bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preliminary results of a phase Ib/II combination study of RC48-ADC, a novel humanized anti-HER2 antibody-drug conjugate (ADC) with toripalimab, a humanized IgG4 mAb against programmed death-1 (PD-1) in patients with locally advanced or metastatic urothelial carcinoma.
Authors: Sheng Xinan , Zhou Li , He Zhisong , Guo Hongqian , Yan Xieqiao , Li Siming , Xu Huayan , Li Juan , Chi Zhihong , Si Lu , Cui Chuanliang , Mao Lili , Lian Bin , Tang Bixia , Wang Xuan , Bai Xue , Guo Jun 
Published: June 2022

4518 Background: RC48-ADC has shown promising data in HER2-positive and even negative patients with metastatic urothelial carcinoma (mUC) who failed with platinum-based chemotherapy. RC48-ADC combined with anti-PD-1 antibody may have a synergistic antitumor effect. Methods: This is an open-label, multicenter, phase 1b/II trial to evaluate the safety and activity of RC48 combined with toripalimab in mUC. Patients received RC48-ADC at 1.5 or 2 mg/kg, in combination with 3mg/kg toripalimab every two weeks in a dose-escalation and expansion cohort until confirmed disease progression, unacceptable toxicity, or voluntary withdrawal. The key primary endpoint was safety; secondary endpoints included efficacy and tumor tissue biomarkers. Results: As of 17 Jan 2022 (data cutoff), 41 la/mUC pts (19 males; median age 66 y [42-76]) were enrolled since 20 Aug 2020. 61% patients were systemic treatment naïve, and 54% had visceral metastases (mets), including 24% with liver mets. The primary site was in upper tract UC in 54%. HER2 expression was positive (IHC 2+ or 3+) in 59% patients, and PD-L1 positive (CPS ≥ 10) in 32%. No dose-limiting toxicity was observed. The recommended dose was RC48-ADC 2mg/kg + toripalimab 3mg/kg every 2 weeks. With a median follow-up of 8.0 mos, 36 patients had at least one tumor assessment, the best ORR was 83.3%, and the confirmed ORR was 76.7% (95%CI: 57.7, 90.1), including 10% CR. The cORR was 82.4% for 1L previously untreated mUC patients, 100% for patients with HER2 IHC (2+ or 3+) & PD-L1 (+), 92.3% for HER2 (2+ or 3+) & PD-L1 (-), 50% for HER2 (0 or 1+) & PD-L1 (+), and 50% HER2 (0 or 1+) & PD-L1 (-). DCR was 96.7% (95%CI: 82.8, 99.9). The median PFS was immature and 9.2 mos (95%CI: 5.49, 10.32) by the time and the median OS was not reached. The most common treatment-related AEs were ALT/AST increase (65.9%), peripheral sensory neuropathy (58.5%), appetite decrease (56.1%), asthenia (56.1%), hypertriglyceridemia (48.8%). Grade ≥3 TRAEs included γ-glutamyl transferase increase (12.2%), ALT/AST increase (7.3%), asthenia (7.3%), hypertriglyceridemia (4.9%), and neutropenia (4.9%). 9 pts had irAEs (22.0%, 7.3% ≥ G3), including immune-related pneumonitis, hepatitis, and myositis. Conclusions: RC48-ADC in combination with toripalimab demonstrated promising efficacy in patients with mUC and a manageable safety profile. A randomized study of RC48-ADC and toripalimab vs. platinum-based chemotherapy in previously untreated la/mUC patients is ongoing. Clinical trial information: NCT04264936. [Table: see text]
Molecular profile and clinical outcomes of renal cell carcinoma brain metastases treated with stereotactic radiosurgery.
