tbuckley/cabot-search huggingface dataset:
TECIC bladder-sparing strategy for high-risk bladder cancer: Exploration and interim analysis of a multicenter, prospective, parallel controlled study (HSCRYO-104).
Authors: Haowen Jiang, Chenyang Xu, Yiling Chen, Lujia Zou, Limin Zhang, Shuai Jiang, Jianming Guo, Lu Sheng, Bin Xu, Jianfeng Luo
Journal: Journal of Clinical Oncology (2024)

e16585 Background: To evaluate the efficacy and safety of transurethral resection of bladder tumors (TURBt) plus endoscopic cryoablation (ECA) combined with Immunotherapy and Chemotherapy (TECIC) as a bladder-sparing therapy in treating high-risk bladder cancer, and to explore the synergistic mechanism between cryoablation and antitumor immunity during the treatment. Methods: The HSCRYO-104 study was a multicenter, nonrandomized, parallel controlled clinical trial with a noninferiority design to evaluate the efficacy of the TECIC modality in treating high-risk non-muscle invasive bladder cancer and early muscle invasive bladder cancer (stage T2). The ratio of the EBCA group and the control group was set as 1:3. In the ECA group, patients received TURBt with immediate ECA at the resection site, and subsequent adjuvant chemoradiotherapy and immunotherapy. The control group was treated with radical cystectomy with pelvic lymphadenectomy and urinary diversion. The primary outcome was overall survival (OS), and secondary outcomes included progression free survival (PFS), in-situ recurrence and incidence of adverse events (AEs). Alterations in the tumor microenvironment were explored. Results: Between December 2021 and August 2023, the interim analysis and exploratory study was completed. A total of 106 patients received screening at four medical centers in Shanghai, and 103 patients were included (25 in the ECA group and 78 in the control group). The two groups were well-balanced at baseline. In the per-protocol analysis, three of the 24 patients in the EBCA group experienced in-situ recurrence and were treated by TURBt and ECA again. No progression or cancer-specific death was observed. Six of 74 patients in the control group died due to disease progression. The interim analysis found that the ECA group was noninferior to the control group in both OS and PFS, with a lower incidence of AEs, enhanced recovery after surgery and shorter hospital stay. Exploratory studies found a significant increase in the proportion of effector memory T cells and upregulation of cytokines (e.g., IL-7 and IL-15) in patients after cryoablation. Conclusions: The TECIC modality as a bladder preserving therapy achieved non-inferior short-term survival to the radical cystectomy with a better quality of life. This strategy has great potential for application in treating patients with bladder cancer. Clinical trial information: ChiCTR2200057679 .
Real-world (RW) comparison of prostate-specific antigen (PSA) response in patients with de novo metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide (APA) versus enzalutamide (ENZ).
Authors: Benjamin H Lowentritt, Ibrahim Khilfeh, Dominic Pilon, Shawn Du, Carmine Rossi, Frédéric Kinkead, Lilian Diaz, Lorie Ellis, Patrick Lefebvre, Gordon Andrew Brown
Journal: Journal of Clinical Oncology (2024)

e17067 Background: Androgen receptor signaling inhibitor (ARSIs) treatment (APA or ENZ), in combination with androgen deprivation therapy (ADT) has improved the prognosis of patients with de novo mCSPC. PSA decline ≥90% (PSA90) after ARSI initiation has been associated with improved survival and delayed disease progression. The objective of this study was to compare PSA90 response at 6-months among next-generation ARSI-naïve patients with de novo mCSPC initiating APA or ENZ. Methods: Clinical data for US community urology practices from PPS Analytics was linked with claims data from Komodo Health Solutions Research Database. Included patients were assigned to exclusive cohorts based on the first APA or ENZ dispensation or pharmacy claim on or after 12/16/2019 (index date). Patients were also included if they had de novo mCSPC, identified if a metastatic diagnosis was observed ≤180 days after the initial prostate cancer (PC) diagnosis, ≥12 months of pre-index clinical activity, and ≥1 PSA measurement within 13-weeks pre-index. Follow-up spanned from index date until the earliest of index ARSI discontinuation (i.e., gap ≥90 