tbuckley/cabot-search huggingface dataset:
Oral APL-1202 in combination with tislelizumab as neoadjuvant therapy in patients with muscle-invasive bladder cancer (MIBC): Interim analysis of ANTICIPATE phase II trial.
Authors: Matt D. Galsky, John P. Sfakianos, Dingwei Ye, Dalin He, Hailong Hu, Xiaodong Song, Haowen Jiang, Hanzhong Li, Shusuan Jiang, Bin Wang, Gongxian Wang, Yujie Wang, Yong Yang, Mingming Zhang
Journal: Journal of Clinical Oncology (2024)

632 Background: APL-1202 (nitroxoline) is a reversible and orally available MetAP2 inhibitor with anti-angiogenic and anti-tumor activities. Single-agent neoadjuvant programmed death 1 (PD-1) antibodies achieve pathological complete responses in a subset of patients (pts) with MIBC. APL-1202 and PD-1 antibody combination therapy demonstrates synergistic effects in several model systems of cancer, including bladder cancer. We hypothesized that APL-1202, in combination with tislelizumab, a humanized IgG4 anti-PD-1 antibody, may be an effective neoadjuvant therapy in MIBC. Methods: This is a prospective multicenter randomized phase II trial for pts with newly diagnosed MIBC for whom radical cystectomy (RC) is planned, and who are cisplatin ineligible or refuse cisplatin based neoadjuvant chemotherapy. Eligible pts are randomly assigned to group 1 (APL-1202 plus tislelizumab) or group 2 (tislelizumab), with randomization stratified by PD-L1 expression. Neoadjuvant treatment is administered every 3 weeks for 3 cycles. The primary endpoint is pathological complete response (pCR, pT0N0) rate. A Simon’s 2-stage design is employed with planned interim analyses after 18 evaluable pts in group 1 and 14 evaluable pts in group 2. Results: 42 pts have enrolled and results for 32 evaluable pts for stage 1 of the 2-stage design are reported. Radical cystectomy was completed in 18/18 pts in group 1 and 13/14 pts in group 2; 1 patient who could not undergo surgery due to disease progression and 10 pts refused RC. The 32 evaluable pts consisted of 11/18 (61%) and 10/14 (72%) cT2, and 6/18 (33%) and 2/14 (14%) cT3, and 1/18 (6%) and 2/14 (14%) cT4a in group 1 and 2, respectively. PD-L1 expression was assessed using the VENTANA PD-L1 (SP263) Assay; 8/18 (44%) pts in group 1 and 7/14 (50%) in group 2 was positive. The pathological response was shown in the table. Treatment emergent adverse events (TEAEs) were reported in 17 (94.4%) pts in group 1 and 11 (78.6%) in group 2; most common (≥ 10%) TEAE of CTCAE grade ≥ 3 were anaemia (4, 22.2%), lymphocyte count decreased (3, 16.7%) in group 1 and intestinal obstruction (3, 21.4%) in group 2. AEs led to drug discontinuation in 3 (16.7%) pts in group 1 (acute kidney injury, anaemia, hepatic function abnormal) and 2 (14.3%) in group 2 (immune hyperthyroidism, COVID-19), and no treatment-related AEs led to death. Conclusions: The pCR rates in both group 1 (APL-1202 plus tislelizumab) and group 2 (tislelizumab) exceeded thresholds to trigger expansion to stage 2 of the 2-stage design. The activity and safety of neoadjuvant APL-1202 plus tislelizumab support further evaluation of this novel regimen (NCT04813107). Clinical trial information: NCT04813107 . [Table: see text]
Regulatory approvals for genitourinary (GU) cancer by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) over 20 years (2003-2023).
