bluuebunny/crossref_metadata_2025_split huggingface dataset:
Updated results of a phase 1b study of regorafenib (REG) 80 mg/day or 120 mg/day plus pembrolizumab (PEMBRO) for first-line treatment of advanced hepatocellular carcinoma (HCC).
Authors: El-Khoueiry Anthony B. , Kim Richard D. , Harris William Proctor , Sung Max W. , Waldschmidt Dirk , Cabrera Roniel , Garosi Vittorio Luigi , Zebger-Gong Hong , Brennan Barbara J. , Wang Ying A. , Mueller Udo , Ishida Tatiane Cristine , Galle Peter R. 
Published: June 2021

4078 Background: REG, a multikinase inhibitor, and PEMBRO, an anti-PD-1 mAb, are approved as monotherapies in advanced HCC after progression on sorafenib. This phase 1b dose-finding study investigated first-line REG plus PEMBRO in advanced HCC. Methods: Patients (pts) in the first cohort received a starting REG dose of 120 mg/day orally for 3 weeks (wks) on/1 wk off, which could be escalated (160 mg) or reduced (80 mg) in later cohorts, plus a fixed dose of PEMBRO 200 mg IV every 3 wks. Due to a high dose modification rate in the REG 120 mg cohort, an exploratory REG 80 mg cohort was introduced. Primary objective was safety and tolerability; secondary aims were to assess the maximum tolerated dose (MTD), recommended phase 2 dose, and anti-tumor activity. Results: 35 pts started on REG 120 mg/day and 22 on REG 80 mg/day. Median age was 66 yrs (range 29–81), 84% of pts were male, 70%/30% had ECOG PS 0/1, 26%/74% were BCLC stage B/C, 100% were C–P A, 46% had extrahepatic spread, and 32% had macrovascular invasion. MTD of REG was 120 mg/day. Grade (Gr) 3/4 treatment-emergent adverse events (TEAE) occurred in 86% of pts on REG 120 mg and 50% on REG 80 mg (Table). Most common Gr 3/4 TEAE for REG 120 mg/80 mg were AST increased (23%/9%), lipase increased (20%/5%), ALT increased (17%/9%), and hypertension (17%/9%). TEAE led to REG/PEMBRO dose reductions or interruptions in 71%/57% of pts on REG 120 mg and 59%/45% on REG 80 mg. Median treatment duration (range) was 3.0 months (mo; 0.2–20.5) for REG 120 mg and 3.5 mo (0.03–24.4) for PEMBRO, and 3.5 mo (0.7–10.8) for REG 80 mg and 3.5 mo (0.8–11.3) for PEMBRO. Of 32 evaluable pts on REG 120 mg, 10 (31%) had a partial response (PR) and 18 (56%) had stable disease (SD); disease control rate (DCR) was 88% (RECIST v1.1). Of 22 pts on REG 80 mg, 4 (18%) had a PR and 16 (73%) had SD; DCR was 91%. As of 17 Dec 2020, 16 pts remain on treatment (REG 120 mg n = 5; REG 80 mg n = 11); median follow up was 11.7 mo and 6.9 mo, respectively. REG pharmacokinetic exposure was as expected for 80 mg and 120 mg doses. Flow cytometry analysis of sequential peripheral blood showed changes in subsets of T-cells and monocytes, which may contribute to clinical benefit. Conclusions: First-line REG plus PEMBRO in advanced HCC showed no new safety signals and encouraging anti-tumor activity (DCR ̃90%). The REG 80 mg cohort appeared to have lower rates of dose reductions and interruptions due to TEAE vs REG 120 mg. Efficacy data for the REG 80 mg cohort are preliminary due to short follow-up. Clinical trial information: NCT03347292. [Table: see text]
Pemigatinib for previously treated locally advanced/metastatic cholangiocarcinoma (CCA): Update of FIGHT-202.