Authors: Ma Jennifer , del Balzo Luke , Khaleel Sari Safaa , Flynn Jessica , Zhang Zhigang , Voss Martin H , Freeman Benjamin , Hakimi A. Ari , Lee Chung-Han , Eichholz Jordan , Kelly Daniel W. , Yang Jonathan T. , Mueller Boris , Carlo Maria Isabel , Motzer Robert J. , Imber Brandon S. , Beal Kathryn , Moss Nelson S. , Kotecha Ritesh , Pike Luke Roy George 
Published: June 2022

4526 Background: Molecular profiles of renal cell carcinoma (RCC) tumors are associated with systemic treatment (ST) responses and clinical outcomes. However, the molecular profiles of RCC brain metastases (BM) and their correlation with ST response and clinical outcomes are not well characterized. Effective management of BM with locoregional therapies including stereotactic radiosurgery (SRS) is critical as ST advances have improved overall survival (OS). Therefore, we sought to identify the clinical and genomic features of RCC BM in a large cohort of patients treated with SRS. Methods: We performed an institutional retrospective analysis of RCC BM patients treated with SRS and evaluated corresponding genomic next generation sequencing (NGS) data via a targeted sequencing panel (MSK-IMPACT). A comparison cohort of all institutional patients with available NGS data was utilized to investigate genes enriched in our BM cohort using Fisher exact testing. Kaplan Meier analyses were performed for OS and intracranial progression-free survival (iPFS). Clinical factors and genes mutated in ≥ 10% of samples were assessed per patient using Cox proportional hazards models, and per individual BMs using clustered competing risks regression with a competing risk of death. Results: From 2010-2021, 91 RCC BM patients underwent SRS for 212 BMs, including 86% clear cell and 14% non-clear cell RCC. NGS data was available for 76 patients (84%), including 18 resected BMs, 26 extra-cranial metastatic lesions (EM), and 32 primary kidney tumors (Table 1). Median follow-up was 3.2 years with median OS of 21 months (m) and median iPFS of 7.8m. Karnofsky performance status ≥80 and extracranial disease control were significantly associated with improved OS on multivariable analyses (MVA; p=0.049 and 0.01, respectively). No clinical variables were significantly associated with iPFS on MVA. At the BM level, SETD2 alterations approached significance for improved iPFS (HR=0.35; 95%CI 0.11, 1.05; p=0.06). Enrichment in SMARCA4 alterations was seen in the BM cohort as compared to primary kidney and EM samples from patients without BM (17% vs 1% vs 2%, p<0.05). Conclusions: To our knowledge, this is the largest study investigating mutational profiles of RCC BM. SMARCA4 alterations were enriched in BM samples and a trend towards improved iPFS was seen in SETD2 variant BMs, warranting further investigation.[Table: see text]
Healthcare resource utilization (HCRU) and costs for patients (pts) with metastatic renal cell carcinoma (mRCC) receiving first-line (LOT1) pembrolizumab plus axitinib (P+A) or ipilimumab plus nivolumab (I+N).
Authors: Shah Neil J. , Shinde Reshma , Moore Kristin , Sainski-Nguyen Amy , Le Lisa , Cao Feng , Song Rui , Singhal Puneet , Motzer Robert J. 