days supply) or switch, radiopharmaceutical initiation, or end of clinical activity/data availability (9/30/2022). Pre-index characteristics (i.e., age, race, region, payer type, index year, time from metastasis, time from PC diagnosis, prior use of ADT, first-generation antiandrogen, or chemotherapy, metastasis locations, most recent PSA and testosterone level, and earliest Gleason score) were balanced between cohorts using inverse-probability of treatment weighting (IPTW). PSA90 was defined as the earliest ≥90% decline in PSA relative to most recent pre-index PSA. The proportion of patients achieving PSA90 was compared using a weighted Kaplan-Meier analysis and the time-to-PSA90 response was compared using a weighted Cox proportional hazards model. Results: Overall, 332 APA and 383 ENZ patients were identified. Patients’ pre-index characteristics were balanced using IPTW (Table). By 6 months post-index, 81.0% of APA and 75.2% of ENZ patients had ≥1 PSA test. PSA90 response at 6 months was achieved by a significantly higher proportion of APA patients, as compared to ENZ patients (62.8% vs 49.6%; p=0.004; Table). Median time to PSA90 response was 3.5 months for APA and 6.1 months for ENZ. Conclusions: This study of RW US data showed that a greater percentage of patients with de novo mCSPC treated with APA achieved a deep, early PSA response by 6 months as compared to those treated with ENZ. [Table: see text]
ALADDIN: Evaluation of darolutamide addition to androgen deprivation therapy and radiation therapy in newly diagnosed prostate cancer with pelvic lymph nodes metastases.
Authors: Stephane Oudard, Pierre Combe, Thomas Boisserie, Ali Hasbini, Thomas Leroy, Stephane Supiot, Ulrike Schick, Nathalie Mesgouez-Nebout, David Pasquier, Ingrid Fumagalli, Jonathan Khalifa, Carole Iriart, Laville Adrien, Paul Sargos, Amandine Ruffier, François-Georges Riet, Etienne Martin, Lysian Cartier, Pierre Graff-Cailleaud, Jean-Emmanuel Bibault
Journal: Journal of Clinical Oncology (2024)

TPS5127 Background: Standard of care for patients with prostate cancer (PC) with pelvic lymph node metastases is radiotherapy (RT) with long-term androgen deprivation therapy (ADT). In the STAMPEDE trial, James et al. assessed the role of abiraterone acetate with prednisolone (AAP) earlier in the disease for N+M0 PC patients. They showed that the addition of AAP to ADT and RT significantly improved failure-free survival (FFS) from 61% to 92.5% (ESMO 2017). Darolutamide improves survival in men with castration-refractory non-metastatic prostate cancer and in mHSPC patients with the addition of ADT plus docetaxel. We hypothesize that adding Darolutamide to ADT and RT could improve FFS for these high-risk patients. Methods: The ALADDIN study (NCT05116475) is a French, prospective, phase 3 trial that will enroll an estimated 152 patients with hormone-naive prostate cancer and pelvic lymph node metastases. Eligible patients are treatment-naive for hormonal therapy, with positive lymph node disease (upper limit defined as L4/L5 interspace) determined by conventional imaging or TEP choline or PSMA, ECOG performance status of 0 to 2, and adequate major organ function. Patients will be randomized by minimization 1:1 to receive ADT + Intensity-Modulated Image-Guided Radiation Therapy (IMRT) with darolutamide or placebo (of darolutamide). IMRT will deliver 78 Gy to the prostate, 70 Gy to the metastatic lymph nodes, and 46 Gy to the pelvic lymph node areas (2 Gy per fraction, 5 days a week) with daily CBCT imaging. ADT will be achieved with LHRH agonists or antagonists for 24 months. The darolutamide regimen will be two tablets of 300 mg orally twice daily for 24 months. The primary endpoint is failure-free survival. Secondary endpoints will be: MFS, progression-free survival, safety, overall survival, and health-related quality of life. Stratification factors are D'Amico risk group and sites. The planned sample size provides 80% power to detect a difference of 20% in FFS (60 vs 80%) at a two-sided 0.05 significance level. The study is expected to last for 7 years, of which accrual will last for 2 years. The first participant was enrolled in the study in August 2022. In total, 23 centers are participating in the ALADDIN study. The DSMB occurred on November 13 th 2023 and allowed the study to continue as planned. Clinical trial information: NCT05116475 .