Authors: Abou-Alfa Ghassan K. , Sahai Vaibhav , Hollebecque Antoine , Vaccaro Gina M. , Melisi Davide , Al-Rajabi Raed Moh'd Taiseer , Paulson Andrew Scott , Borad Mitesh J. , Gallinson David H. , Murphy Adrian Gerard , Oh Do-Youn , Dotan Efrat , Catenacci Daniel , Van Cutsem Eric , Lihou Christine Francis , Zhen Huiling , Féliz Luis , Vogel Arndt 
Published: June 2021

4086 Background: Pemigatinib (PEMI), a potent, selective, oral FGFR1-3 inhibitor, has shown efficacy and safety in patients (pts) with CCA and FGFR2 rearrangements/fusions in FIGHT-202 (NCT02924376; objective response rate [ORR], 35.5%; duration of response [DOR], 7.2 months [mo]). Overall survival (OS: 21.1 mo) was not mature in the primary report (Abou-Alfa. Lancet Oncol 2020; cutoff: Mar 22, 2019); herein we report matured efficacy and safety data from FIGHT-202 (cutoff: Apr 7, 2020). Methods: Pts (≥18 y) with known FGF/FGFR alterations and progression after ≥1 prior therapy had FGFR2 rearrangements/fusions (cohort A), other FGF/FGFR alterations (B), or no FGF/FGFR alterations (C). Pts received PEMI 13.5 mg QD (21-d cycle; 2 wks on, 1 wk off) until progression or toxicity. Primary endpoint: independent, centrally confirmed ORR (cohort A); secondary endpoints: ORR (cohorts B, C; cohorts A and B combined); DOR, disease control rate (DCR), progression free survival (PFS), OS, and safety. A post-hoc analysis in cohort A evaluated mOS in responders (pts with complete response [CR] or partial response [PR]) vs non-responders (pts with progressive disease [PD] or stable disease (SD]). Results: At cutoff, 147 pts were enrolled (cohort A, n=108; B, n=20; C, n=17; FGF/FGFR status undetermined, n=2); median follow-up was 30.4 (range, 4.9–38.7) mo and median treatment duration was 5.9 (0.2–36.5) mo. In cohort A, 9.3% of pts remained on therapy at cutoff; in cohorts B and C, all pts had discontinued. Pts discontinued mainly for PD (67.6%, 75%, and 64.7% in cohorts A, B, and C respectively). Independent, centrally confirmed ORR was 37.0%; mOS was 17.5 mo (95% CI, 14.4-22.9) in cohort A (Table 1). mOS for responders (n=40) vs non-responders (n=68) was 30.1 (95% CI, 21.5-NE) mo vs 13.7 (9.6-16.1) mo. Overall, most common all-cause treatment-emergent adverse events (TEAEs) were hyperphosphatemia (58.5%; grade ≥3, 0%), alopecia (49.7%; 0%), diarrhea (46.9%; 3.4%), fatigue (43.5%; 5.4%), nausea (41.5%; 2%), and dysgeusia (40.8%; 0%); 10.2%, 13.6% and 42.2% of pts discontinued, had dose reduction, and treatment interruption due to TEAEs, respectively. Conclusions: These results reinforce the primary data, showing continued, durable responses and sustained tolerability in pts receiving PEMI for CCA harboring FGFR2 rearrangements/fusions. Notably, the matured OS is longer than historical data; OS for responders was more than twice as long vs for non-responders. Clinical trial information: NCT02924376. [Table: see text]
Natural history of patients (pts) with advanced cholangiocarcinoma (CCA) with FGFR2 gene fusion/rearrangement or wild-type (WT) FGFR2.