Authors: Sanjay Khanna, Naveed Sarwar, Reece Caldwell, Jonathon Krell, David Joseph Benjamin, Matthew James Hadfield, Ali Raza Khaki, Jeremy Lyle Warner, Mark Lythgoe
Journal: Journal of Clinical Oncology (2024)

432 Background: The past 2 decades has witnessed a transformation in the GU cancer therapy armamentarium. In this study, we analysed GU cancer therapy approvals (initial &amp; supplemental) by the two largest global regulators (EMA and FDA) by evaluating approval timing, labels, biomarker requirements and drug withdrawal(s). Methods: A cross-sectional analysis of approved drugs and indications made for GU cancer medicines from each regulatory database from 2003-2023 was performed. We compared new approved therapies, indications and biomarker requirements. Results: The FDA approved 40 new therapies, corresponding to 57 indications, with 2 withdrawals. The EMA approved 33 new therapies, corresponding to 43 indications with 1 withdrawal. Overall, the FDA approved new GU cancer therapies 128 days earlier (table). In renal cell carcinoma (RCC), the FDA approved 14 new therapies across 18 indications, compared to 14 new therapies across 16 indications for the EMA. The FDA approved new RCC therapies 113 days earlier than the EMA. For concomitant approvals the FDA label was broader for 5 indications, more restrictive for 2 and equivocal for 9. In urothelial cancer (UC), the FDA approved 9 new therapies across 14 indications, compared to 7 new therapies across 7 indications for the EMA. The FDA approved new UC therapies 110 days earlier than the EMA. For concomitant approvals, the FDA label was broader for 4 indications and equivocal for 3. In prostate cancer (PC), the FDA approved 17 new therapies across 25 indications, compared to 12 new therapies across 20 indications for the EMA. The FDA approved new PC therapies 157 days earlier than the EMA. For concomitant approvals, the FDA label was broader for 2 indications and equivocal for 18. Across GU cancer, 8 therapies (both FDA and EMA) had biomarker-based eligibility with 3 notable differences in urothelial cancer: the EMA uniquely requires a PD-L1 combined positive score (CPS) ≥ 10 and PD-L1 ≥ 1% for pembrolizumab (platinum-ineligible) and Nivolumab (adjuvant), respectively. Although biomarker requirement was similar, the FDA has withdrawn atezolizumab in UC unlike the EMA. Conclusions: Over the past 20 years, there has been a substantial increase in new therapies to manage GU cancers. Patients in the US typically have access to more new therapies, earlier and across broader indications than those in Europe. However, a greater number of therapies are withdrawn after approval in the US. Biomarker-eligibility is broadly similar, with some discordance in UC. [Table: see text]
Clinical impact of C-reactive protein flare response in patients with advanced urothelial carcinoma who received pembrolizumab.
Authors: Ikko Tomisaki, Mirii Harada, Akinori Minato, Katsuyoshi Higashijima, Tomohisa Takaba, Yujiro Nagata, Kenichi Harada, Naohiro Fujimoto
Journal: Journal of Clinical Oncology (2024)

634 Background: C-reactive protein (CRP) has been reported as one of the useful predictive markers in patients with advanced urothelial carcinoma (UC). Not only baseline revel, kinetics of CRP during medical treatment also has been demonstrated. However, there are extremely limited data on temporary elevated CRP levels followed by decreasing below baseline (CRP flare response) after administration of immune checkpoint inhibitors. The aim of this study was to clarify the clinical significance of CRP flare response after administering pembrolizumab in patients with advanced UC. Methods: We retrospectively reviewed patients with advanced UC who consecutively received pembrolizumab as second-line or later therapy between March 2018 and January 2023 at one academic center and six general hospitals. Patients were categorized into 3 groups according to early CRP kinetics: flare-responder (CRP levels had increased to more than double from baseline within 1 month after pembrolizumab administration (CRP flare) and decreasing to below-baseline levels within 3 months); responder (CRP levels decreased ≥30% from baseline within 3 months without CRP flare); non-responder (the remaining patients). Tumor responses, overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were compared among the groups. Results: A total of 97 eligible patients, 15, 25, and 57 patients were classified into flare-responder, responder, and non-responder group, respectively. Objective response rates of flare-responder (43%) and responder (52%) were higher than that of non-responder groups (17%). Median follow-up was 7.8 months. Progression and death were observed in 83 and 70 patients during follow-up, respectively. Median OS was 19.8, 15.2, and 7.8 months in the flare-responder, responder, and non-responder group, respectively (P= 0.03). Furthermore, Median PFS was 8.1, 6.3, and 2.7 months in the flare-responder, responder, and non-responder group, respectively (P= 0.006). In multivariate analysis, CRP-flare response was a significant favorable predictive factor associated with OS. The patients who developed any grade AEs were 33, 40, 20.7% in the flare-responder, responder, and non-responder group, respectively (P= 0.16). Similarly there were no significant differences in occurrence of severe AEs (≥Grade 3). Conclusions: CRP flare response was observed in 15% of patients with advanced UC who received pembrolizumab and favorable oncological outcomes were observed in these patients. CRP-flare might be a promising predictive and prognostic marker in patients with advanced UC who underwent pembrolizumab therapy.
