bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized phase 2 study of nab-paclitaxel and gemcitabine with or without tocilizumab as first-line treatment in patients with advanced pancreatic cancer (PACTO).
Authors: Chen Inna Markovna , Johansen Julia S. , Theile Susann , Madsen Kasper , Dajani Olav , Lorentzen Torben , Zimmers Teresa , Nielsen Dorte
Published: June 2023

4147

Background: Pancreatic cancer (PC) presents one of the most aggressive malignancies for which currently available treatments are modestly effective. We report the findings of a randomized phase 2 trial (NCT02767557) to test the efficacy of gemcitabine/nab-paclitaxel (gem/nab) with or without tocilizumab (toc), as first-line treatment in patients with locally advanced or metastatic PC. Methods: Prior to randomization, a safety cohort of 6 participants received gem 1000 mg/m2, nab 125 mg/m2 (days 1, 8, and 15 of each 28-day cycle) and toc 8 mg/kg (day 1 of each cycle). Participants were then randomized 1:1 to receive gem/nab or gem/nab/toc. Patients had modified Glasgow Prognostic Score of 1 or 2 and were stratified by performance status (PS) and stage. The primary endpoint was the overall survival (OS) rate at 6 months (OS6). Secondary end points included median progression-free survival (PFS), median OS, overall response rate (ORR), and safety. Results: A total of 147 patients were treated; 141 were randomized to receive gem/nab/toc (n = 70), or gem/nab (n = 71). As of January 9, 2023, the median follow-up was 8.1 months (IQR 4.2–13.9). OS6 was 68.6 % (95% CI, 56.3-78.1) in gem/nab/toc group and 62.0% (95% CI, 49.6-72.1) in gem/nab group (p = 0.41). No significant differences in the median OS or PFS were observed between the gem/nab/toc group and the gem/nab group (OS, 8.4 versus 8.0 months; HR, 0.75; 95% CI, 0.54-1.05; p = 0.10), and (PFS, 5.6 versus 5.5 months; HR, 0.85; 95% CI, 0.61-1.20; p = 0.36). The 12, 18 and 24-month OS rates were 37.1% (95% CI, 26.0%-48.3%), 27.1% (17.4%-37.8%), 10% (4.4%-18.3%) for gem/nab/toc and 28.2% (18.3%-38.9%), 7.0% (2.6%-14.5%), 2.8% (0.5%-8.8%) for gem/nab, respectively. The ORR was 37.1% (95% CI, 25.9%-49.5%) in gem/nab/toc group and 35.2% (24.2%-47.5%) in gem/nab group. The incidence of grade 3 or higher treatment related adverse events was 88.2% in gem/nab/toc and 63.4% in gem/nab group (p < 0.001). Of those, neutropenia (55.3% versus 16.9%), and thrombocytopenia (40.8% versus 11.3%) were most common. Two and one treatment-related deaths, respectively, in gem/nab/toc and gem/nab group, occurred during the study. Conclusions: In patients with advanced PC, the addition of tocilizumab to gem/nab did not result in improved OS rate at 6 months. Although more patients were alive at 18 months in the gem/nab/toc, long-term survival rates exceeding 24 months were not different between groups. The biomarkers for selection of patients who might benefit from gem/nab combined with tocilizumab are to be identified. Clinical trial information: NCT02767557 .
Validation of the PDACai signature in predicting relative benefit from frontline FOLFIRINOX (FFX) and gemcitabine/nab-paclitaxel (GA) for patients (pts) with metastatic pancreatic cancer (mPDAC).
Authors: Pishvaian Michael J. , Blais Edik Matthew , Thach Dzung , Brody Jonathan Robert , Matrisian Lynn McCormick , Halverson David Charles , DeArbeloa Patricia , Rocha Flavio G , Hendifar Andrew Eugene , Petricoin Emanuel
Published: June 2023

