bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final prespecified overall survival (OS) analysis of CLEAR: 4-year follow-up of lenvatinib plus pembrolizumab (L+P) vs sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC).
Authors: Motzer Robert J. , Porta Camillo , Eto Masatoshi , Powles Thomas , Grünwald Viktor , Hutson Thomas E. , Alekseev Boris , Rha Sun Young , Merchan Jaime R. , Goh Jeffrey C. , Kapoor Anil , De Giorgi Ugo , Melichar Bohuslav , Hong Sung-Hoo , Gurney Howard , Rodriguez-Lopez Karla , He Cixin S. , Okpara Chinyere , McKenzie Jodi , Choueiri Toni K. 
Published: June 2023

4502 Background: In the phase 3 CLEAR trial, L+P showed clinically meaningful and statistically significant benefits in PFS (primary endpoint) and OS, and improved ORR compared with S in 1L aRCC (Motzer NEJM 2021). Here, we report 4-yr follow-up results from the final prespecified OS analysis of CLEAR (data cutoff: 31 Jul 2022). Methods: Treatment-naïve pts (n=1069) who had aRCC with a clear-cell component were randomized (1:1:1) to receive: L 20 mg PO QD + P 200 mg IV Q3W; or L 18 mg + everolimus 5 mg PO QD; or S 50 mg PO QD (4 wks on/2 wks off). Stratification factors were geographic region and MSKCC prognostic risk group. This final prespecified OS analysis was triggered by ~304 death events in 2 arms. OS, PFS, ORR, duration of response (DOR), and PFS on next-line therapy (PFS2) were assessed for L+P and S. PFS, ORR and DOR were assessed per independent review using RECIST v1.1. Nominal P-values are shown. Results: At a median follow-up (IQR) of 49.8 mos (41.4–53.1) for L+P and 49.4 mos (41.6–52.8) for S, 149 and 159 deaths had occurred, respectively. OS benefit with L+P vs S was maintained (HR, 95% CI; 0.79, 0.63–0.99). OS favored L+P vs S across MSKCC risk groups (HR, 95% CI; favorable [fav]: 0.89, 0.53–1.50; intermediate [int]: 0.81, 0.62–1.06; poor: 0.59, 0.31–1.12). PFS benefit of L+P vs S was maintained (HR, 95% CI; 0.47, 0.38–0.57). PFS favored L+P vs S across MSKCC risk groups (HR, 95% CI; fav: 0.46, 0.32–0.67; int: 0.51, 0.40–0.65; poor: 0.18, 0.08–0.42). ORR was greater with L+P (71.3%; complete response [CR], 18.3%) vs S (36.7%; CR, 4.8%) (relative risk, 95% CI; 1.94, 1.67–2.26). Less pts in the L+P arm (181/355, 51.0%) received subsequent anticancer therapies compared with the S arm (246/357, 68.9%); 56 (15.8%) and 195 (54.6%) received PD-1/PD-L1 checkpoint inhibitors, respectively. Analysis of OS adjusted for subsequent therapies will be presented. PFS2 was longer with L+P vs S (43.3 vs 25.9 mos; HR, 95% CI; 0.63, 0.51–0.77). Grade ≥3 treatment-related adverse events occurred in 74.1% and 60.3% pts in the L+P and S arms, respectively. Conclusions: L+P continues to demonstrate clinically meaningful benefit vs S in OS, PFS, ORR, and CR in the 1L treatment of pts with aRCC at 4-yr follow-up, thus supporting the robustness of the primary analysis data from CLEAR. Clinical trial information: NCT02811861 .[Table: see text]
Overall survival (OS) by response to first-line (1L) induction treatment with atezolizumab (atezo) + platinum/gemcitabine (plt/gem) vs placebo + plt/gem in patients (pts) with metastatic urothelial carcinoma (mUC): Updated data from the IMvigor130 OS final analysis.