Authors: Shroff Rachna T. , Rearden Jessica , Li Ai , Moran Susan , Shepherd Stacie Peacock , Lamarca Angela 
Published: June 2021

4089 Background: CCA is a rare, heterogeneous malignancy with poor prognosis due to late onset of symptoms and relative resistance to available therapies. FGFR2 fusions are common, occurring in 10–16% of intrahepatic CCA (iCCA). There is increasing awareness of the importance of molecular profiling to inform treatment choices, although real-world data (RWD) are lacking on the natural history of pts with CCA and FGFR2 fusions/rearrangements receiving therapies for advanced disease. This retrospective, observational, natural history study used a nationwide (US-based) de-identified clinico-genomic database (CGDB) to compare overall survival (OS) in pts with advanced CCA and FGFR2 fusions/rearrangements vs. those with wild-type (WT) FGFR2. Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine CCA CGDB (FH-FMI-CGDB). The data originated from approximately 280 US cancer clinics (̃800 sites of care). Pts were ≥18y of age, had chart-confirmed advanced CCA, comprehensive genomic profiling, and ≥2 visits within the Flatiron Health network since Jan 1, 2011. Primary objective: evaluate OS in pts with FGFR2 fusions/rearrangements and WT FGFR2 from the index date (date of diagnosis of advanced CCA) to date of death from any cause. A key secondary objective was to evaluate the influence of FGFR status on OS after adjusting for potential prognostic variables. Risk-set adjustment was used to account for left truncation for all time-to-event analyses. Results: As of May 2020, 571 pts from the CCA FH-FMI-CGDB met the inclusion criteria; 75 pts with FGFR2 fusions/rearrangements (median age 63y; 64% female; 95% iCCA; 68% stage IV at initial diagnosis), and 496 pts FGFR2 WT (median age 65y; 48% female; 74% iCCA; 55% stage IV at initial diagnosis). Median OS was numerically higher, but not statistically different, for pts with FGFR2 fusions/rearrangements vs FGFR2 WT (12.1m [95% CI 8.5−17.1] vs 7.1m [95% CI 5.7−8.8]; log rank p = 0.184). Median OS was also numerically higher, but not statistically different, for FGFR2 fusions/rearrangements vs FGFR WT in the subset of 437 pts with iCCA (12.1m [95% CI 8.4−17.1] vs 7.8m [95% CI 6.1−10.0]; log rank p = 0.375). FGFR2 status was not a significant factor contributing to OS in univariate, bivariate, or multivariate models after adjusting for potential prognostic covariates. Conclusions: This analysis of RWD did not demonstrate a clear survival advantage for pts with FGFR2 fusions/rearrangements vs FGFR2 WT CCA receiving therapies for advanced disease, although a non-significant trend towards longer OS was observed in pts with FGFR2 fusions/rearrangements. FGFR2 status was not a significant predictor of OS after adjusting for potential prognostic covariates. An additional sub-analysis is ongoing to determine OS from time of initiation of second-line therapy in pts with FGFR2 fusions/rearrangements.
Comparative effectiveness of sorafenib, lenvatinib, and nivolumab as first-line systemic therapy for patients with advanced hepatocellular carcinoma and Child-Pugh class B cirrhosis treated at VA Medical Centers.
Authors: Chapin William Joseph , Hwang Wei-Ting , Karasic Thomas Benjamin , McCarthy Anne Marie , Kaplan David Edward 
Published: June 2021

4102 Background: Up to 90% of cases of hepatocellular carcinoma (HCC) in the U.S. occur in patients with cirrhosis. As prognosis in patients with decompensated cirrhosis may be more related to liver function than tumor stage, patients with Child-Pugh (CP) class B and C cirrhosis are often excluded from randomized trials despite representing up to 30% of patients treated with systemic therapy in clinical practice. While prospective data such as the GIDEON registry and CHECKMATE-040 have demonstrated safety of sorafenib and nivolumab in CP B cirrhosis, studies of comparative effectiveness of sorafenib, lenvatinib, and nivolumab are lacking. Methods: We performed a retrospective cohort study of patients with HCC and CP B cirrhosis at U.S. Veterans Affairs Medical Centers who initiated first systemic therapy with sorafenib, lenvatinib, or nivolumab between 9/22/2017 and 2/13/2021. Overall survival (OS) by first systemic therapy was assessed with Kaplan Meier analysis and Cox proportional hazards modeling with pre-specified candidate covariates and a backward elimination approach for variable selection. Missing data were imputed by multiple imputation with chained equations. Results: Among 401 CP B patients undergoing first systemic therapy, 98% were male, 29% had macrovascular invasion (MVI), 35% had extrahepatic spread (EHS), 57%/29%/13% had CP score 7/8/9, 5% had hepatic encephalopathy, 37% had ascites, 63%/2%/36% had HCV/HBV/non-viral cirrhosis, 63% had prior embolization or ablation, and 35% had ECOG performance status of > = 2. Of these patients, 320 received sorafenib, 33 received lenvatinib, and 48 received nivolumab. In univariate analysis, median OS was 4.8 months (95% CI 3.8 – 6.0; 1 year OS 21.8%) in the sorafenib cohort, 6.9 months (95% CI 4.4 – 8.4 months; 1 year OS 27.8%) in the lenvatinib cohort, and 7.7 months (95% CI 3.9 – 9.1 months; 1 year OS 31.7%) in the nivolumab cohort. Covariates with at least one category significantly associated with survival that were retained in the multivariate model included CP score, MELD-Na, BMI, log(AFP), time from diagnosis to systemic treatment, ECOG performance status, Cirrhosis Comorbidity index, and VA complexity level (all p < 0.05); MVI, EHS, and age were retained in the model as pre-specified despite lack of statistical significance. Compared with sorafenib, nivolumab was associated with significantly lower hazard of death (adjusted HR 0.63; 95% CI 0.43 – 0.91; p = 0.015) while hazard of death for lenvatinib treatment was not significantly different (adjusted HR 0.83; 95% CI 0.54 – 1.28, p = 0.41). Conclusions: Among patients with HCC and CP class B cirrhosis undergoing first systemic therapy, nivolumab was associated with significantly lower hazard of death compared to sorafenib after adjusting for important covariates.