4149

Background: Nearly 50% of pts with mPDAC never receive a 2nd line of therapy for metastatic disease following frontline FFX or GA. Genomic alterations in the DDR pathway (e.g. BRCA1/2) are associated with increased progression-free survival (PFS) on platinum-containing regimens (e.g. FFX), but other biomarker-treatment associations that predict benefit from GA and/or FFX in mPDAC remain unexplored. In this retrospective real-world evidence (RWE) study, we use a data-driven machine learning approach to gain new insights from the mutational landscape in mPDAC and validate the PDACai signature in predicting personalized benefit from both FFX and GA. Methods: We analyzed real-world outcomes from 711 pts with mPDAC who underwent genomic profiling via the Know Your Tumor program or were referred to Perthera by treating oncologists. Chart-abstracted PFS data on either 1st line FFX or GA were split (60:40) into independent training and validation cohorts for each regimen. All models integrate a shared set of clinical (age < 63, sex) and lab-agnostic molecular features derived from clinical NGS testing reports (DDR pathway alterations, specific KRAS variants, frequently mutated genes). Relative benefit scores predicted by FFX or GA models were evenly binned into three PDACai signature categories representing lower, middle, and upper tertiles for each independent cohort. Statistical differences in median PFS were evaluated using ordinal Cox regression. Results: Median PFS followed predicted trends as generated by PDACai for each therapy in training and validation cohorts. The predictive utility of PDACai was confirmed in the independent validation cohorts when comparing PFS on FFX (p = 0.03744; HR = 0.75 [95% CI: 0.58-0.98]) and GA (p = 0.00006861; HR = 0.65 [95% CI: 0.53-0.8]) across tertiles. Conclusions: Response to chemotherapy is heterogeneous and difficult to predict in pts with mPDAC. Using RWE, the PDACai signature successfully predicted relative differences in PFS on both FFX and GA in mPDAC. With prospective validation, personalized insights generated by PDACai from pts with similar biomarker profiles could be used to tailor treatment sequencing in pts with NGS testing results, particularly those without actionable genomic findings. [Table: see text]
Tandem duplicator phenotype: A novel targetable subgroup in pancreatic cancer?
Authors: Farooq Abdul Rehman , Zhang Amy , O'Kane Grainne M. , Denroche Robert Edward , Jang Gun Ho , Fischer Sandra , Dodd Anna , Holter Spring , Wilson Julie , Grant Robert C. , Aung Kyaw Lwin , Zogopoulos George , Elimova Elena , Prince Rebecca M. , Jang Raymond Woo-Jun , Biagi James Joseph , Notta Faiyaz , Gallinger Steven , Knox Jennifer J. , Tsang Erica S
Published: June 2023

4161

Background: Validated biomarkers are urgently needed to provide a more precise approach in pancreatic cancer (PDAC). Homologous recombination deficiency (HRD) is a heterogenous cohort in PDAC and predicts platinum and PARP inhibitor sensitivity. The BRCA-1 genotype associates with distinct tandem duplications (TDs), however non-BRCA 1 TD phenotypes (TDP) have been observed across tumour types and may be associated with perturbations in CDK12, FBXW17, and CCNE1. Here, we characterize the prevalence and outcomes of TDP in a large series of prospectively sequenced PDAC. Methods: Whole-genome sequencing was performed in 191 early stage resected and 275 advanced PDAC cases in the PanCuRx initiative and the COMPASS trial at the Ontario Institute for Cancer Research and Princess Margaret Cancer Centre. Tumors underwent laser capture enrichment prior to sequencing. TD scores were calculated as previously described by Menghi et al, and HRDetect scores assigned. Samples were classified as classical or basal-like by Moffitt. Outcomes of patients with TDP tumors were evaluated. Tumors that are nonHRD and nonTDP are referred to as typicals. Results: Of 466 cases, 46 were identified as TDP (9.9%; 17 resected, 29 advanced). Subgroups of TDP by etiology included BRCA1 (n=8; 6 germline, 2 somatic), somatic CCNE1 (n=1), and unknown (n=37; no identified alterations in TDP-related genes). Pathogenic germline variants were not found in unique genes other than BRCA1. HRD TDP was associated with a significantly smaller TD size compared to nonHRD TDP (median 12 kb vs. 125 kb, p<0.0001) and median TD load of 114. NonHRD TDP genomes exhibited elevated TD load (median 70 vs. 13, p<0.0001) and HRDetect scores (p<0.0001) compared with typicals. NonHRD TDP was not prognostic in resected PDAC disease (p=0.6361) compared with typicals. We observed a trend towards improved response to 1st-line platinum therapy in nonHRD TDP vs. typicals (p=0.066) for patients with advanced disease. When stratified for only ‘classical’ RNA subtype cases as per Moffitt classification (HRD TDP:2 basal-like, 8 classical, 1 unknown; nonHRD TDP: 9 basal-like, 25 classical, 1 unknown), platinum therapy was correlated with better response in non-HRD TDP vs. typicals (n= 10, 70% ORR, p=0.0108) highlighting the chemoresistance of the basal-like subgroup. Superior survival was not observed in this small cohort. Conclusions: In PDAC, the etiology of nonHRD TDP is unclear but may represent a potential marker for platinum and DNA damage response agents. Further investigation is warranted with a larger sample size.
Minimally invasive versus open distal pancreatectomy for resectable pancreatic cancer (DIPLOMA): An international randomised trial.
Authors: Abu Hilal Mohammed , Korrel Maarten , Jones Leia , van Hilst Jony , Björnsson Bergthor , Boggi Ugo , Bratlie Svein Olav , Butturini Giovanni , Casadei Riccardo , Edwin Bjørn E. , Esposito Alessandro , Falconi Massimo , Groot Koerkamp Bas , Keck Tobias , de Kleine Ruben , Kokkola Arto , Lips Daan , Luyer Misha , Zerbi Alessandro , Besselink Marc G.
Published: June 2023