Authors: Grande Enrique , Bamias Aristotelis , Galsky Matt D. , Kikuchi Eiji , Davis Ian D. , Arranz José A. , Rezazadeh Arash , Garcia del Muro Xavier , Park Se Hoon , De Giorgi Ugo , Alekseev Boris , Mencinger Marina , Izumi Kouji , Puente Javier , Li Jian-Ri , Lee Chooi , Bernhard Sandrine , Nicholas Alan , Telliez Julie , De Santis Maria 
Published: June 2023

4503 Background: For pts without disease progression during 1L plt-based chemotherapy (chemo), maintenance immunotherapy is a new mUC treatment option. IMvigor130 was a global, randomized Phase III study evaluating 1L atezo + plt/gem (Arm A) vs atezo monotherapy (Arm B) and placebo + plt/gem (Arm C) in patients with mUC (Galsky Lancet 2020). The final analysis showed that improved OS in Arm A vs Arm C of the intention-to-treat (ITT) population did not reach statistical significance (Galsky ASCO GU 2023). Here we report a post hoc analysis examining OS outcomes by response during atezo/placebo + chemo “induction” based on the final OS analysis. Methods: For Arms A and C, per protocol, investigators pre-specified the type of chemo pts received (gem + either cisplatin [cis] or carboplatin [carbo]), which was also a randomization stratification factor. Pts without progressive disease (PD) were allowed to continue atezo or placebo after 4 to 6 cycles of plt/gem. This post hoc analysis evaluated post-induction (Wk 18) OS in pts who completed 4 to 6 cycles of chemo followed by ≥1 dose of atezo or placebo and who had a best response of at least stable disease (SD) without PD at any time (up to and including Wk 18 tumor assessment). Post-progression OS was evaluated in pts who had PD at any time (up to and including Wk 18 tumor assessment). OS analyses by type of chemo were also performed. Multivariable Cox proportional hazards models were used, with HRs adjusted for known prognostic factors (and response for non-PD pts) and stratified by enrollment stage. Results: The time from last pt randomized to the data cutoff (Aug 31, 2022) was 49 mo (overall ITT population). OS improvements favoring Arm A vs C appeared greater for pts treated with cis than with carbo. In the cis subgroup, OS rates at 36 mo were 47% (Arm A) and 34% (Arm C) for pts who achieved at least SD during induction. Additional efficacy data are shown. Conclusions: In this post hoc analysis, the initial response to induction therapy did not seem to impact OS outcomes. Consistent with prior analyses, these data suggest that cis-treated pts may derive a greater benefit from the addition of atezo than carbo-treated pts. Clinical trial information: NCT02807636 . [Table: see text]
Erdafitinib (ERDA) vs ERDA plus cetrelimab (ERDA+CET) for patients (pts) with metastatic urothelial carcinoma (mUC) and fibroblast growth factor receptor alterations (FGFRa): Final results from the phase 2 Norse study.
Authors: Siefker-Radtke Arlene O. , Powles Thomas , Moreno Victor , Kang Taek Won , Cicin Irfan , Girvin Angela , Akapame Sydney , Triantos Spyros , O'Hagan Anne , Zhu Wei , Tammaro Meggan , Loriot Yohann 
Published: June 2023

4504 Background: First-line (1L) therapy for cisplatin (cis)-ineligible pts with mUC remains an unmet need and includes alternative chemotherapy or anti-PD-(L)1 monotherapy for PD-L1 positive tumors. FGFRa tumors are enriched for the luminal 1 subtype with lower immune cell infiltrate and potential lower benefit from anti-PD-(L)1 monotherapy. We studied ERDA+CET in 1L, FGFRa, mUC to determine the potential impact in this setting (NCT03473743). Methods: Pts aged ≥ 18 y with mUC, susceptible FGFRa and measurable disease (no prior systemic therapy for mUC, cis-ineligible) were randomized 1:1 to once-daily ERDA 8 mg (with pharmacodynamically guided uptitration (UpT) to 9 mg) or ERDA 8 mg (no UpT) + IV CET 240 mg every 2 weeks (wks) at cycles 1-4 and 480 mg every 4 wks thereafter. Primary endpoints were investigator-assessed overall response rate (ORR) per RECIST 1.1 and safety; secondary included duration of response (DOR), time to response (TTR), progression free survival (PFS) and overall survival (OS). There were no pre-planned statistical comparisons between treatment arms. Results: As of the data cutoff, 87 pts were randomized and treated; 44 to ERDA+CET and 43 to ERDA: median age was 69 vs 72 y; visceral metastases were present in 60.0 vs 63.6%. Median follow-up time was 14.2 months (mo). ORR for ERDA+CET was 54.5% with 6 (13.6%) CRs and 12 mo OS 68%. 