tbuckley/cabot-search huggingface dataset:
Impact of squamous histology on outcomes with enfortumab vedotin in patients with advanced urothelial carcinoma: Analysis of the UNITE study.
Authors: Tanya Jindal, Omar Alhalabi, Charles B Nguyen, Dimitra Rafailia Bakaloudi, Amanda Nizam, Mehmet Asim Bilen, Arnab Basu, Yousef Zakharia, Matthew I. Milowsky, Jason R Brown, Deepak Kilari, Sumit Shah, Hamid Emamekhoo, Petros Grivas, Christopher J. Hoimes, Shilpa Gupta, Joaquim Bellmunt, Matthew T Campbell, Ajjai Shivaram Alva, Vadim S Koshkin
Journal: Journal of Clinical Oncology (2024)

651 Background: Squamous histology (SH) is the most common variant of Urothelial Carcinoma (UC) and is associated with lower response rates to chemotherapy. The impact of SH on outcomes with enfortumab vedotin (EV) is less defined. We hypothesized that increased SH component would correlate with inferior outcomes with EV treatment. Methods: UNITE is a multi-institutional retrospective study in pts advanced UC (aUC) treated with targeted agents. In this analysis, we compared EV monotherapy outcomes in pts with pure UC (pUC) and pts with urothelial predominant histology (UCP) [&lt;50% SH], SH-predominant [50-99% SH] and pure SH (pSH) [100% SH] respectively. We also compared pSH to UCP and SHP. Observed Response Rate (ORR) was compared in evaluable pts with scans after ≥1 cycle of EV using Chi-squared test. Progression-free survival (PFS) and overall survival (OS) from EV start were assessed and compared using the KM method and Cox proportional hazard test. Results: This analysis included 460 pts from 17 US sites treated with EV monotherapy. 366 pts had pUC and 94 pts had SH component (including pSH). In the overall cohort, median age was 70, 73% men, 88% Caucasian, 73% ECOG PS 0-1, 67% lower tract tumor, 30% liver mets, 38% bone mets, 65% had ≥ 2 prior therapy lines. There were no significant differences in baseline clinical characteristics between pts with pUC vs SH component except for higher incidence of liver mets in pts with pUC (32% vs 20%; p = 0.02). Among all 460 pts, median follow up was 20.7 mos from EV start, ORR was 51%, mPFS and mOS were 5.8 mos (95% CI: 5.3-6.4) and 12.7 mos (95% CI: 11.5-14.3). Among 94 pts with SH component, 70 were UCP, 17 SHP and 7 pSH. Inferior outcomes were noted in pts with pSH relative to pts with pUC and pts with UCP (Table). No differences in outcomes were seen across other cross-group comparisons. Conclusions: These hypothesis-generating findings suggest that SH component may impact outcomes with EV treatment in pts with aUC. A subset of pts with SH-predominant histology can have robust responses and outcomes with EV treatment, but larger studies and further biomarker data are needed to determine pts most likely to benefit. Patients with pSH are shown to have worse outcomes with EV, but further studies with a larger sample size are needed to validate our findings and define the role of EV for this rare and biologically distinct entity. [Table: see text]
Guiding adjuvant instillation in intermediate-risk non-muscle invasive bladder cancer by drug screens in patient-derived organoids.
Authors: Martin Egger, Marta De Menna, Pavel Lyatoshinsky, Jennifer Blarer, Raphael Hösli, Dominik Abt, Roland Seiler
Journal: Journal of Clinical Oncology (2024)

TPS711 Background: Recurrence rates in intermediate risk non-muscle invasive bladder cancer (NMIBC) are high and therefore, clinical guidelines recommend adjuvant instillations. However, the exact regimen with an exact number of instillations and the chemotherapeutic agent to be used are not clearly defined. During the last years we have established a standardized pipeline to generate patient-derived organoids (PDO) from cold cup biopsies of NMIBC. We showed that the subsequent organoids maintain key features of the parental tumor and share the molecular landscape. Moreover, our pipeline allows to investigate drug response to different agents in a standardized manner. Methods: In this ongoing, open-label, single center phase II trial, we aim to use drug screens in PDO of patients with intermediate risk NMIBC to guide drug selection for intravesical instillation. Patients with diagnosis of intermediate-risk NMIBC are enrolled. PDO are generated from biopsies prior transurethral resection of the bladder tumor. On the generated PDO drug response is determined to four chemotherapeutic agents that have already been used for bladder instillations in the literature (Epirubicin, Mitomycin C, Gemcitabine and Docetaxel). The most effective drug is selected for adjuvant instillation into the bladder once weekly for 6 instillations. The follow-up thereafter is performed according to European guidelines. The primary endpoint of the study is to determine the proportion of patients for which a specific selection of chemotherapeutic agent for intravesical instillation can be determined by using drug screens in PDOs. Secondary endpoints are recurrence- and, progression free survival, quality of life and translational studies. The null hypothesis, that a drug prediction will only be possible in 65% of patients, will be tested against a one-sided alternative. Assuming that the real proportion is 85%, 31 participants should show a statistically significant result at 5% significance and 80% power (exact binomial test). Due to early termination of 10%, a total number of 34 patients will be included. We are successfully conducting a trial to implement drug screens in PDO into daily routine and to guide patient treatment. This is a novel concept to precise treatment selection in patients with intermediate-risk NMIBC. When the primary endpoint is met, a modification of the trial with larger sample size, novel compounds and a focus oncological outcomes is foreseen. Clinical trial information: NCT05024734 .