Clinical impact of pathogenic germline variants in pancreatic cancer: Results from a multicenter prospective universal genetic testing study.
Authors: Uson Junior Pedro Luiz Serrano , Riegert-Johnson Douglas , Boardman Lisa A. , Borad Mitesh J. , Ahn Daniel H. , Sonbol Mohamad Bassam , Faigel Douglas O , Fukami Norio , Pannala Rahul , Kunze Katie , Golafshar Michael A , Esplin Edward D. , Nussbaum Robert Luke , Bekaii-Saab Tanios S. , Samadder Jewel 
Published: June 2021

4118 Background: Germline variations in cancer susceptibility genes have important implications on treatment and family counseling in pancreatic cancer (PC). We report the prevalence and clinical outcomes of unselected PC patients with pathogenic germline variants (PGV) detected using a universal testing approach. Methods: We undertook a prospective multi-site study of germline sequencing using an >80 gene next-generation sequencing platform among 250 PC patients (not selected for age or family cancer history) between April 1, 2018 and March 31, 2020. Demographic, tumor characteristics and clinical outcomes were compared between PGV carriers and non-carriers. Results: Of 250 patients, the mean age was 65 years (SD 8.7), 56% were male, 83.6% were white and 65.6% had advanced disease (Stage III and IV). PGV were found in 15.2% (N=38) of patients, two patients had more than one PGV. Variants of uncertain significance were found in 44.4% (N=111). Family history of cancer (OR 2.36, 95% CI: 1.14-5.19, p=0.025) was associated with a higher risk of PGV. In a median follow up of 16.5 months, median overall survival was 16.8 months in PGV carriers compared with 16.5 months in non-carriers (HR 0.51, 95 %CI, 0.25-1.01, p=0.05). Higher levels of CA 19-9 and advanced stages (III and IV) were associated with worse outcomes in both groups. Overall, 68% of PGV carriers had mutations in homologous recombination repair (HRR) genes, including BRCA1, BRCA2, PALB2, ATM, CHEK2, NBN, RAD51C. In 65% of HRR gene carrier’s systemic therapy with platinum was used. Conclusions: Universal multi-gene panel testing in pancreatic cancer reveals that 1 in 6 patients are carriers of PGV and is associated with improved survival. Multi-gene germline testing should be used to aid in treatment selection, prognostication, and familial cancer counseling. Distribution of the 40 PGV by penetrance status.[Table: see text]
Genomic profiling of KRAS wide-type pancreatic ductal adenocarcinomas identifies targetable genetic alterations.