11/24 responders were ongoing. ORR for ERDA was 44.2% with 1 CR and 12 mo OS 56%. 9/19 responders were ongoing. 4 pts in each arm were PD-L1 positive. 3/4 (75%) PD-L1 positive pts responded to ERDA+CET vs 0 for ERDA. The most frequent treatment-emergent AEs (any grade) were hyperphosphatemia (68.9 vs 83.7%), stomatitis (59.1 vs 72.1%) and diarrhea (45.5 vs 48.8%) for ERDA+CET and ERDA respectively. Grade ≥3 treatment-related AEs occurred in 45.5 (ERDA+CET) and 46.5% (ERDA) of pts. There was one CET-related death in ERDA+CET secondary to pulmonary failure. Conclusions: Combination ERDA+CET demonstrated clinically meaningful activity and was well tolerated. These results, in 1L cis-ineligible pts, support previously described activity of ERDA monotherapy in FGFRa mUC. The safety profile was consistent with the known profile for ERDA and CET with no additive toxicity for the combination. Clinical trial information: NCT03473743 . [Table: see text]
Adjuvant nivolumab plus ipilimumab vs placebo for patients with localized renal cell carcinoma at high risk of relapse after nephrectomy: Subgroup analyses from the phase 3 CheckMate 914 (part A) trial.
Authors: Motzer Robert J. , Russo Paul , Grünwald Viktor , Tomita Yoshihiko , Barthélémy Philippe , Goh Jeffrey C. , Cutuli Hernán Javier , Simsek Burcin , Spiridigliozzi Julia , Chudnovsky Aleksander , Bex Axel 
Published: June 2023

4506 Background: In part A of the CheckMate 914 trial, adjuvant nivolumab plus ipilimumab (NIVO+IPI) did not improve disease-free survival (DFS) vs placebo (PBO) in patients (pts) with localized renal cell carcinoma (RCC) at high risk of post-nephrectomy relapse (Motzer RJ, et al. Lancet 2023). Exploratory analyses were conducted to better understand outcomes in key pt subsets and with early NIVO+IPI discontinuation. Methods: Key study inclusion criteria were radical/partial nephrectomy with negative margins > 4 and ≤ 12 weeks before randomization; predominant clear cell histology; pathological TNM stage T2a (grade [G] 3/4) N0M0, T2b-T4 (any G) N0M0, or any pT (any G) N1M0; and no evidence of residual disease/metastases. Pts in part A were randomized 1:1 to NIVO 240 mg Q2W (× 12) + IPI 1 mg/kg Q6W (× 4) or equivalent PBO for 24 weeks or until recurrence/unacceptable toxicity. Primary endpoint is DFS per blinded independent central review. Exploratory analyses assessed DFS by key subsets including Fuhrman grade, sarcomatoid features (yes/no), PD-L1 expression, and NIVO+IPI exposure (≤ 6 cycles [1–2 IPI doses] vs > 6 cycles [3–4 IPI doses]). Safety was assessed by exposure. Results: 816 pts were randomized to adjuvant NIVO+IPI (N = 405) or PBO (N = 411). At 37.0 months median follow-up (min, 15.4 months), subset analyses suggested a DFS benefit for NIVO+IPI vs PBO in pts with Fuhrman grade 4 or sarcomatoid features. DFS by PD-L1 expression will be reported in the presentation. Pts who received > 6 NIVO+IPI cycles trended toward improved DFS vs pts receiving ≤ 6 NIVO+IPI cycles. Of the 102 pts who received ≤ 6 NIVO+IPI cycles, 3% had sarcomatoid features, and 20% had Fuhrman grade 4; treatment discontinuation in these pts was due to study drug toxicity (75%), unrelated adverse events (AEs; 6%), pt request (5%), recurrence (4%), consent withdrawal/non-compliance (4%), or other (6%), and most pts receiving ≤ 6 NIVO+IPI cycles were discontinued without initial dose delay (NIVO, 84%; IPI, 89%). In the group of patients who received ≤ 6 NIVO+IPI cycles, grade 1–2 all-cause AEs were reported in 35% of pts (grade ≥ 3, 63%) and 31% of pts discontinued treatment due to grade 1–2 all-cause AEs (grade ≥ 3, 44%). Conclusions: Exploratory analyses suggest that tumor grade and sarcomatoid features influence outcomes with adjuvant NIVO+IPI. Limited NIVO+IPI exposure (≤ 6 cycles) and discontinuation for low-grade AEs may have contributed to the lack of DFS benefit observed in CheckMate 914 part A. Clinical trial information: NCT03138512 . [Table: see text]
Impact of histology on the efficacy and safety of pembrolizumab (pembro) monotherapy for advanced urothelial carcinoma (UC) in the phase 3 KEYNOTE-045 and KEYNOTE-361 trials.