4163

Background: In the absence of randomised trials, the oncological safety of minimally invasive distal pancreatectomy (MIDP) in patients with pancreatic cancer continues to be a matter of debate. Methods: An international randomised non-inferiority trial including patients with resectable pancreatic cancer from 35 centres in 12 countries. Patients were randomly assigned to either MIDP (laparoscopic or robotic) or open distal pancreatectomy (ODP). Both patients and pathologists were blinded to the assigned approach. Primary endpoint was radical resection (R0, <1mm free margin) in patients who had ultimately undergone resection. Analyses for the primary endpoint were by modified intention-to-treat, excluding patients who did not undergo a resection. The pre-defined non-inferiority margin was set at -7%. Results: Between May 8, 2018 and May 7, 2021, 258 patients were randomly assigned to MIDP (131 patients) or ODP (127 patients). The modified intention-to-treat population included 117 patients in the MIDP group and 114 patients in the ODP group. An R0 resection occurred in 83 (73%) patients in the MIDP group and in 76 (69%) patients in the ODP group (difference 4%, 90% CI -6 to 14%; p=0.039). Median lymph node yield was comparable (22.0 [16.0-30.0] vs 23.0 [14.0-32.0] nodes, p=0.86), as was the rate of intraperitoneal recurrence (41% vs 38%, p=0.45). Other postoperative outcomes were comparable. Conclusions: In this trial, the rate of radical resection following MIDP was non-inferior compared to ODP. This confirms the oncological validity of the minimally invasive approach in patients with resectable pancreatic cancer. Clinical trial information: ISRCTN44897265 .
Incidence, epidemiological characteristics, and cause-specific survival analysis of ampullary carcinoma using the SEER database.
Authors: Gor Rajvi , Gwalani Pranav , Gor Dhairya , Gwalani Twinkle , Narvel Hiba , Vegivinti Charan Thej Reddy , Desai Sudhamsh , Vikash Fnu , Vikash Sindhu , Yusuf Hasiya , Kumar Abhishek
Published: June 2023