Optimal sequential therapy for metastatic castration-resistant prostate cancer after androgen receptor pathway inhibitors in the up-front era.
Authors: Yushi Naito, Jun Nagayama, Yuta Sano, Satoshi Inoue, Kazuna Matsuo, Tomoyasu Sano, Shohei Ishida, Yoshihisa Matsukawa, Masashi Kato, Shusuke Akamatsu
Journal: Journal of Clinical Oncology (2024)

168 Background: The optimal sequential therapy for metastatic castration-resistant prostate cancer (mCRPC) following the use of up-front androgen receptor pathway inhibitors (ARPIs) for metastatic hormone-sensitive prostate cancer (mHSPC) is still unclear. Methods: A total of 220 patients who received systemic therapy for de novo mHSPC at Nagoya University Hospital and its affiliated institutions between 2014 and 2022 were included in the study. Patients who received up-front therapy with ARPI as first-line therapy for mHSPC, followed by ARPI as primary therapy for mCRPC were defined as the AA group, followed by docetaxel (DOC) as primary therapy for mCRPC were defined as the AD group. On the other hand, the vAA group was defined as patients who received androgen deprivation therapy alone or combined androgen blockade as “vintage” first-line therapy for mHSPC, followed by two consecutive ARPIs as sequential therapy for mCRPC, and the vAD group was defined as patients who received ARPI followed by DOC as sequential therapy for mCRPC. Patient characteristics and progression-free survival (PFS) of the second agent after the first ARPI were compared in each group. Results: We identified 14 patients in the AA group, 16 in the AD group, 84 in the vAA group, and 59 in the vAD group. There were no differences in patient background such as initial PSA, Gleason score, and metastatic burden between the groups, while patient age was lower in the AD and vAD groups compared to the AA and vAA groups. The PFS of the second agent in the AA group was significantly shorter than that in the vAA group (median, 6.8 vs. 1.9 months; hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.25-0.87; p=0.017). In contrast, there was no significant difference in PFS of the second agent in the vAD and AD groups (median, 7.0 vs. 4.0 months; HR, 0.63; 95%CI, 0.29-1.34; p=0.235). Conclusions: The effect of each agent after ARPI therapy in the UP-FRONT era may be poorer than that in the VINTAGE era. In the setting after up-front ARPI, sequential therapy with DOC may be more appropriate than sequential therapy with ARPI.
Real-world treatment patterns for patients with high-risk biochemically recurrent nonmetastatic castration-sensitive prostate cancer.
Authors: Stephen J. Freedland, Amanda Ribbands, Jake Butcher, Tom Brown, David Russell, Christopher S Bland, Maelys Touya, Jasmina I. Ivanova
Journal: Journal of Clinical Oncology (2024)

299 Background: Patients with biochemically recurrent (BCR) nonmetastatic castration-sensitive prostate cancer (nmCSPC) who are identified as high-risk of developing metastases may benefit from earlier treatment. This study analyzed treatment patterns in these patients. Methods: The Adelphi Real World nmCSPC retrospective survey was completed by urologists and radiation oncologists in the US. For this analysis, data from medical charts for patients diagnosed with high-risk BCR nmCSPC from Jan 2021–Jul 2023 were extracted; physicians completed a chart for their last 6–8 patients. Data were analyzed descriptively for first line (1L) treatment received (regardless of time) since high-risk BCR diagnosis for the total patient sample and subgroups of interest. Physicians documented those with no treatment as on observation. Results: Aggregated data were analyzed for 376 patients with high-risk BCR nmCSPC; 252 (67%) had prostate-specific antigen doubling time (PSADT) ≤9 months after BCR and initial definitive therapy of radiotherapy (RT) and/or radical prostatectomy (RP). Overall, 84% were treated by urologists and 16% by radiation oncologists. Median age was 70 years; 64% were White, 31% were Black/African American. Median PSA at high-risk BCR diagnosis was 5 ng/mL. Median follow-up after high-risk BCR diagnosis was 249 days. Median time between high-risk BCR diagnosis and initiation of 1L treatment was 17 days. Most common 1L treatments were androgen deprivation therapy (ADT) alone, salvage RT, novel hormonal therapy (NHT) + ADT, and observation alone. For patients on observation alone, median follow-up after high-risk BCR diagnosis was 181 days. Few numerical differences were seen in treatment patterns depending on how patients were determined as high-risk (Table). Patients treated by urologists rather than radiation oncologists had numerically higher proportions of 1L treatment with NHT + ADT (21% / 2%) and observation alone (17% / 8%), and numerically lower proportions of ADT alone (27% / 34%) and salvage RT (12% / 44%). Conclusions: First line treatments were typically initiated rapidly following high-risk BCR nmCSPC diagnosis, with only 15% of patients receiving observation alone during available follow-up. [Table: see text]
Real world experience of <i>FGFR</i> gene alterations and clinical outcomes in advanced/metastatic urothelial cancer in Japan: MONSTAR-SCREEN database study.