Published: June 2022

4528 Background: Approval of immuno-oncology (IO) agents have changed treatment paradigm for mRCC pts. While IO-based therapies have demonstrated improved survival, these can be associated with considerable HCRU and costs necessitating their examination in real-world practice. Methods: This retrospective claims analyses utilizing Optum Research Database included adult pts with mRCC diagnosis from July-2017 to Aug-2020 and received P+A or I+N as LOT1 from Jan-2018 to May-2020 (first claim=index date). All eligible pts required continuous enrollment for minimum of 6-months prior and 3-months post the index date unless death occurred. All-cause HCRU counts, and associated costs were examined during the first 90 days (LOT1-90) and entire LOT1 duration and reported as overall and per-pt-per-month (PPPM) estimates. Results: The study identified 507 pts (P+A=126, I+N=381). Average age of the entire cohort was 67 years, 71% were male, mean NCI Charlson score was 2.4, and lung (55%) and bone (33%) were the most common metastatic sites. Mean (SD) distance from mRCC diagnosis to index date was 97 (172) days. Pts with P+A and I+N had similar baseline characteristics. Total % of pts with ambulatory visits was similar for P+A and I+N for LOT1-90 and entire LOT1 (99.2 vs. 100.0%, p=0.082 for both). During LOT1-90, we observed a lower % of pts on P+A with ER visits and inpatient (IP) stay compared to I+N (34 vs. 48, p=0.008; 19 vs. 38, p<0.001, respectively). We also observed a shorter mean (SD) IP stay for P+A vs. I+N during LOT1-90 (1.9 (6.5) vs. 5.6 (13.24) days, p<0.001). Similarly, P+A had lower mean PPPM ambulatory visits, IP stay, and ICU stay during both LOT1-90 and entire LOT1 (Table). In addition, mean PPPM total (medical + pharmacy) and mean PPPM medical costs were lower for P+A compared to I+N, but mean PPPM pharmacy costs were higher for P+A for both LOT1-90 and entire LOT-1 (Table). Conclusions: This study noted significantly higher HCRU with I+N including higher mean PPPM ambulatory visits, IP stays, and ICU stays compared to P+A. Although, P+A had higher mean PPPM pharmacy costs, the total medical plus pharmacy costs were significantly lower compared to I+N. [Table: see text]
Association between tumor burden and response to immunotherapy in patients with metastatic renal cell carcinoma.
Authors: Yasin Hesham Abdallah , Chen Yu-Wei , Tucker Matthew D , Beckermann Katy , Schaffer Kerry , Davis Nancy B. , McAlister Renee , Wallace Deborah , Kaiser Elizabeth , Rini Brian I. 
Published: June 2022

4541 Background: Immunotherapy (IO) has become the standard of care in patients with metastatic renal cell carcinoma (mRCC), yet clinical biomarkers of outcome remain elusive. Preclinical and clinical studies have demonstrated that a lower tumor volume burden is associated with better response to IO in melanoma and lung cancer. Methods: Retrospective chart review of mRCC patients treated with Immunotherapy/Immunotherapy or Immunotherapy/Tyrosine kinase inhibitors (TKI) combinations at Vanderbilt Ingram Cancer Center was conducted. Baseline target tumor lesions including primary kidney tumors and treatment response were assessed by RECIST 1.1 criteria. The association between baseline tumor burden and outcomes of interest [progression-free survival (PFS) and overall survival (OS)] were assessed with multivariable Cox regression model. Results: 79 patients with mRCC were included in the cohort. The median age was 64, 80% were male, 82% had clear cell histology, and 73% were IMDC intermediate/poor risk group. 53% received IO/IO and 39% received IO/TKI. 71% had prior nephrectomy and 14% had prior systemic therapy. The median baseline tumor burden was 87 mm (range: 16-363 mm). After adjusting for age, gender, histology, prior nephrectomy/systemic therapy and IMDC risk, baseline tumor burden was not associated with either PFS (p-value: 0.42) or OS (p-value: 0.99). At the initial follow-up scan (median time of 3.1 months from treatment initiation) 22 (28%) patients had an objective response and 41 (52%) patients had stable disease. Among patients with tumor shrinkage, every 10% decrease seen in the sum of the target lesions was associated with improved PFS (AHR: 0.77, 95%CI: 0.63-0.94, p-value:0.009) and OS (AHR: 0.62, 95%CI: 0.42-0.93, p-value:0.02). Conclusions: While baseline tumor burden volume was not associated with clinical outcome to immunotherapy-based therapy in patients with metastatic RCC; however, the degree of early tumor shrinkage was significantly associated with better outcomes. Large tumor burden does not preclude response and good outcome to immunotherapies.
A classification system for urothelial carcinoma (UC) defined by genomic drivers and the tumor microenvironment (TME) is predictive of immunotherapy response.