4168

Background: Ampullary carcinomas (AC) are rare and comprise only 0.2% of gastrointestinal malignancies, and there is a paucity of studies analyzing them. We studied the incidence, demographics, tumor characteristics, and survival variables of patients with AC using the Survival, Epidemiology, and End Results [SEER] November 2021 database. Methods: We identified 3650 patients aged >18 with microscopically confirmed adenocarcinoma of the ampulla using ICD-O-3 site code C241 and histology codes (8140-8147, 8480, 8490, 8500). The epidemiological characteristics and the survival variables included were age, gender, ethnicity, and American Joint Committee on Cancer [AJCC] Staging. The overall 5-year survival (OS), cause-specific 5-year survival (CSS), and CSS plots across different strata were plotted using the Kaplan-Meier Method. The analysis was done using the Cox proportional hazard regression model (p<0.05). Results: The overall age-adjusted incidence of AC was 0.3 per 100,000 cases. The median age at diagnosis was 69 (Interquartile range - 59, 78). It was more common in males (56.03%) and Non-Hispanic White (58.96 %), with the most common stages at a presentation being stage 2B IIB (22.08%) and stage III (22.11%). The observed overall 5-year survival was 31%, and the cause-specific 5-year survival was 37.5%. The CSS was not significantly associated with gender (p=0.06). The estimated hazards of death attributed to AC increase by 13% (p < 0.0001) for every 10-year increase in age at diagnosis above 67 years. The CSS was also associated with race, with African Americans and Hispanics being associated with higher hazards of death attributed to AC when compared to Non-Hispanic Whites with HR of 1.5 (p<0.0001) and 1.12 (p=0.01), respectively. Conclusions: Ampullary carcinoma is more commonly seen in males and non-Hispanic Whites with a median age of 69 years. Patients are typically diagnosed in stages IIB and III. Lower CSS rates were associated with advancing age, African American, and Hispanic populations. We need further studies to determine whether these disparities between different races are due to socioeconomic, genetic, or biological factors. Additional studies investigating how different treatment options affect AC survival, especially in this population subset, can be explored. [Table: see text]
Multi-institutional study evaluating the role of circulating tumor DNA (ctDNA) in management of appendiceal cancers (AC).
Authors: Belmont Erika , Bansal Varun Vivek , Zeineddine Mohammad A. A. , White Michael , Polite Blase N. , Liao Chih-Yi , Eng Oliver S. , Turaga Kiran , Shen John Paul Y.C. , Shergill Ardaman
Published: June 2023

4170

Background: AC frequently present with peritoneal metastases (PM) which are difficult to accurately measure with imaging techniques or serum tumor markers. ctDNA is a novel, promising biomarker to assess minimal residual disease (MRD) and therapy response. Its utility in AC with PM is poorly studied due to the rarity of this disease condition. This is a report on the role of ctDNA in AC management. Methods: Patients with AC managed at two high volume centers between 01/01/2019 to 12/15/2022were included in this study. CtDNA measurements were prospectively collected using Signatera tumor informed ctDNA assay during clinical care and these data were abstracted retrospectively. Cox-proportional hazards were utilized for survival analysis. Results: 97 patients with AC were included with a median age of 57 (IQR 53-66) years, majority being non-Hispanic white (85%) and female (63%). 68 (70%) patients had ctDNA assay drawn at the time of confirmed clinical disease (radiographic or laparoscopic). The sensitivity of ctDNA was 56% (CI 44% - 67%)) for all grades, and 66% (CI 49% - 80%) for grade 3 tumors. 65 (67%) patients underwent cytoreductive surgery (CRS), of which 16 (24.6%) had preoperative ctDNA assays. Sensitivity in this cohort of surgical patients was 25% and positive ctDNA showed poor correlation with PCI score at time of surgery (n=4, r = 0.38, p = 0.14). Any positive value for post-operative ctDNA was associated with lower disease free survival (DFS) (9 months (CI 5-13) in low grade AC and 10 months (CI 7-14) in high grade AC, compared to not reached for those persistently negative (p<0.001) over a median follow-up duration of 17 months. This difference persisted despite adjusting for adjuvant chemotherapy for high-grade disease (aHR = 11.2 (1.4-88.6), p = 0.023). Conclusions: This is the largest study reported to date of tumor informed ctDNA testing in patients with AC. These data show that ctDNA has low sensitivity in both the metastatic unresectable and in pre-operative settings. However, ctDNA positivity after CRS in AC has prognostic value and could be used to guide systemic therapy decisions.
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.
Real-world outcomes among patients with advanced/metastatic renal cell carcinoma (mRCC) treated with cabozantinib or other tyrosine kinase inhibitors (TKIs) after checkpoint inhibitor (CPI) therapy.
Authors: Heng Daniel Yick Chin , Doshi Gury K. , Dutailly Pascale , Houchard Aude , Lothgren Mickael , Monnette Alisha , Wang Yunfei , Perrot Valérie , Lalani Aly-Khan A.
Published: June 2023