Authors: Nobuaki Matsubara, Takahiro Osawa, Takashige Abe, Mototsugu Oya, Koshiro Nishimoto, Toshiyuki Iwahori, Hiroaki Tsuchiya, Maiko Murota, Masaki Yoshida, Yohei Tatematsu, Yosuke Nakano, Masatoshi Eto, Norio Nonomura
Journal: Journal of Clinical Oncology (2024)

647 Background: Gene alterations (GA) in fibroblast growth factor receptors ( FGFR) may be oncogenic drivers in urothelial cancer (UC). However, the association between FGFR GA status and the prognosis with platinum-based chemotherapy has not been well investigated, especially in Asian patients. This study aims to elucidate the proportion and prognosis of FGFR2 or 3 (2/3) GA-positive advanced or metastatic UC (a/m UC). Methods: This study included patients registered during 2019 and 2022 in the “MONSTAR-SCREEN” database, where FoundationOneLiquid (F1L) was used for detecting 324 cancer-related genes, including FGFR. Analyzed FGFR2/3 GA variants included FGFR3 mutations (R248C, S249C, G370C, and Y373C) and FGFR2/3 fusions (FGFR2-BICC1, FGFR2-CASP7, FGFR3-TACC3, and FGFR3-BAIAP2L1). The positive ratio of FGFR2/3 GA and other gene alterations except FGFR was obtained at registration in eligible patients; besides, FGFR2/3 GA status was also evaluated after systemic treatment. Progression-free survival (PFS) in each treatment line was estimated, summarized by FGFR2/3 GA positive/negative. Results: Among the registered 2,224 cancer patients in this database, 138 eligible a/m UC patients were included (median age [SD] 72.0 [9.1] years for all; 95 males [68.8%]). The primary tumor site was the bladder in 70 patients (50.7%), renal pelvis in 50 patients (36.2%), and ureter in 18 patients (13.0%). FGFR2/3 GA was positive in 16 patients (11.6% [95% confidence interval: 6.8, 18.1]); the proportion of other typical gene alterations was 92.8%, 41.3%, 23.2%, and 23.2% in TP53, TERT, ARID1A and BRCA2, respectively. F1L was performed both before and after systemic treatment twice or more in 55 patients (39.9%). The FGFR concordance was analyzed in 55 patients available for both before and after treatment F1L results. Among them, 3 of the 6 FGFR2/3 GA-positive patients (50.0%) remained positive, and 1 of the 49 FGFR2/3 GA-negative patients (2.0%) before systemic treatment turned positive after treatment. The median PFS after first-line treatment was 6.8 months in FGFR GA-positive and 6.4 months in the negative patients. The estimated survival rate after first-line treatment was also similar between FGFR GA-positive and -negative patients at 12 months (68.8% vs. 81.0%). Conclusions: The results showed a similar trend to previous studies, where FGFR GA was reported in approximately 20% of metastatic UC patients. No difference was found in the PFS and the estimated survival rate by FGFR2/3 GA-positive or -negative patients. Our data showed that treatment pressure did not alter the FGFR status commonly.
Predicting abiraterone efficacy in advanced prostate cancer: Insights from marker of proliferation Ki-67.