Authors: Giannatempo Patrizia , Machiels Jean-Pascal H. , Sassa Naoto , Arranz Arija Jose Angel , Fujii Yasuhisa , Su Wen-Pin , Keam Bhumsuk , Culine Stephane , Shen Ying-Chun , Muñoz-Langa José , Sarid David Leonid , Aarts Maureen J.B. , Calabro Fabio , Rosenbaum Eli , Goldman Olesya , Homet Moreno Blanca , Bavle Abhishek Amar , Xu Jin Zhi , Rha Sun Young 
Published: June 2023

4512 Background: For patients (pts) with advanced UC, pembro monotherapy has shown antitumor activity as first-line (1L) therapy in the phase 3 KEYNOTE-361 (NCT02853305) study of pembro ± platinum-based chemotherapy (chemo) vs platinum-based chemo and as second-line therapy in the phase 3 KEYNOTE-045 (NCT02256436) study of pembro vs investigator’s choice chemo. This exploratory analysis evaluated efficacy and safety of pembro monotherapy by UC histology in KEYNOTE-361 and KEYNOTE-045. Methods: KEYNOTE-361 enrolled pts with advanced UC and no prior systemic therapy; KEYNOTE-045 enrolled pts with advanced UC whose disease progressed or relapsed after 1L platinum-based chemo. Pure transitional cell (TC) and mixed predominant TC histology, as assessed by investigator, were allowed. Pembro monotherapy was given at a dose of 200 mg IV Q3W for up to 2 y or until disease progression, unacceptable toxicity, or withdrawal of consent in both studies. End points for this exploratory analysis were ORR, DOR, and PFS per RECIST v1.1 by central radiology assessment, and OS and safety in pts with pure TC or mixed predominant TC allocated to receive pembro monotherapy. Results: A total of 307 randomly assigned pts (280 [91.2%] pure TC histology; 27 [8.8%] mixed predominant TC histology) from KEYNOTE-361 and 268 pts (186 [69.4%] pure TC histology; 82 [30.6%] mixed predominant TC histology) from KEYNOTE-045 were included. Median follow-up for both studies was ≥32 mo. PFS, ORR, DOR, and OS for pembro were generally similar in pts with mixed predominant TC histology and pts with pure TC histology. In treated pts, grade 3-5 treatment-related AEs occurred at similar rates in KEYNOTE-361 (17.3% [48/277] pure TC; 18.5% [5/27] mixed predominant TC) and KEYNOTE-045 (16.9% [31/183] pure TC; 17.3% [14/81] mixed predominant TC). Conclusions: The observed clinical activity and safety profile of pembro monotherapy was generally consistent irrespective of histology in pts with UC in the KEYNOTE-361 and KEYNOTE-045 studies. Small sample size in some subgroups and limited data available to classify histology subgroups were limitations of this exploratory analysis. Clinical trial information: NCT02256436; NCT02853305 . [Table: see text]
Estimated net benefit of avelumab (AVE) + best supportive care (BSC) vs BSC alone for patients (pts) with advanced urothelial carcinoma (aUC) using a quality-adjusted time without cancer symptoms or toxicity (Q-TWiST) analysis.