Avelumab or pembrolizumab: Which is the better subsequent treatment in patients with advanced urothelial carcinoma who did not show progression after 4 cycles of first line chemotherapy?
Authors: Ikko Tomisaki, Mirii Harada, Akinori Minato, Katsuyoshi Higashijima, Tomohisa Takaba, Yujiro Nagata, Kenichi Harada, Naohiro Fujimoto
Journal: Journal of Clinical Oncology (2024)

633 Background: In platinum eligible patients with advanced urothelial carcinoma (UC), there are two treatment options if they did not show progression after 4 cycles of first line chemotherapy. One is switching to avelumab maintenance therapy and the other is pembrolizumab after the disease progression on first line chemotherapy. However, there is no data witch treatment strategy demonstrate better survival. This study aimed to compare the efficacy between avelumab and pembrolizumab after first line chemotherapy without disease progression. Methods: We retrospectively reviewed patients with advanced UC who received avelumab or pembrolizumab as subsequent therapy following first line platinum-based chemotherapy between March 2018 and Jun 2023. In patients who receive pembrolizumab, only patients who did not show progression after 4 cycles of first line chemotherapy were included in the study cohort. The oncological outcomes were compared between the patients who received avelumab and pembrolizumab. Results: Thirty-three and 100 patients received avelumab and pembrolizumab during study periods, respectively. Among 100 patients who received pembrolizumab, 14 patients did not show progression during 4 cycles of first line chemotherapy. Median 4 and 6 cycles of first line chemotherapy were performed in patient treated with avelumab and pembrolizumab, respectively. All patients treated with pembrolizumab showed disease progression after 1st line chemotherapy. With the median follow-up of 16.7 months, progression was observed in 19 (57%) and 12(86%) patients in avelumab and pembrolizumab group, respectively. Among the patients with progression, all patients had treated with avelumab received subsequent treatment mainly enfortumab vedotin. However, only 2 patients (17%) had treated with pembrolizumab received subsequent treatment and the other patients were not candidate of additional treatment due to poor PS or cachexia. Although median progression free survival from starting first line chemotherapy was shorter in patients with avelumab compared to pembrolizumab (9.7 vs. 19.9 months, P=0.06), median OS was longer in patients with avelumab (40.9 vs. 24.9 months, P=0.34). Conclusions: In patients who did not show progression after 4 cycles of first line chemotherapy, avelumab maintenance therapy might be a better treatment option with longer overall survival compared to pembrolizumab.
North American patterns of care in clinical stage I testicular cancer from SWOG S1823.
Authors: Antoine Morin Coulombe, Sarah Colby, Jennifer King, Marian L. Neuhouser, Banu Arun, Siamak Daneshmand, Andrea Harzstark, Kathryn B. Arnold, Craig R. Nichols, Lucia Nappi
Journal: Journal of Clinical Oncology (2024)

509 Background: SWOG/CCTG S1823/GCC-001 is a non-interventional translational prospective cohort investigation with a primary endpoint of defining pre-treatment operational characteristics of the liquid germ cell cancer biomarker microRNA 371a-3p in predicting the presence of active germ cell malignancy. Opened in June 2020, 813 of the projected 956 patients have been registered with anticipated completion of accrual in early 2024. While analysis of the final endpoint awaits complete accrual and sufficient follow-up, S1823 creates a rich template of baseline clinical information and real-world treatment. Herein, we report baseline patterns of care in modern day real-world care delivery for Clinical Stage I (CSI) germ cell tumors across academic and community practices in North America. Methods: Data is obtained from case report forms and source documents for 547 S1823 enrollees with CSI seminoma or nonseminoma. Aggregate baseline clinical data unrelated to the primary endpoint are described to understand baseline clinical characteristics and management recommendations for CSI germ cell tumors. Results: Clinical characteristics and management recommendations for CSI are described in the table. The leading contributor to date is the Kaiser Permanente NCI NCORP followed by Canadian Institutions which together make up 38% of accruals from top level institutions. The majority of these largely young males were overweight or obese (67%). S1823 did not stipulate management which was at the discretion of local institutions/investigators. Active surveillance is the dominant strategy in both CSI seminoma and nonseminoma (85% overall). In CSI seminoma, adjuvant treatment with radiation is very rare (1/547) and adjuvant treatment with single agent carboplatin (1 or 2 cycles) is uncommon (4%). In CSI nonseminoma, adjuvant retroperitoneal lymph node dissection is also uncommon (3%) as is adjuvant chemotherapy with BEP X 1 or 2 (6%). Conclusions: In this large prospective multi-institutional observational cohort, surveillance appears to be the predominant management strategy for CSI germ cell tumors with very limited use of adjuvant chemotherapy or RPLND and virtual elimination of recommendation for radiation therapy for seminoma. Clinical trial information: NCT04435756 .[Table: see text]
Phase Ib trial of erdafitinib (E) combined with enfortumab vedotin (EV) following platinum and PD-1/L1 inhibitors for metastatic urothelial carcinoma (mUC) with FGFR2/3 genetic alterations (GAs).