A phase 1 study of JNJ-69086420 (JNJ-6420), an actinium-225 (<sup>225</sup>Ac) -labeled antibody targeting human kallikrein 2 (hK2), for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Michael J. Morris, Jeffrey Y.C. Wong, Luke Nordquist, Russell Zelig Szmulewitz, Neeraj Agarwal, Edward F. Attiyeh, Steven I Max, Chaitanya R. Divgi, Daniel Patricia, Yu Cao, Xiang Li, Alex Yu, Karen Urtishak, Josh David Lauring, Oliver Sartor
Journal: Journal of Clinical Oncology (2024)

5010 Background: hK2 (encoded by the KLK2gene) is a novel target expressed on the cell surface of prostate cancer cells with restricted expression elsewhere. JNJ-6420 is a first-in-class anti-hK2 antibody–based targeted radiotherapy delivering 225 Ac, a high-energy short-range alpha-particle emitter, to prostate cancer cells. Here we report the first-in-human study evaluating JNJ-6420 in heavily pretreated biomarker-unselected participants (pts) with mCRPC who received ≥1 prior androgen receptor pathway inhibitor. Methods: Intravenous JNJ-6420 was escalated from 50 μCi to 400 μCi every 8-12 weeks in the outpatient setting with no residential radioprotective restrictions. Prior radioisotopic therapy was an exclusion criterion. Primary objectives were safety and defining a recommended phase 2 dose (RP2D). Secondary objectives included preliminary assessment of clinical activity. Results: As of January 5, 2024, 67 pts received ≥1 JNJ-6420 dose. Exposure and clinical activity for the 57 pts in the ≥150 μCi JNJ-6420 cohorts are summarized (see Table); 35/57 (61.4%) experienced grade ≥3 TEAEs, and 21 (36.8%) had a serious TEAE. TEAEs of note included thrombocytopenia (63.2%) and interstitial lung disease (ILD, 9%). All instances of ILD occurred at cumulative doses ≥500 μCi and prior to implementation of pulmonary function surveillance. Grade ≥3 TEAEs (≥10%) included anemia (26.3%), thrombocytopenia (17.5%), lymphopenia (10.5%), and leukopenia (10.5%). 9/57 (15.8%) pts discontinued treatment due to TRAEs; 4 TRAEs resulted in death. At doses ≥150 μCi, the PSA50 rate was 45.6%. To date, across all dose cohorts, 31 pts (46%) remained on treatment for ≥24 weeks. Prolonged clinical, biochemical, and radiographic responses were noted in pts receiving doses of 150 μCi and higher. Durable responses included pts on treatment for 112 weeks (96 weeks since last dose), 88 weeks (13 weeks since last dose), and 46 weeks (after a single dose). Conclusions: In this first-in-human study, key TEAEs of JNJ-6420 were thrombocytopenia and ILD, both associated with repeated dosing. At ≥150 μCi, 1-2 doses of JNJ-6420 elicited profound and durable biochemical and radiographic responses. Evaluation of the RP2D is ongoing. These data highlight hK2 as a novel target for targeted alpha-particle therapy. Clinical trial information: NCT04644770 . [Table: see text]
Preliminary results of sexual quality of life (QOL) outcome for intermediate-high risk prostate cancers treated by stereotactic radiotherapy (SBRT) and androgen deprivation therapy (ADT): Clinical and dosimetric factors.