4530

Background: CPI-based therapy is the first-line standard of care for patients with mRCC, but effectiveness data for subsequent targeted therapies are limited. Cabozantinib, a multi-targeted TKI, is indicated for patients with mRCC in the USA and may be prescribed after doublet CPI therapy. Methods: Retrospective study of cabozantinib vs other TKI treatment after CPI therapy for mRCC using the US Oncology Network electronic health record database and chart review. Patients initiated TKI therapy between May 1, 2016 and Nov 30, 2021, immediately after CPI therapy. The primary endpoint was real-world response rate over the first 6 months of treatment (rwRR6months) based on physician assessment (complete response (CR): documented CR/indication of remission/disappearance of all lesions/no evidence of disease, or partial response (PR): documented PR/improved disease/responding disease). Covariates were adjusted by inverse probability of treatment weighting. Noninferiority was assessed using a 90% confidence interval (CI) and 10% noninferiority margin; if noninferiority was met, superiority was evaluated using a 95% CI and chi-square test. Results: In total, 485 patients were included. Baseline characteristics were similar for the cabozantinib and other TKIs subgroups, including proportions of patients with ≥ 2 metastatic sites (74.7% vs 68.2%) and metastases in bone (45.0% vs 43.5%), brain (8.8% vs 7.1%), liver (18.1% vs 19.5%), lung (35.0% vs 44.2%) and lymph nodes (38.7% vs 31.8%). At 6 months, tumor assessment data were available for 75.5% of patients (cabozantinib, 79.8% of cabozantinib and 66.2% of other TKIs, 66.2%) patients. Adjusted rwRR6months was 62.5% for cabozantinib and 46.0% for other TKIs (rate difference: noninferiority, 16.5% [90% CI, 9.3–23.7], p < 0.0001; superiority, 16.5% [95% CI, 7.8–25.1], p = 0.0002). Conclusions: In patients with mRCC receiving standard of care treatment in the USA, cabozantinib was effective post-CPI therapy, including in patients without prior TKI therapy. Difference in adjusted rwRR6months significantly favored cabozantinib vs other TKIs. These data may inform global jurisdictions that restrict cabozantinib to the post TKI setting. [Table: see text]
Phase 2 study of batiraxcept (AVB-S6-500, an AXL inhibitor) as monotherapy, in combination with cabozantinib (cabo), and in combination with cabo and nivolumab (nivo) in patients with advanced clear cell renal cell carcinoma (ccRCC).
Authors: Beckermann Katy , Campbell Matthew T , Haas Naomi B. , Ornstein Moshe Chaim , Gao Xin , Mao Shifeng S. , Hammers Hans J. , George Saby , Nelson Ariel Ann , Gourdin Theodore Stewart , Keshava-Prasad Holavanahalli , Hussain Arif , Hoimes Christopher J. , Yan Hongxia , Esquibel Vanessa , McIntyre Gail , Geller Robert B. , Voss Martin H , Rini Brian I. , Shah Neil J.
Published: June 2023