Authors: Powles Thomas , Cislo Paul , Kirker Melissa , Chang Jane , Gharibian Norbek , Thompson Allison , Costa Nuno , Grivas Petros 
Published: June 2023

4515 Background: The JAVELIN Bladder 100 (JB-100) trial (NCT02603432) showed that treatment with AVE first-line maintenance (1LM) + BSC significantly prolonged overall survival (OS) and progression-free survival (PFS) vs BSC alone in pts with aUC that had not progressed after 1L platinum-based chemotherapy. Safety and patient-reported outcomes (PROs) were previously reported. This post hoc analysis used JB-100 data to assess between-treatment differences using a Q-TWiST analysis, an integrated measure that incorporates efficacy, safety, and PROs into a single value. Methods: Mean OS was partitioned into 3 health states: time with all-cause grade ≥3 toxicity (TOX) prior to progression, time without all-cause grade ≥3 toxicity or symptoms of disease progression (TWiST), and time after progression or relapse (REL). To ensure equal observation time for each arm, analysis time was restricted to a period of 47.7 months from randomization, which was the shorter follow-up time between arms. A range of utility values were explored and weighted by the time in each health state then summed to estimate Q-TWiST to account for differences in quality of life. Mean between-treatment differences for each health state were also calculated. Bootstrap methods were used to estimate CIs for means and difference between means. Results: Time in TOX was slightly longer with AVE + BSC vs BSC alone; however, time spent in TWiST was much longer with AVE + BSC. Time in REL with AVE + BSC appears shorter vs BSC alone because pts experienced more time in the progression-free state, which led to less time in REL. Regardless of the range of utility values explored for each health state, the Q-TWIST estimate was always longer with AVE + BSC, with mean differences ranging from 3.7 to 7.1 months (95% CI not including 1). Conclusions: Pts receiving AVE + BSC demonstrated a consistently longer Q-TWiST (vs BSC alone), indicating a net benefit. Pts receiving AVE + BSC achieved greater quality-adjusted time by progressing more slowly (shorter REL) and living longer (greater OS). The Q-TWiST advantage reflects the safety profile of AVE in the context of a survival benefit. Restricted health state durations in months (mean, 95% CI). Clinical trial information: NCT02603432 . [Table: see text]
Biomarker-driven prospective clinical trial in renal cell carcinoma: Developing machine learning models to allocate patients to treatment arms using RNA sequencing.
Authors: Reddy Anupama , Haake Scott Mattox , Beckermann Katy , Nesta Alex , Derti Adnan , Rathmell Wendy Kimryn , Nirmala Nanguneri , Rini Brian I. 
Published: June 2023

4525 Background: RNA sequencing has shown promise in defining the biology of individual renal cell carcinoma (RCC) tumors. However, these biomarkers have not yet been translated to the clinic for prospectively assigning optimal treatments to patients. Challenges for RNA-seq biomarker development include translating classifiers across different assays/platforms, normalization of data collected from single patients in the clinic and establishing robust thresholds for assigning prediction groups. We have designed the prospective phase II OPTIC RCC clinical trial (clinicaltrials.gov NCT05361720) to test the utility of an RNA-seq based biomarker in predicting treatment based on biologic drivers relevant to angiogenesis (anti-angiogenesis; TKI) and immune microenvironment (immunotherapy; IO). Here, we will describe the development and optimization of a machine learning model for assigning individual patients to biologically driven clusters in real time to facilitate RNA-seq based biomarker trials. Methods: We have utilized RNA-seq data from the IMmotion 151 trial (ref) to develop a machine learning model. Clusters were grouped into three based on their association to tumor biology and treatment: (1) Cluster 1+2 (angiogenic signature → TKI+IO therapy), (2) Cluster 4+5 (immune/proliferative signature → dual IO therapy), (3) Cluster 3+6 (neither signature → exclude). Random forest classifier was used to train a multi-class model to predict the three groups. The model is evaluated using bootstrapped cross-validation. Results: Our machine learning classifier was built using 188 genes and has a cross-validation accuracy of 85% and sensitivity of >90% in predicting patients into one of the three biological clusters from our training data. Predictions of the classifier are significantly associated with progression-free survival across different treatments within each of the predicted groups. We also observed significant odds ratios when comparing responders (CR/PR/SD) to non-responders (PD) across the treatment groups. The model was then validated in two independent test sets treated with Angio and IO inhibitors: (1) 61 patient renal cell carcinoma cohort (2) 12 patient clear cell renal cell carcinoma cohort. We observed a significant enrichment of responders to Angio+IO treatment for the predicted Cluster_Angio patients compared to IO treatment (p=0.05), highlighting the importance of matching patients to their optimal treatment. Conclusions: We have developed an accurate machine learning model to assign individual patients to RNA-seq clusters in real time. This classifier will facilitate the prospective OPTIC RCC trial. If successful, our biomarker strategy will serve as a proof of concept for selecting optimal treatments for RCC patients.