Authors: Trinanjan Basu, Jay Prakash Sahu, Ratheesh Gnair, Shounak Jairam Kamat
Journal: Journal of Clinical Oncology (2024)

e17085 Background: There has been numerous evidence about ADT and radiotherapy on sexual QOL among prostate cancer (Pca) patients. This study analyzed the impact of SBRT on sexual health of Pca treated by SBRT and ADT. This also monitored dosimetry related to penile bulb (PB) and neurovascular bundles (NVB). Methods: Consecutive series of 40 Pca patients of intermediate and high-risk group (NCCN) were included. Baseline sexual function was assessed using Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC‐CP) questionnaire for sexual symptoms score. Patients received ADT as per risk groups. Radical SBRT was 36.25Gy in 5 fractions (Pelvic nodal 25 Gy in 5 fractions for high risk) on alternate days or weekly. Mean Dose to penile bulb and dose received by bilateral NVB were documented. Sexual function by EPIC-CP monitored at baseline and then 6 monthly till last follow up. Results: With median age of 61 years and median follow up of 20 months, 20% (8) patients belong to NCCN intermediate favourable risk category,15% (6) Intermediate unfavourable risk category and 65% (26) High risk category. All high risk Pca received elective pelvic nodal radiotherapy. Mean dose to penile bulb was in range of 9.5-29.4Gy. NVB Dose ranged from V34.4 (83.3% - 91.8%), V32 (94.5-99.16%) V28(99.76-100%). The EPIC‐CP for sexual symptoms score reported (out of 12) median score at baseline of 3 (range2-4), at 6 months 4.5 (range3-6)), at 12 months 5 (range 3-7), at 24 months 5.5 (range 4-7) and at 30 months 7 (range 6-8). The higher score represented worsening sexual function QOL. Till last follow up 38/40 patients were biochemically controlled with acceptable gastro-intestinal and genito-urinary late effects. Both the median and mean score of EPIC-CP sexual domain declined over follow up period representing clinical effect of ADT and dose received to PB and NVB. Sexual function scores declined gradually in both risk groups (High risk &gt; intermediate risk) and vitality/hormonal scores were unchanged from baseline in both groups at 3 and 6 months. Few patients beyond 3 years of follow up reported some degree of recovery in EPIC-CP score in sexual function domain. Conclusions: A substantial group of patients in our study had mild or no erectile dysfunction at base-line but compromised sexual health after ADT and SBRT. The technical challenge of sparing NVB for high risk Pca patients combined with effect of ADT remains a concern. However, PB dosage were in the acceptable range signifying multitude of factors besides only dosimetric features. Late recovery of sexual function to some extent probably a possibility. There are limitations in documentation of sexual QOL by EPIC-CP in our cohort and future prospective documentation and pragmatic sparing of NVB can highlight specific issues related to sexual QOL.
The efficacy and safety of presurgical therapy with tislelizumab and axitinib for renal cell carcinoma with inferior vena cava tumor thrombus.
Authors: Xuegang Wang
Journal: Journal of Clinical Oncology (2024)

e16508 Background: There is no currently consensus on presurgical therapy for renal cell carcinoma (RCC) with inferior vena cava (IVC) tumor thrombus. Tyrosine kinase inhibitor (TKI) combined with immune checkpoint inhibitor (ICI) had shown a survival benefit in metastatic RCC patients in clinical trials. However, the efficacy of presurgical therapy with combined ICI and TKI for nonmetastatic RCC with IVC tumor thrombus has not been adequately investigated. Methods: We retrospectively evaluated 7 patients of nonmetastatic RCC with IVC tumor thrombus treated with tislelizumab and axitinib as presurgical therapy and radical nephrectomy and tumor thrombectomy at the First Affiliated Hospital of Xiamen University from May 2020 to December 2022. All patients received combination therapy of tislelizumab and axitinib preoperatively for 3 cycles. The IVC tumor thrombus improvement by Mayo level and diameter were evaluated on magnetic resonance imaging (MRI), and clinical response of primary renal mass and adverse events (AEs) were evaluated using Response Evaluation Criteria in Solid Tumors 1.1 criteria and National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 criteria. Results: 7 RCC with IVC tumor thrombus patients received neoadjuvant tislelizumab combined axitinib, with a median age of 62 (50-72) years. 71.4% (5/7) were male, 71.4% (5/7) were diagnosed histologically with clear cell RCC, while 28.6% (2/7) were Type I papillary RCC. 57.1% (4/7) were Mayo level 2 tumor thrombus and 42.9% (3/7) were Mayo level 3. At follow-up after systematic therapy, 57.1% (4/7) patients had a reduction in Mayo level of tumor thrombus. The median decrease in thrombus dimeter and length was 5.3 (1.8-17.2) mm and 18.5 (4.4-41.5) mm, respectively. The overall response rate (ORR) in primary renal mass was 57.1% (4/7) with 4 partial responses (PR). Radical nephrectomy and thrombectomy were performed for all 7 patients at 1.5 months after finish of presurgical therapy, with 5 patients performed robotic surgery and 2 patients performed open surgery. 3 patients were planned to have hepatic vein clamping and liver mobilization but following treatment, neither of these manoeuvers was needed. The median operative time was 293 (240-322) minutes, the median blood loss was 1187 (750-2000) mL. The most common AE were all grade 1-2, only 1 patient occurred grade 4 liver function injury which did not affect normal operation after symptomatic treatment. During a median follow-up of 24.9 (14.0-45.0) months, only 1 patient had local IVC tumor thrombus metastasis, disease recovered stabilized after stereotactic radiotherapy. Conclusions: Presurgical therapy with tislelizumab and axitinib for RCC patient could be effective in reducing IVC tumor thrombus and were able to undergo easier radical surgery without serious AE.
