancer care. Methods: Using Seahorse, immunohistochemistry, immunofluorescence, metabolomics, and transcriptomics in patient-derived cell lines and murine xenograft models, we investigated the impact protein restriction and alternate day fasting have on energy dynamics in preclinical models of clear cell and translocation RCC. Results: Interestingly, regardless of inherent metabolic phenotype, alternate day fasting was more effective than protein restriction at reducing tumor growth in vivo. Integrated multi-omics analyses of these tumors revealed increased bile acid metabolism with alternate day fasting, indicating a potential tumor suppressive role for these metabolites. Surprisingly, alternate day fasting induced a strong reduction of circulating amino acids that was not observed with protein restriction. Similarly, protein restriction significantly reduced serum triglyceride levels which were not observed in the alternate day fasting group to the same extent. Furthermore, analysis of non-tumor bearing animals revealed distinct metabolite signatures for each dietary restriction that can be easily detected in the blood as a marker of the metabolic state of the host during treatment. Ongoing combination studies with either protein or calorie restriction and targeted therapies, such as standard of care receptor tyrosine-kinase inhibitors, suggest the benefit of using dietary interventions as an adjunct therapy in RCC. Conclusions: Overall, these studies reveal that selective dietary interventions alter the metabolic landscape of RCC and expose vulnerabilities that can be exploited further with targeted therapy.
Efficacy of erdafitinib in FGFR2/3-altered metastatic urothelial cancer including patients with CDK2NA/B or MTAP loss: Analysis of UNITE study.
Authors: Jiang Cindy Y. , Jindal Tanya , Epstein Ilana B. , Nguyen Charles B , Nizam Amanda , Bakaloudi Dimitra Rafailia , Taylor Amy K , Milowsky Matthew I. , Shah Sumit , Hoimes Christopher J. , Bilen Mehmet Asim , Zakharia Yousef , Emamekhoo Hamid , Grivas Petros , Gupta Shilpa , Bellmunt Joaquim , Alva Ajjai Shivaram , Koshkin Vadim S , Alhalabi Omar , Campbell Matthew T
Published: June 2024

e16571

Background: Erdafitinib (erda) is a fibroblast growth factor receptor (FGFR) inhibitor used in previously-treated FGFR2/3-altered locally advanced/metastatic urothelial cancer (LA/mUC). FGFR2/3 alterations (alts) are present in 15-20% of patients (pts) with LA/mUC. We aimed to investigate “real-world” outcomes of erda in LA/mUC. We hypothesized that efficacy of erda would be similar to clinical trial data. Methods: Pts with FGFR2/3 alts who received erda were included. Overall survival (OS) and progression-free survival (PFS) measured from erda start were assessed with KM method and group comparison by long rank test. Categorical variables and observed response rate (ORR) were compared using Fisher’s exact test with Baptista-Pike method for 95% confidence intervals. Cox regression model used to describe PFS and OS for subgroups. Results: Among 633 pts from 16 US sites, 487 (77%) had NGS data, 94 (19%) had FGFR2/3 alts and 39 (41%) received erda. In erda treated pts, median age was 70, most were male (79%), white (87%), had primary bladder tumor (68%), and pure urothelial pathology (74%). Most received prior anti-PD1/L1 (92%) with pembrolizumab as the most common (72%); 56% received prior platinum-based chemotherapy with 77% cisplatin-based. Median prior therapy lines was 2. ORR to erda was 32% (12/37; all partial responses); another 12 pts had stable disease as best response. Median PFS was 7.5 months (mos) and median OS 18 mos. CDK2NA/B or MTAP loss was seen in 15 pts (38%) and ORR in these pts was 35%. 33 pts had canonical FGFR2/3 alts (S249C, Y373C, R248C, and FGFR3-TACC3 fusion) and 6 pts had non-canonical alts (A248C, A391E, Y375C, V555L/T807L, and JAKMIP1-FGFR3 fusion) with no significant difference in PFS (HR 0.8; CI 0.29, 2.3; p = 0.66), OS (HR 0.4; CI 0.06, 2.3; p = 0.086) or ORR (OR 2.1; CI 0.27, 27.7; p = > 0.99). Subgroup PFS/OS analysis in Table. Conclusions: Erda showed efficacy similar to clinical trial data. In this retrospective study with notably underpowered analyses, non-canonical FGFR2/3 alts or CDK2NA/B or MTAP loss did not seem to effect outcomes. Larger prospective studies, including granular NGS data, are needed to further validate “real world” data and further explore predictive biomarkers for erda to inform optimal therapy sequencing. [Table: see text]
PD-1 inhibitor plus paclitaxel, pingyangmycin and platinum-based chemotherapy as bladder-sparing therapy for high-risk non-muscle-invasive bladder cancer/muscle-invasive bladder cancer: A retrospective study.
Authors: Li Jun , Wang Ziyong , Li Zheng , Li Ruiqian , Jiang Haiyang , Hu Chen , Bi Ying , Zhu Yong , Wu Wenzhao
Published: June 2024