Effect on outcomes of toxicity-related dose reduction in TKI monotherapy or TKI-IO combination therapy for advanced renal cell carcinoma.
Authors: Nuvola Giacomo , Marmolejo Castañeda David Humberto , Mollica Veronica , Santoni Matteo , Navarro Garces Victor , González Macarena , Morales-Barrera Rafael , Carles Joan , Massari Francesco , Suárez Cristina 
Published: June 2023

4528 Background: Tyrosine kinase inhibitors (TKI) in monotherapy or TKI in combination with immunotherapeutic agents (IO) are standard of care fist-line treatment for advanced or metastatic renal cell carcinoma (RCC). Dose reduction due to toxicity is extremely frequently and represents an important clinical management issue, with frequent dose reduction, treatment suspension and change of schedule. We examined the outcomes of patient treated with TKI in monotherapy and in combination with immunotherapy (TKI-IO). Methods: We performed a retrospective analysis of clinical outcomes in patients with RCC treated with TKI (cohort 1) or TKI-IO (cohort 2) in Italian and Spanish institutions. A descriptive analysis was performed. Univariate logistic regression models were carried out to estimate the association between best response (CR or PR vs SD or PD) and type of TKI (monotherapy or combination therapy). Survival curves were estimated using the Kaplan-Meier method and were compared by the log-rank test. Cox proportional-hazard models were used to obtain hazard ratios (HRs) with 95%. Median follow-up was calculated using the reverse Kaplan-Meier method. Results: A total of 401 patients were divided in cohort 1 (329 patients) and cohort 2 (72 patients). Median Follow-up was 81.22 months in cohort 1 and 19.02 months in cohort 2. Most frequent toxicities that lead to dose reduction were mucositis (20.13%), Asthenia (16.88%) and Hand-foot syndrome (15.58%). Overall Response Rate was higher in patients that reduced dose, both in cohort 1 (48% vs 29%, p<0.01) and cohort 2 (81% vs 40%, p<0.01). In cohort 1 Progression Free Survival (PFS) was longer in patients with dose reduction (27.14 months vs 16.59 months) (HR 0.77 [0.6; 0.98]; p=0.04). Overall Survival (OS) was also improved (55 months vs 34.17) (HR 0.71 [0.53; 0.93]; p=0.01). In cohort 2, both PFS (39.13 months vs 41.3 months) (HR 0.63 [0.27; 1.48]; p=0.29) and OS (39.13 months vs 55.85 months) (HR 0.65 [0.26; 1.63]; p=0.29) did not statistically differ between patients that reduced dose and patients that did not reduce dose. Conclusions: TKI dose reduction due to toxicity seems to be related to improved outcomes, both in ORR and PFS/OS. ORR was statistically improved in both cohort 1 and cohort 2. PFS and OS in cohort 1 favoured patients that experienced dose reduction. PFS and OS in cohort 2 did not show a statistically significant difference, probably due to the short follow-up and small number of patients. However, outcomes seem to show a trend toward favouring patients that reduce dose.