Efficacy of erdafitinib in FGFR2/3-altered metastatic urothelial cancer including patients with CDK2NA/B or MTAP loss: Analysis of UNITE study.
Authors: Cindy Y. Jiang, Tanya Jindal, Ilana B. Epstein, Charles B Nguyen, Amanda Nizam, Dimitra Rafailia Bakaloudi, Amy K Taylor, Matthew I. Milowsky, Sumit Shah, Christopher J. Hoimes, Mehmet Asim Bilen, Yousef Zakharia, Hamid Emamekhoo, Petros Grivas, Shilpa Gupta, Joaquim Bellmunt, Ajjai Shivaram Alva, Vadim S Koshkin, Omar Alhalabi, Matthew T Campbell
Journal: Journal of Clinical Oncology (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 = &gt; 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]
A phase 1/2 study of EG-70 (detalimogene voraplasmid) intravesical monotherapy for patients with BCG-unresponsive non-muscle invasive bladder cancer with carcinoma in situ.
Authors: Richard Bryce, Christine Tosone, James C. Sullivan, Tammy Linback, Gary D. Steinberg
Journal: Journal of Clinical Oncology (2024)

TPS4626 Background: High-risk non-muscle-invasive bladder cancer (NMIBC) is treated with adjuvant intravesical Bacille Calmette-Guérin (BCG). However, approximately 50% of patients experience recurrence and/or progression after BCG treatment and are considered unresponsive. EG-70 (detalimogene voraplasmid) is an investigational drug product that was specifically engineered for intravesical administration to elicit local stimulation of anti-tumor immune responses in the bladder and drive durable efficacy in patients with BCG-unresponsive NMIBC, while mitigating the risk of systemic toxicities from immune stimulation. The phase 1 (dose-escalation) part of the first-in-human LEGEND (NCT04752722) phase 1/2, open-label, multicenter study of EG-70 in patients with high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) is complete: intravesical instillation of EG-70 was well tolerated with an overall complete response (CR) rate of 73%; and the recommended phase 2 dose (RP2D) was identified. Here we describe the ongoing phase 2 part of the study, which opened to enrollment in May 2023. Methods: Patient eligibility criteria: age ≥18 years; ECOG PS 0−2; BCG-unresponsive NMIBC with CIS, with or without resected coexisting papillary tumors, ineligible for, or have elected not to undergo, cystectomy; satisfactory bladder function with ability to retain study drug for ≥60 minutes. Prior checkpoint inhibitor treatment is allowed if completed within 30 days before study entry. Patients are treated with EG-70 at the RP2D (800 µg in 50 mL) by intravesical administration on weeks 1, 2, 5, and 6 of a 12-week cycle, for 4 cycles in one of two cohorts: BCG-unresponsive (Cohort 1); BCG-naïve or BCG-incompletely treated (Cohort 2). Patients in either cohort who exhibit stable disease (SD) or CR at week 12 will continue treatment until week 24; patients with progressive disease (PD) will discontinue treatment. Patients who experience or maintain CR at week 24 will receive additional cycles every 12 weeks until week 48; patients with SD or PD at week 24 will discontinue treatment. Patients with PD at any time after week 24 will discontinue treatment. Phase 2 primary objective: evaluate efficacy (CR rate at week 48) and safety of EG-70. Secondary objectives: evaluate progression-free survival, CR rate at 12, 24, 36 and 48 weeks, and duration of response. The study is being conducted in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines and with the principles of the Declaration of Helsinki. All patients provide written informed consent. The ongoing, registration-enabling phase 2 portion of the LEGEND study is anticipated to recruit approximately 100 patients from sites in North America, Europe, and the Asia-Pacific region. Clinical trial information: NCT04752722 .