Authors: Fengnian Zhao, Jinge Zhao, Yifu Shi, Xinyuan Wei, Ni Chen, Pengfei Shen, Hao Zeng
Journal: Journal of Clinical Oncology (2024)

176 Background: The marker of proliferation Ki-67 (KI67) is a well-known biomarker reflecting cell proliferation activity and was reported to be associated with the treatment efficacy of chemotherapy in different tumors. However, it is unknown whether KI67 also has a role in predicting the efficacy of the next-generation hormone therapies, e.g., abiraterone, for patients with prostate cancer (PCa). Methods: Clinicopathological data of 144 men with metastatic PCa who received abiraterone therapy were retrospectively collected. The KI67 positivity was examined by immunohistochemistry (IHC) using the prostate biopsy specimen. The predictive value of KI67 and other factors on the therapeutic efficacy of abiraterone treatment was explored. Kaplan-Meier curve and COX regression analysis were used for survival analysis. The endpoints were PSA progression-free survival (PSA-PFS) and radiographic progression-free survival (rPFS) according to the PCWG3 criteria. Results: Among the 144 included patients, 82 (56.9%) and 62 (43.1%), respectively, received abiraterone therapy at metastatic hormone-sensitive (mHSPC) and castration-resistant PCa (mCRPC) stage. The median KI67 positivity was 20% for the total cohort (interquartile range: 10%-30%). When taken as a continuous variable, KI67 positivity was adversely related to both PSA-PFS (HR, 95%CI: 1.02, 1.01-1.03, P=0.001) and rPFS (HR, 95%CI: 1.02, 1.02-1.03, P=0.001) of the abiraterone therapy, while was not associated with PSA response. The results of multivariate COX regression analysis implied that, after adjusting by mHSPC/mCRPC stage, ISUP grading, pain score, visceral metastasis, and metastatic burden, KI67 was still an independent predictor of PSA-PFS (HR, 95%CI: 1.02, 1.01-1.03, P=0.001) and rPFS (HR, 95%CI: 1.02, 1.01-1.03, P=0.008) of the abiraterone therapy. Moreover, when patients were divided into two groups with high and low KI67, using cutoffs of 10%, 20%, and 30%, KI67 remained a significant predictor of both PSA-PFS (HR: 1.67, 1.91, 2.29; P value: 0.052, 0.004, &lt;0.001) and rPFS (HR: 1.54, 1.83, 1.88; P value: 0.119, 0.008, 0.008) of the abiraterone treatment. Subgroup analysis based on whether patients received abiraterone at mHSPC or mCRPC stage suggested that KI67 30% (median PSA-PFS: 11.4- vs. 27.6-Mo, P&lt;0.001; median rPFS: 16.6- vs. 33.6-Mo, P=0.001) was the optimal cutoff to maximize patient prognostic differentiation for the mHSPC cohort, while KI67 20% (median PSA-PFS: 6.9- vs. 14.9-Mo, P=0.033; median rPFS: 10.1- vs. 16.5-Mo, P=0.030) was the optimal cutoff for the mCRPC cohort. Conclusions: Our study revealed that KI67 positivity in prostate biopsy specimens was a robust predictor of abiraterone efficacy for patients with advanced PCa. Further validation using datasets from other centers is needed to strengthen the findings of our work.
Real world evidence comparison of first-line (1L) immune-oncology(IO)/tyrosine kinase inhibitor (TKI) vs. IO/IO combination therapy in renal cell carcinoma (RCC).
Authors: Patrick Bolan, Gavin Hui, Yen Low, Saurabh Gombar, Alice C. Fan, Divya Ahuja Parikh, Sumit Shah, Sandy Srinivas, Ali Raza Khaki
Journal: Journal of Clinical Oncology (2024)

402 Background: IO/IO and IO/TKI are the preferred first-line combinations for treatment of RCC. While these combinations have been superior to sunitinib, no head-to-head clinical trials have been completed, which leaves uncertainty about the preferred combination. Here, we have leveraged ASCO Cancerlinq data to compare overall survival for RCC patients (pts) receiving first line IO/IO vs. IO/TKI combinations. We hypothesized that IO/IO and IO/TKI would have similar survival. Methods: We performed a retrospective cohort study comparing IO/IO vs IO/TKI therapy for pts with metastatic RCC. We used the Atropos health platform, which is a commercial platform and queried ASCO CancerLinq data for this study. We identified pts with kidney cancer who received IO/IO or IO/TKI combinations between 2019 and 2023. For our primary analysis, we included only pts with ICD10 code consistent with clear cell [cc]RCC, but also did a secondary analysis including all pts with kidney cancer. The IO/TKI pts received either avelumab/axitinib, pembrolizumab/axitinib, nivolumab/cabozantinib, pembrolizumab/lenvatinib, or