Authors: Rohit K. Jain, Jazlyn Heiligh, Youngchul Kim, Richard Piekarz, Lorraine Cheryl Pelosof, Yuanquan (Aaron) Yang, Anishka D'souza, Risa Liang Wong, Laura Graham, Sumati Gupta, Anna Park, Timothy W. Synold, Guru P. Sonpavde
Journal: Journal of Clinical Oncology (2024)

625 Background: Erdafitinib (E) is a treatment option in mUCpatients with somatic FGFR2/3 GAs after progression on platinum-based chemotherapy (PBC). Enfortumab Vedotin (EV) is approved as a single agent to treat mUC patients following prior PBC and PD1/L1 inhibitors or as second-line therapy for cisplatin-ineligible patients. Retrospective studies suggest that the activity of EV is not compromised by FGFR2/3 GAs. E and EV have different mechanisms of activity, and toxicities are mostly non-overlapping. Hence, there is rationale to evaluate the feasibility of combination E + EV, to overcome the difficulties of resistance and sequencing agents in mUC patients with FGFR2/3 GAs. Methods: This is an ongoing, single arm, multicenter, dose-escalation and expansion study of combination E + EV evaluating the safety, tolerability, pharmacokinetics (PK), and antitumor activity in patients with mUC harboring somatic FGFR2/3 GAs who have progressed after PBC and/or PD1/L1 inhibitor therapies. Dose escalation phase aims to identify the maximum tolerable dose and recommended phase 2 dose of EV at dose levels of 1 mg/kg and 1.25 mg/kg in combination with E at 8 mg/day as shown in the table. Preliminary safety, PK, and efficacy data for Dose Level (DL) 1 and 2 are presented in this abstract. Results: As of data cutoff, based on 3+3 design, total 8 patients are enrolled and finished dose limiting toxicity (DLT) period (1 st cycle). Six patients were enrolled in DL1 with 1 DLT (skin rash) and 2 patients in DL2. The most common treatment-related adverse events (TRAE) included hyperphosphatemia (88%), mucositis (88%), hypercalcemia (75%), high AST (75%), hand foot syndrome (75%), peripheral neuropathy (75%), alopecia (63%), diarrhea (63%), hypoalbuminemia (63%) and hypomagnesemia (63%). Grade 3 TRAE included hand foot syndrome (50%), anemia (17%), rash (17%), anorexia (17%) and paronychia (17%). One patient developed grade 4 Stevens-Johnson syndrome related to EV which subsequently improved. PK data are available for all 6 subjects in DL1. The average steady-state Cmin of E and monomethyl auristatin E (MMAE) was 1430 ± 639 ng/mL and 1.4 ± 0.9 ng/mL, respectively, and the average Cmax of MMAE was 3.9 ± 0.9 ng/mL at DL1. All 8 patients are evaluable for response, and best response is partial response in all. Detailed safety and additional efficacy data will be presented. Conclusions: Combination E + EV is feasible and preliminarily exhibits antitumor activity. Dose escalation is ongoing to identify the MTD or recommended dose for expansion of the trial. Clinical trial information: NCT04963153 . [Table: see text]
Hierarchical clustering analysis for predicting 30-day readmissions after major surgery for prostate cancer.