e16601

Background: Radical cystectomy (RC) in combination with cisplatin-based neoadjuvant chemotherapy is the standard approach for muscle-invasive bladder carcinoma (MIBC), and also a treatment option for high-risk non-muscle-invasive bladder cancer (HR-NMIBC), but removal of the bladder has a significant impact on pts quality of life. Bladder-sparing treatment have emerged to be an alternative choice for patients who are concerning about the life quality after surgery. we aim to investigate the efficacy and safety of neoadjuvant PD-1 inhibitor plus paclitaxel, pingyangmycin and platinum-based chemotherapy as a bladder-sparing therapy for high-risk NMIBC/MIBC patients. Methods: This retrospective study enrolled HR-NMIBC/MIBC patients who received at least one cycle of PD-1 inhibitor plus paclitaxel、pingyangmycin (bleomycin A5 hydrochloride) and platinum-based chemotherapy ["4P" therapy] and underwent imaging evaluation from Feb 2022 to Nov 2023. The objective response rate (ORR), pathological complete response rate (pCR), bladder-intact event-free survival (BI-EFS), Recurrence free survival (RFS), overall survive (OS) and adverse events (AEs) were observed. Results: Twenty-three pts (4 pts HR-NMIBC,19 pts MIBC) were included, with median age of 70 and 87.5% male, of which 5 pts (21.7%) received 1 cycle and 18 pts (78.2%) received 2 cycles of treatment. In all pts, the ORR was 87.0% (20/23), with 34.8% (8/23) had a complete response, 52.2% (12/23) had a partial response, 13.0% (3/23) had a stable disease. In different PD-1 therapy group, toripalimab group has 100% (15/15) of ORR, 40.0% (6/15) had a complete response; tislelizumab group has 62.5% (5/8) of ORR, 25.0% (2/8) had a complete response. 18 of the 23 pts underwent TURBT and 5 pts declined TURBT. Among 18 evaluable pts, pCR was achieved in 7 pts (38.9%). The cut-off date of data collection was Feb 1 2024, median follow-up time was 6.5 months[range:2.1-23.3 months], 2 patients relapsed and underwent TURBT without RC. None of the 23 patients have underwent RC. Survival data are not yet mature, 1 patient died of pneumonia (unrelated to chemotherapy or PD-1 inhibitor). Any grade of adverse event occurred in 23 pts (100%), grade 3 or higher toxicity rate was 30.4% (7/23). 18 pts (78.3%) experienced immune-related AEs, and 1 patient (4.3%) had grade 3 immune-related AEs. No discontinuations due to immune-related AEs. Conclusions: These data support neoadjuvant PD-1 inhibitor plus paclitaxel, pingyangmycin and platinum-based chemotherapy as a potential bladder-sparing option for patients with HR-NMIBC/MIBC.
Bladder preservation in muscle invasive bladder cancer (MIBC): A population based analysis.
Authors: Ozgun Guliz , Eigl Bernhard J. , Parimi Sunil
Published: June 2024