Authors: Chernyshov Konstantin , Miheecheva Natalia , Love Anna , Nomie Krystle , Fowler Nathan , Frenkel Felix 
Published: June 2022

4591 Background: UC is associated with high recurrence rates, progression, and resistance to platinum-based therapy. Checkpoint inhibitors (CPIs) are often used for treating UC, but predictive biomarkers that characterize response are lacking in the majority of patients. Defining the TME is essential to understanding patient response to CPIs. Employing a transcriptome-based classification platform, we sought to identify predictive and prognostic subtypes of UC using malignant cell and TME features. Methods: We collected a metacohort of 2,418 UC samples from 14 publicly available datasets, one of which had atezolizumab response data (IMvigor210). Using the methodology described in Bagaev et al. 2021, we selected 28 signatures composed of specific gene sets reflecting distinct cellular processes. Analysis of signature expression and unsupervised clustering was performed. Results: We identified 7 recurring novel UC subtypes (Table 1) with unique genomic and molecular characteristics. The subtypes and key findings include: an immune desert (D) subtype characterized by genomic instability high HER2 expression; an immune desert, FGFR-altered (D-FGFR) subtype with FGFR alterations; an immune enriched (IE) subtype with an enriched TME and high CPI response; a fibrotic (F) subtype with a mesenchymal TME, and strong TGFβ signaling; an immune enriched, fibrotic (IE-F) subtype with a mixed TME and a high CPI response rate; a fibrotic, basal (F-B) subtype with a mesenchymal TME and minimal genomic targets, and a neuroendocrine-like (NE-L) subtype with a high CPI response rate. Conclusions: UC can be classified into 7 subtypes with distinct prognoses, CPI response rates, and druggable targets using malignant cell and TME profiling. Patients with IE, IE-F, and NE-L UCs may be good candidates for CPIs. D UCs may benefit from HER2-i and PARP-i, while FGFR-i might be more suitable for D-FGFR UCs. TGFβi and PARPi may be effective for F UCs, but F-B UCs have no targetable findings. These findings warrant additional investigation for clinical translation. [Table: see text]
A phase 2 randomized study of oral docetaxel plus ritonavir (ModraDoc006/r) in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Vaishampayan Ulka N. , Keessen Marianne , Heath Elisabeth I. , Dreicer Robert , Buchler Tomas , Árkosy Péter Ferenc , Csoszi Tibor , Wiechno Pawel J. , Kholtobin Denis , Kopyltsov Evgeny , Shore Neal D. , Nosov Aleander , Orlov Sergey , Plekhanov Alexey , Smagina Maria , Varlamov Sergey , Vogelzang Nicholas J. 
Published: June 2022

5016 Background: Intravenous (IV) docetaxel and oral prednisone is a standard of care regimen in patients (pts) with mCRPC. ModraDoc006 is an oral formulation of docetaxel. To enhance bioavailability of ModraDoc006, it is co-administered with ritonavir (/r). The ModraDoc006 and ritonavir combination is active in multiple docetaxel and cabazitaxel-resistant prostate cancer cell-lines The oral combination (ModraDoc006/r) was compared to IV docetaxel in a randomized phase 2b study in pts with mCRPC evaluating two doses of ModraDoc006/r (30-20/200-100 mg and 20-20/200-100 mg). Data on outcomes in the larger cohort, receiving the lower dose, are being presented. Methods: Eligible pts had mCRPC, performance status of 0-1 and no prior chemotherapy for mCRPC. Sixty-two pts were enrolled in open label 1:1 randomized study comparing ModraDoc006/r 20-20 mg combined with 200-100 mg ritonavir in a bi-daily weekly schedule (“20-20/200-100 mg”), with IV docetaxel 75 mg/m2 in 21-day cycles. All pts received 5 mg oral prednisone twice daily. Primary endpoint was radiographic progression free survival (rPFS) per PCWG-3 criteria. Secondary objectives included ORR, PSA-PFS, time to skeletal related events, disease control rate, duration of response, and safety assessments. Results: 31 pts were enrolled on IV docetaxel 75 mg/m2 and 31 on ModraDoc006/r 20-20/200-100 mg. Of these, 57 were