Authors: Atulya Aman Khosla, Nitya Batra, Mohammad Arfat Ganiyani, Rohit Singh, Karan Jatwani, Lakshmi Prajwala Chedella Venkata, Mukesh Roy, Venkataraghavan Ramamoorthy, Muni B. Rubens, Anshul Saxena, Ishmael A. Jaiyesimi, Rohan Garje
Journal: Journal of Clinical Oncology (2024)

311 Background: Effective risk assessment techniques and follow-up strategies are scarce for patients with prostate cancer because of the heterogeneity of the population. We aimed to conduct a study for better risk stratification, applying machine learning–based classification to patients with prostate cancer who underwent major surgery. Methods: We identified eligible patients who underwent prostatectomy or surgeries related to excision of the prostate using data from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) for the years 2016–2021. Hierarchical clustering was conducted with variables such as age, BMI, smoking status, taking HTN medication, past medical history (diabetes, COPD, and CHF), preoperative labs (Na, BUN, creatinine, WBC count, HCT, and platelet count), operation time in minutes, and major complications. A multivariate logistic regression analysis was also conducted with a 30-day readmission as an outcome. The model accounted for cluster groups (high risk vs. low risk), among other variables. Results: The median [Q1, Q3] age of the sample ( n = 83,776) was 65.0 [59.0, 69.0] years. The participants were divided into two clusters (low-risk cluster, n = 72891; high-risk cluster, n = 10885) by hierarchical clustering, using 31 clinical variables. Patients in the high-risk cluster showed higher median levels of BUN (21 vs. 16 mg/dL), WBC count (7 vs. 6.5 /uL), platelet count (225 vs. 221/μL), and operation time (231 vs. 197 minutes). 30-day readmission rates were higher among the high-risk cluster (12.1% vs. 5.4%; p &lt; 0.001). Similar trends were observed for minor complications (10.7% vs. 5.2%), major complications (8% vs. 2.5%), and reoperation (3.4% vs. 1.3%). Results from logistic regression showed that cases in the high-risk cluster were 1.10 (95% CI: 1.03, 1.17; p &lt; 0.0015) times as likely to return to the hospital within 30 days of discharge as compared to the cases in the low-risk cluster (AUROC: 78.6%). Conclusions: In our study, hierarchical clustering divided prostate cancer cases into subgroups with a higher 30-day readmission risk. Applying machine learning–derived classification to prostate cancer patients undergoing major surgery may contribute to better risk stratification, leading to better prognosis and follow-up strategies.[Table: see text]
High doses of chemotherapy and autologous hematopoietic stem cell transplantation in patients with relapsed/refractory testicular germ cell tumors: Multicenter real-world experience in Argentina.
Authors: Federico Losco, Martin Angel, Juan Pablo Sade, Adriana Verónica Vitriu, Tomás Soulé, Luis Ayala, Olivia Gelo, Jeremías Sierra, Mariano Berro, Martín Castro, Silvina Palmer, Ruben Burgos, Soledad Cruset, Gonzalo Ariel Ferini, Mariel Perez, Priscila Wernicke, Sofia Pelayes Tortosa, Patricio Duarte, Sebastián Yantorno, María Cecilia Foncuberta
Journal: Journal of Clinical Oncology (2024)

508 Background: Germ cell tumors (GCTs) are the most common type of cancer in adolescent and young adult males. Most of them are curable with multimodal treatment: platinum-based chemotherapy (CT) + surgery. Patients who fail first-line treatment usually receive salvage CT with response rates between 30 and 50%. High-dose chemotherapy and autologous hematopoietic stem cell transplantation (HDCT) is an effective treatment in this context. Methods: We conducted a multicenter retrospective analysis of patients ≥ 15 years old with relapsed/refractory GCTs who received HDCT in 13 centers of the Argentine Group of Bone Marrow Transplantation and Cellular Therapy (GATMO-TC) from 2010 to 2022. Results: 114 patients were included, with a median age of 32 years (range: 15-58). Most had non-seminoma histology (66%); The primary tumor site was testis (65%), retroperitoneum (17%), and mediastinum (9%). Forty percent (n:46) had an unfavorable prognosis according to the IGCCCG score. Eighty-two % received ≥ 2 lines of CT before HDCT, 27% being platinum-refractory disease (PRD), and 45% received 2 consecutive courses of HDCT (tandem). All patients received a carboplatin-etoposide-based conditioning regimen. The median engraftment time was 12 days (d) (r8;25) for neutrophils and 15 d (r6;58) for platelets. Bacteremia (25%) and Hepatotoxicity (14.9%) were the most frequent G3-4 adverse events. With a median follow-up of 12.6 months (r1-138), 100 pts were evaluable for survival. 12- and 24-months OS was 67%- 64%; and PFS 56%; - 54% respectively. PRD patients had worse OS and PFS. Eighteen patients remained alive and without relapsing beyond 5 years of follow-up. Conclusions: This real-world multicentric study demonstrates that some patients with refractory/relapsed metastatic GCT are curable by HDCT, being an effective and safe feasible treatment with response rates similar to those described in the literature. The superiority of the tandem approach could not be demonstrated due to the heterogeneity of the sample.[Table: see text]