e16608

Background: Although available data supports trimodal therapy (TMT) as a bladder sparing treatment for MIBC with outcomes comparable to cystectomy, uptake in Canada is low. A retrospective evaluation in British Columbia, Canada, was undertaken to evaluate real-world outcomes in MIBC patients (pts) undergoing bladder sparing radiotherapy (RT). Methods: MIBC pts were identified from the BC Cancer registry who received RT with curative intent between Jan 1, 2002, and Dec 31, 2020. Disease free survival (DFS), overall survival (OS), and disease specific survival (DSS) were calculated for those receiving RT versus combined modality treatments. Further analysis was undertaken to identify factors associated with outcomes. Results: The population was 231 pts, predominantly male (74%), median age 81 (range: 44-95). Almost all (97%) presented with high-grade MIBC, and 67.1% had an ECOG score of 0-1. The reasons for bladder preservation were frailty/comorbidities (77.1%), pt preference (16%) and inoperability (6.9%). 170 (73.6%) pts underwent RT alone; the remainder were treated with chemoRT (16.5%), neoadjuvant chemotherapy (nCT)+RT alone (5.6%), nCT+chemoRT (3%), chemoRT+adjuvantCT (0.9%), and RT+adjuvantCT (0.4%). The median OS in the RT-only group (25.2 months, 95% CI, 19.5-31) was significantly lower than for chemoRT (39.7 months, 95% CI, 13.5-65.9, p=0.013). Pts who underwent maximal transurethral resection of the bladder tumor (TURBT) in the chemoRT group exhibited significantly prolonged OS (56.5 vs. 31.9 months, p=0.006). Pts with maximal TURBT who had a second TURBT while waiting for RT demonstrated a significant improvement, compared to those with a second TURBT due to submaximal TURBT (59.3 vs. 13.3 months, p<.001). Despite these findings, DSS analysis did not show statistically significant differences between the treatment groups (p=0.38), even when stratified by maximal TURBT (p=0.207). Similarly, the median DFS did not represent a difference between the groups (26.6 vs. 22.2 months, p=0.772). Cox regression analysis revealed the absence of carcinoma in situ trended towards a decreased risk of death (HR: 0.52, p<0.001), as did the absence of hydronephrosis (HR: 0.65, p=0.009) and an increase in the total number of RT fractions (HR: 0.92, p=0.001). In the analysis of treatment modalities (RT vs. chemoRT), there was a significant difference in the distribution of recurrence sites (Chi-Square=4.15, p=0.04). Local recurrences were identified less frequently in the chemoRT group. Conclusions: This population-based study showed notable demographic and treatment-related characteristics that influenced OS, DSS, and DFS. While respecting the limitations of retrospective cohort studies, overall outcomes in this cohort are inferior to those predicted for TMT, but adherence to best practices such as maximal TURBT and combined modality chemoRT result in acceptable long term survival rates.
The tumor immune profile of bladder cancer (BC) with HER2 over-expression and the investigation into RC48-ADC versus BCG in high-risk non-muscle invasive BC with HER2 over-expression.
Authors: Liu Haoyang , Chen Junru , Liu Haolin , Zhu Qiyu , Bao Yige , Liao Banghua , Zeng Hao
Published: June 2024

e16614

Background: Patients diagnosed with high-risk non-muscle invasive bladder cancer (HR-NMIBC) face a challenging prognosis, with a 5-year disease progression rate reaching up to 40%. The current standard treatment for HR-NMIBC involves transurethral resection of bladder tumor (TURBT) followed by adjuvant intravesical Bacillus Calmette-Guérin (BCG) therapy. BCG therapy is reported to exert anti-tumor therapeutic effects by inducing both innate and adaptive immunity. Multiple studies have reported HER2 positivity in 20-44% of NMIBC cases, and HER2 overexpression is strongly associated with poor tumor immunity and an unfavorable cancer prognosis. Disitamab Vedotin (DV; RC48-ADC) is an antibody-drug conjugate (ADC) comprising a fully humanized HER2-directed monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a protease-cleavable mc-vc linker. This study aims to evaluate the therapeutic potential of RC48-ADC in HR-NMIBC patients and explore the association between HER2 expression and immune profile of Bladder Cancer (BC). Methods: A retrospective analysis was conducted on patients diagnosed with NMIBC exhibiting HER2 overexpression (immunohistochemistry ≥2+) who underwent adjuvant therapy with either RC48-ADC or BCG at West China Hospital of Sichuan University between 2019 and 2023. The primary study endpoint was recurrence-free survival (RFS). Utilizing molecular data on bladder cancer (BC) from The Cancer Genome Atlas (TCGA), we included 100 cases each of HER2-low and HER2-high, determined by HER2 expression levels before and after a 25% threshold, to assess differences in tumor immunity between the two cohorts. Results: The study included 27 patients diagnosed with HR-NMIBC displaying HER2 over-expression. After TURBT, 10 patients received adjuvant therapy with RC48-ADC, while 17 received adjuvant therapy with BCG. Kaplan-Meier analysis revealed that patients receiving RC48-ADC exhibited better RFS compared to those receiving BCG (p=0.027). Additionally, in the RC48-ADC-treated group, the twelve-month RFS rate was 100%, while in the BCG-treated group, it was 58.8%. According to TCGA molecular data, our results showed that HER2-low BC demonstrated higher expression levels of various immune-related cytokine, including CXCL5, CXCL8, CXCL9, CXCL11 and so on. ESTIMATE analysis revealed that HER2 expression was negatively correlated with the interstitial score, immune score, and ESTIMATE score. Moreover, ssGSEA revealed stronger immune infiltration in the HER2-low BC group, including NK cells, B cells, CD8 T cells, Th1 cells, Th2 cells, and others. Conclusions: HER2 over-expression significantly influences the tumor immunity of BC and the HER2-directed ADC RC48 has demonstrated promising efficacy as adjuvant therapy in patients with HR-NMIBC according to RFS.
Utilization of neoadjuvant chemotherapy (NAC) and pathologic outcomes in upper tract urothelial carcinoma (UTUC).
Authors: Xu Vincent Eric , Azari Sarah , Klein Matthew Nicholas , Drouaud Arthur , Chang Phat , Antar Ryan Michael , Gordon Olivia French , Smith Armine , Whalen Michael Joseph
Published: June 2024