4534

Background: AXL is up-regulated by hypoxia-inducible factor-1 signaling in VHL-deficient tumor cells, playing a critical role in metastasis and resistance to VEGF-targeted therapies. Batiraxcept is a recombinant fusion protein containing an extracellular region of AXL combined with the human immunoglobulin G1 heavy chain (Fc), demonstrating potent and specific AXL inhibition through competitive binding of its ligand GAS6. A prior Phase 1b study showed promising outcomes for batiraxcept + cabo combination in patients who had failed first line (1L) therapy. Methods: This trial tested batiraxcept 15 mg/kg every 2 weeks (q2w) in 3 cohorts of ccRCC patients: 1) batiraxcept monotherapy (n=10) in patients with relapsing disease and no curative options; 2) batiraxcept + cabo 60 mg daily (QD) in patients with at least 1 prior therapy (n=25); and 3) batiraxcept + cabo 40 mg QD and nivo 240 q2w or 480 mg q4w in 1L (n=11). Primary endpoint was investigator assessed objective response rate (ORR) by RECIST v1.1, and key secondary endpoints were safety, progression free survival (PFS), and overall survival. Results: Enrollment has completed as of 17-January-2023. In the 3 cohorts, IMDC intermediate + poor risk was 80%, 76%, and 27%, and median prior lines of therapy were 4, 2, 0. Prior immunotherapy (IO) was received by 100%, 88%, and 0% patients. One hundred percent of patients receiving monotherapy and 40% of 2L patients receiving batiraxcept + cabo had received prior VEGF-TKIs. We describe efficacy and safety across the 3 cohorts. Conclusions: Batiraxcept monotherapy was well tolerated but had limited clinical activity. Batiraxcept-based combinations demonstrated efficacy and tolerability. Given encouraging safety and efficacy signals, batiraxcept + cabo will be further studied in a phase 3 trial of 2L+ ccRCC patients whose disease has progressed on prior IO and VEGF-TKI treatment. Exploratory analysis for a baseline serum soluble AXL/GAS6 ratio biomarker was found to have predictability for clinical activity in the phase 1b study evaluating batiraxcept + cabo in patients who had failed 1L therapies; a similar analysis using the biomarker is ongoing for this patient population. Clinical trial information: NCT04300140 . [Table: see text]
Unique molecular underpinnings by genetic ancestry in localized clear cell renal cell carcinoma.
Authors: Elias Roy , Nirschl Thomas , Rezaee Michael , Yerrapragada Anirudh , Wang Shirley , Cheaib Joseph G. , Alam Ridwan , Patel Sunil H. , Jing Yuezhou , Allaf Mohamad E. , Yegnasubramanian Srinivasan , Ged Yasser , Singla Nirmish
Published: June 2023

4536

Background: Clinical studies evaluating the impact of race on outcomes in renal cell carcinoma (RCC) are inconsistent and conceivably influenced by both biological and socioeconomic factors. Self-reported African Americans (AA) are also largely underrepresented in clinical trials and molecular studies of clear cell (cc) RCC compared to their White (W) counterparts. Herein, we sought to comprehensively characterize molecular differences by genetic ancestry in localized ccRCC. Methods: We performed whole exome (WES) and transcriptome (RNAseq) sequencing on a case-matched cohort of AA and W patients (pts) who underwent nephrectomy for localized ccRCC at our institution. Germline single nucleotide polymorphisms were combined with reference panels from the 1000 Genomes Project, and ancestry was estimated using ADMIXTURE. Molecular subtypes were defined according to the IMmotion151 (IMm151) subtypes, and a random forest model was trained to predict subgroups. Results: From an initial selected cohort of 84 pts, WES and RNAseq data of adequate quality were available for 61 pts including 28 of African (AFR) and 33 of European (EUR) descent. We augmented our institutional cohort with a 3:1 EUR:AFR matched subset of the TCGA KIRC by stage, nuclear grade (NG), and gender. The final analytic cohort contained 75 pts of AFR and 177 pts of EUR descent. There were no significant differences in stage, NG, or gender between AFR and EUR groups. We observed that VHL [OR 0.22, CI [0.11-0.43], p <0.001) and PBRM1 (OR 0.4, CI [0.19-0.79], p = 0.005) mutations are enriched in pts with EUR ancestry and identified a unique association of KMT2C somatic mutations (OR 3.7, CI [1.1-13.5], p = 0.027) with AFR ancestry. Consistent with a lower frequency of VHL mutations, gene-set variation analysis revealed lower enrichment for angiogenesis (-0.23 vs 0.045; p < 0.001) in AFR vs EUR ancestry, respectively. AFR ancestry was associated with an increased proportion of the “Proliferative” IMm151 subtype (14.9% [n = 11/74] vs 3.4% [n = 6/177], p = 0.002). There was no association between overall survival (OS) and ancestry; however, IMm151 subtypes stratified OS with longest survival in the “Angiogenic/Stromal” group (median OS NR) and shortest OS in the T-Effector/Proliferative subtype (5.5yrs CI [2.3 - NR], p = 0.01). Conclusions: Our findings indicate that genetic ancestry is associated with distinct molecular subtypes of ccRCC. Biological drivers of ccRCC pathogenesis and therapeutic response may vary by ancestry, underscoring the need for racially diverse representation in future studies.