included in the analysis for rPFS, and 32 pts with measurable disease were included in the ORR analysis. Median PSA was 46 (range 1 to 1460 ng/ml). Prior therapy with enzalutamide in 8 pts, abiraterone in 10 pts. ModraDoc006/r was better tolerated with 0% all grades neutropenia and anemia, as compared to 26% (19% ≥G3) and 16% respectively on IV docetaxel. Neuropathy was significantly reduced at 9.7% G1 only on ModraDoc006/r vs 9.7% G1 and 19.4% G2 on IV docetaxel, whereas alopecia was reduced to 16.1% G1 and 6.5% G2 on ModraDoc006/r vs. 22.6% G1 and 19.4% G2 on IV docetaxel. GI toxicities were broadly comparable with diarrhea 32% (3% ≥G3) vs 29%, nausea 29% vs 13% and stomatitis 3% (G3) vs 13% (3% ≥G3), respectively. Conclusions: ModraDoc006/r demonstrated a favorable safety profile and comparable efficacy to IV docetaxel in pts with mCRPC, thus providing a compelling rationale for conduct of an expanded pivotal program. A key clinical program focus is the comparison of ModraDoc006/r to best available therapy in refractory mCRPC. Studies of ModraDoc006/r in other malignancies are also in active development. Clinical trial information: NCT04028388. [Table: see text]
Pathologic complete response (pCR) rates for HR+/HER2- breast cancer by molecular subtype in the I-SPY2 Trial.
Authors: Huppert Laura Ann , Rugo Hope S. , Pusztai Lajos , Mukhtar Rita A. , Chien Amy Jo , Yau Christina , Wolf Denise M. , Berry Donald A. , van 't Veer Laura , Yee Douglas , DeMichele Angela , Esserman Laura ,   I-SPY2 Consortium
Published: June 2022

504 Background: Hormone receptor positive (HR+), HER2- breast cancer (BC) is a heterogenous disease. We hypothesized that molecular subtypes capturing luminal, basal, and immune biology could predict response for patients (pts) with HR+/HER2- disease in the I-SPY2 trial. Methods: I-SPY2 trial is a phase II, randomized, adaptive study evaluating multiple investigational agents as neoadjuvant BC therapy; the primary endpoint is estimated pCR rate. Investigational agents are given with control weekly paclitaxel x 12, followed by AC x 4. Regimens graduate when the predicted pCR rate in any signature meets the pre-specified threshold of 85% probability of success in a hypothetical 300 pt randomized, phase 3 trial. We analyzed estimated pCR rates for the 1st 7 investigational agents in the HR+/HER- subset, analyzed by clinical/molecular features: BluePrint (BP) Luminal vs. Basal, Mammaprint High1 [MP1] vs. Mammaprint High2 [MP2], MP2 is < -0.57, Responsive Predictive Subtype-5 (RPS-5) (classification based on HR, HER2, immune, DNA-repair, and basal/luminal markers), histology, and stage/nodal status. Results: 38% (379/987) of pts had HR+/HER2- disease. Only pembrolizumab met the pre-specified graduation criteria for HR+/HER2- BC. pCR rates by treatment arm and molecular subtype are described in the Table. 28% were MP2; 72% were MP1. Overall, pCR rates were higher in pts with MP2 vs MP1 disease (30% vs 11%) including with pembrolizumab (55% vs. 21%). 29% were BP Basal, 71% were BP Luminal; BP Basal was more likely to be MP2 than BP Luminal (77% vs 8%). In all arms except MK2206, HR+/HER2- BP Basal pts were more likely to achieve pCR than BP Luminal pts. For MK2206, BP Luminal pts were more likely to achieve pCR. Immune+ by RPS-5 (39% of HR+/HER2-) predicted pCR to pembrolizumab irrespective of BP Basal or Luminal status (11 pCR/16 pts). Results by histology and stage/nodal status will also be reported. Conclusions: Our data suggest that MP2 and BP Basal signatures identify a subset of HR+/HER2- BC more likely to respond to neoadjuvant therapy; and that an immune signature can identify pts more likely to respond to pembrolizumab. These findings will aid in guiding prioritization of targeted agents with the goal to optimize pCR for all pts. Clinical trial information: NCT01042379. [Table: see text]
Survival analysis of the randomized phase II trial to investigate androgen signaling inhibitors with or without androgen deprivation therapy (ADT) for castration-sensitive prostate cancer: LACOG 0415.