e16620

Background: UTUC is a rare malignancy with a poorer prognosis compared to bladder urothelial carcinoma. Radical nephroureterectomy (RNU) remains the standard treatment for high-risk UTUC. Considering the decline in renal function with RNU and promising pathologic complete response rates from the phase II trial ECOG-ACRIN 8141, NAC has emerged as a favored perioperative treatment regimen for chemo-eligible patients with high-risk UTUC. However, RCTs exploring NAC's efficacy are absent, and large-scale studies examining NAC's role and predictors for its use are scarce. Methods: This study aimed to assess trends in NAC utilization, determinants for receiving NAC, and pathologic outcomes. The National Cancer Database was queried for patients with high-grade cM0 UTUC treated with RNU from 2004-2019. Outcomes included pathologic response (pR) and pathologic complete response (pCR), defined as ≤pT1pN0/X and pT0pN0/X, respectively. Multivariate regressions were adjusted for relevant patient and tumor characteristics. Results: Of 6,436 patients treated with RNU alone and 209 with RNU and NAC, older age, greater home distance from the treatment facility, and higher comorbidity scores decreased the likelihood of receiving NAC. In contrast, higher cT stage (OR 1.72, p=0.028) and cN+ status (OR 7.40, p<0.001) predicted NAC treatment. NAC was more commonly used in academic centers (OR 2.02, p<0.001). Use of NAC peaked in 2016 at 10%, but dropped to ~2% by 2019. There was minimal nodal response to NAC (23.4% cN+ vs 22.0% pN+). NAC was associated with 34.0% pR and 5.3% pCR rates, increasing the likelihood of pCR (OR 57.5, p<0.001). In cT2-4 UTUC, 19.3% and 7.1% of patients had pR and pCR with NAC, and NAC improved odds of pR (OR 1.78, p=0.024). Conclusions: Our study demonstrated variable NAC use for UTUC, illustrating the evolving landscape of perioperative systemic therapies. We report significant response rates even in cT2-4 UTUC. Our observed poor nodal response to NAC emphasizes the crucial role of retroperitoneal lymph node dissection in staging, regardless of NAC status. We note poor NAC utilization in non-academic settings and among patients living farther from care facilities, underscoring the need for improved care quality in the context of regionalization and multi-disciplinary approaches in UTUC management. [Table: see text]
Real world data of 177 Lutetium-PSMA-617 for metastatic castration resistant prostate cancer (mCRPC): Analysis of patients treated from 2 large reference centers.
Authors: Bruzzi Helena F. , Herchenhorn Daniel , Lopes Gabriela C. K. , Bekierman Hannah , Altino de Almeida Sergio , Mosci Camila , Magalhães Chisthiane , Palazzo Isabella , Fernandes Laura , Freire Vinicius , Andrade Juliana Tarouquella da Silva
Published: June 2024

e17050

Background: 177Lu-PSMA-617 was recently approved for the treatment of patients with mCRPC in the USA. While treatment is associated with improved survival, responses to therapy are lower in patients with visceral metastasis and with FDG avid disease. In this study, we aim to characterize response to the therapy trying to optimize patient selection for 177Lu-PSMA-617. Methods: Patients treated from 2020 to 2023 in 2 large oncology centers in Brazil were analyzed. Our primary endpoint was to investigate the PSA response rate. Secondary endpoints included overall survival (OS), time to next sequential therapies (TNST) and PSA response in patients with visceral disease. Patients were treated after being submitted to a double image consisting of PET-CT PSMA and a PET-CT FDG (as indicated by the TheraP trial, Hoffman et al.) confirming disease uptake without divergent disease. Results: A total of 32 patients with mCRPC were included in this analysis. The median age was 73 years. Median number of prior lines of therapy for mCRPC was 3 with 20 receiving more than one androgen receptor signaling inhibitor (ARSI) and 5 receiving more than one taxane. The percentage with a PSA response was 48,5% and visceral disease was present in 56,3% of patients. Response rate for pts with visceral disease versus non-visceral was 21,9% vs 43,8%. The Medians of TNST and OS were respectively 7 and 9,6 months. The characteristics of patients with and without a PSA response are detailed in the table. Conclusions: Our cohort, characterized by advanced age, extensive prior treatments, and elevated PSA values, exhibited a PSA response that aligns with patients treated in randomized trials. Notably, our patients with visceral disease demonstrated a lower PSA response. [Table: see text]