atezolizumab/cabozantinib within two weeks of each other. The IO/IO pts were identified as pts receiving ipilimumab and nivolumab within 2 weeks of each other without interceding TKI. We conducted a survival analysis of time to death using Cox proportional hazards regression to compare the two groups. The analysis was performed under three different confounder adjustment scenarios: without adjustment, with basic matching on sex and age, and with high dimensional propensity score (hdPS) using inverse probability of treatment weighting. Results: A total of 584 pts (286 IO/IO and 296 IO/TKI) with kidney cancer and 146 with ccRCC (75 IO/IO and 71 IO/TKI) were included. Mean age was 63-65 years and 30-35% female sex across groups. Table shows the restricted mean survival time (RMST) and HR for the Cox models. In the ccRCC cohort, 20 pts with IO/IO and 7 with IO/TKI died with RMST of 947 and 1071 days, respectively (hdPS HR 0.35, p=0.03). In the RCC cohort, 76 pts with IO/IO vs 49 with IO/TKI died with RMST 1126 vs 1017 (hdPS HR 0.61, p=0.04). Conclusions: In this exploratory, hypothesis-generating analysis of CancerLinq data, pts treated with IO/TKI had longer OS vs those treated with IO/IO. Limitations include the retrospective nature of the study, low power, lack of randomization, and potential unmeasured confounding factors (e.g., confounding by indication). Further investigation and prospective validation are needed to confirm these findings. [Table: see text]
Imaging predictive biomarkers of response in patients with prostate cancer undergoing high-intensity focused ultrasound (HIFU) focal therapy.
Authors: Egesta Lopci, Giovanni Lughezzani, Vittorio Fasulo, Davide Maffei, Alberto Saita, Paolo Casale, Roberto Peschechera, Rodolfo Hurle, Alessio Benetti, Luisa Pasini, Silvia Zandegiacomo, Marcello Rodari, Roberta Zanca, Luca Balzarini, Giorgio Ferruccio Guazzoni, Nicolo' Buffi, Massimo Lazzeri
Journal: Journal of Clinical Oncology (2024)

288 Background: The current study is designed to evaluate the role of PSMA PET/CT for response prediction in prostate cancer (PCa) patients who are candidates for High-Intensity Focused Ultrasound (HIFU) focal therapy (FT). Methods: BetweenOctober 2020 and June 2023, overall 65 patients have been enrolled in our prospective, single-center study. Inclusion criteria were: PSA&lt;20ng/mL, radiological stage ≤T2bN0M0, ISUP grade 1-3, PSMA PET/CT at baseline and at response evaluation 6-12 months post-treatment. Follow up included: PSA at 3, 6 and 12 months. Post-treatment biopsies were scheduled per-protocol at 12 months or earlier if imaging suspicious. Biochemical response and treatment failure were correlated to mpMRI and PSMA PET data, comprising PI-RADS, Primary score, SUVmax, SUVratio, and their variations after HIFU FT. Results: Median age was 67 years (range 53-80), initial PSA (iPSA) was 6.56ng/mL (range 2.25-13.25) and prostate volume was 45mL (range 20-160). The majority of the patients presented with ISUP 1 (66%). mpMRI results were: 14 patients with PI-RADS 1-2 (21.5%) and 51 with PI-RADS 3-4. Baseline Primary scores were: 30 score 1-2 (45%), and 35 score 3-5. Median baseline SUVmax and SUVratio resulted 5.4 (range 1.5-33.2) and 1.43 (range 0.86-9.39), respectively. At 3 months post-HIFU, 23% of the patients obtained a PSA response ≥50%; whereas at 6 months and 12 months, PSA responses were 26% and 45%, respectively. Post-treatment PSMA PET/CT was available in 40 patients. Median SUVmax and SUVratio post-treatment resulted 3.4 (range 1.4-28.4) and 1.1 (range 0.64-10), respectively, with a median ΔSUVmax of 39% and ΔSUVratio of 42%. There was a moderate negative correlation between post-treatment SUVmax and SUVratio with PSA response at 12 months (rho=-0.504, p=0.0280, and rho=-0.521, p=0.0231, respectively), while a positive moderate correlation was confirmed for ΔSUVmax (rho=0.475, p=0.0383). PET parameters were also statistically significantly correlated to treatment failure at 12months (p=0.020, p=0.048 and p=0,04, respectively for SUVmax, SUVratio and Primary), with Primary scores confirmed as predictive on logistic regression (OR=10.5; 95%CI 1.12-98.9). Conclusions: PSMA PET/CT provides useful information for treatment monitoring in PCa patients undergoing HIFU FT. Baseline and post-treatment SUV parameters and Primary score can predict biochemical response and treatment failure at 12 months post-completion.