Authors: Maluf Fernando Cotait , Soares Andrey , Bastos Diogo Assed , Schutz Fabio A. B. , Cronemberger Eduardo , Luz Murilo , Martins Suelen P. S. , Muniz David Queiroz Borges , Carcano Flavio Mavignier , Smaletz Oren , Peixoto Fábio A , Gomes Andrea J , Cruz Felipe Melo , Franke Fabio , Herchenhorn Daniel , Gidekel Rosemarie , Rebelatto Taiane Francieli , Gomes Rafaela , Souza Vinicius Carrera , Fay Andre P. 
Published: June 2022

5076 Background: LACOG 0415 is a phase II, open-label, clinical trial evaluating ADT-free alternatives for advanced castration sensitive prostate cancer (CSPC). Methods: Patients with locally advanced, high-risk biochemical recurrence or metastatic CSPC were randomized (1:1:1) to receive ADT with abiraterone acetate plus prednisone (ADT+AAP), apalutamide alone (APA), or apalutamide with AAP (APA+AAP). The primary endpoint of the trial was the proportion of patients who achieved PSA≤0.2 ng/mL level at week 25. Patients without disease-progression and with clinical benefit after week 25 were allowed to maintain treatment at the discretion of physicians. Herein, we presented the outcomes of 2 year-overall survival (2y-OS) and time-to-treatment failure (TTF). The time-to-event endpoint was estimated by Kaplan-Meier method and compared by stratified log-rank test. Results: 128 patients were randomized to the ADT+AAP (n = 42), APA (n = 42), and APA+AAP (n = 44) arms. At week 25, PSA≤0.2 ng/mL was observed in 75.6% (95%CI 59.7%-87.6%), 60.0% (95%CI 43.3%-75.1%), and 79.5% (95%CI 63.5%-90.7%) of patients in the ADT+AAP, APA, and APA+AAP arms, respectively. 110 patients continued treatment after week 25. At the 2-year visit, 80 (62.5%) patients remained on the study medication. Median TTF was 24.0 months (95%CI 23.3 - 24.0) with ADT+AAP, 24.0 months (95%CI not estimated) with APA, and 24.0 months (95%CI 13.0-24.0) with APA+AAP. The main reasons for treatment discontinuation were disease progression (n = 8, 6.3%), toxicity (n = 10, 7.8%), death (n = 6, 4.7%), withdrawal (n = 4, 3.1%), and other (n = 19, 14.8%). The estimated proportion of patients who were alive at 2 years (2y-OS rate) was 92.5% (95%CI 84.3-100) with ADT+AAP, 87.9% (95%CI 77.9-97.8) with APA, and 92.7% (95%CI 84.8-100) with APA+AAP (p = 0.5926). 2y-OS was 92.9% (95% CI 85.3 - 96.2) in patients with PSA ≤ 0.2 ng/mL at week 25, while 2y-OS was 85.0% (95% CI 72.9-97.1) in patients with PSA > 0.2 ng/mL at week 25 (p = 0.1250). Conclusions: Patients with advanced CSPC treated with ADT+AAP, APA, or APA+AAP had high rates of PSA response and favorable 2y-OS. PSA ≤ 0.2 ng/mL at week 25 seems to be a surrogate prognostic predictor of OS in advanced CSPC. In the overall sample, patients with PSA ≤ 0.2 ng/mL at week 25 had higher 2y-OS rate than those with PSA > 0.2 ng/mL at week 25 (92.9% vs. 85.0%), however without statistical significance. Clinical trial information: NCT02867020.