Authors: Wei Deng , Li Xiaomo , Zhang Xinsheng , Ma Tonghui , Liu Rong 
Published: June 2021

4121 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and the 5-year survival of PDAC patients is below 10%. The oncogenic KRASmutations account for about 90% of PDAC cases. Unfortunately, there is no FDA-approved targeted therapy for KRAS mutations. Therefore, the genomic profiling of KRAS wide-type PDACs can provide invaluable sights to the etiology of these patients and offer them the opportunity of precision therapy trials. Methods: To characterize actionable targets in 521 Chinese PDAC patients, deep sequencing of a 831-gene panel (OncoPanscan, Genetronhealth) was applied to assess somatic mutations of their tumor tissues including SNV, insertions/deletions, CNV and re-arrangements, as well as possible pathogenic germline variants of paired genomic DNA sample. Results: There were 89% (463/521) of patients in our PDAC cohort harbored KRAS mutations. Among the remaining 58 patients in KRAS wild-type subgroup, 33% (19/58) carried activating mutations in the RTK/Ras/MAPK pathway. Targetable BRAF mutations were seen in five (9%) patients: V600E (1/5), G464V (1/5), N486_P490del (2/5) and BRAF fusion (1/5). The frequency of BRAF mutations was 9% (5/58) in KRAS wild-type PDACs but only 0.4% (2/463) in KRAS-mutated PDACs (P < 0.001). We found one classic EGFR activing mutation (L747_A750delinsP) and one MAP2K1 activating mutation (F53_Q58delinsL), which can be targeted by EGFR-TKIs and MEK inhibitor trametinib, respectively. An oncogenic ERBB3 mutation (V104L) was seen in one patient, who was eligible for HER2-targeted therapy clinical trials. We also found STK11/TSC2 inactivating mutations and a dominant-negative mutation of PTEN (R130Q) which could be targeted by mTOR inhibitor everolimus and AKT inhibitor capivasertib, respectively. Additionally, we observed a patient with high level amplification of MET and another patient with the NCOA4-RET fusion gene which can be targeted by MET inhibitor carbozantinib. Interestingly, we also identified two patients with inactivating mutations in ELF3 (one frameshift and one in splicing-site), which is a driver gene of ampullary carcinoma. Lastly, two patients carried deleterious germline mutations in BRCA1 and PALB2, which may be targeted with PARP inhibitors. Overall, at least 29% (17/58) KRAS wide-type patients harbored potentially actionable genomic alterations to currently used anticancer drugs. Conclusions: The mutational landscape of our PDAC cohort provided compelling evidence that targetable driver mutations accounted for a significant portion of KRAS wide-type tumors. Our findings demonstrated that genomic profiling of PDAC patients can enable physicians to optimize their clinical management and enroll them into genomically matched clinical trials.
Efficacy and safety of KN046 plus nab-paclitaxel/gemcitabine as first-line treatment for unresectable locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC).
Authors: Jin Gang , Guo Shiwei , Zhang Yanqiao , Ma Yue , Guo Xiaodong , Zhou Xiaocui , Yu Qin 
Published: June 2021

4138 Background: Pancreatic ductal adenocarcinoma（PDAC）is one of the most lethal malignancies worldwide and is characterized by extremely poor prognosis. Nab-paclitaxel plus gemcitabine has been recommended by international guidelines for first-line treatment of advanced PDAC but chemoresistance is difficult to avoid. Combination of immune checkpoint inhibitors (ICIs) and chemotherapy has demonstrated substantial promise for the treatment of several advanced malignancies. A few recent studies have begun to explore the effect of ICIs monotherapy or co in advanced PDAC with few meaningful results. KN046, a novel recombinant humanized bispecific antibody, can simultaneously block PD-1/PD-L1 and CTLA-4 pathways and restore T-cell immune response to tumor. The purpose of this study is to evaluate the efficacy and safety of KN046 plus nab-paclitaxel/gemcitabine as first-line treatment for unresectable locally advanced or metastatic PDAC. Methods: This ongoing phase II trial in China enrolled pts with histologically or cytologically confirmed unresectable locally advanced or metastatic PDAC who have ECOG PS of 0-1 and never received systemic anti-tumor therapy for advanced or metastatic diseases. KN046 (5mpk, Q2W) plus nab-paclitaxel (125mg/m2, D1, 8, 15, Q4W) and gemcitabine (1000mg/m2, D1, 8, 15, Q4W) were administered 4-6 cycles followed by KN046 (5mpk) maintenance therapy every 2 weeks. Tumour response was assessed according to RECIST 1.1 every 8 weeks. The primary endpoint is investigator-assessed ORR. Secondary endpoints are DCR, DOR, TTP, PFS, OS and safety. Results: As of December 15, 2020, 17 pts were enrolled, median (range) age was 56 (36-75) years, 9 pts ECOG 1, and 7 pts had liver metastases. Median KN046 exposure time was 9.5 wks. 9 pts were included in the efficacy analysis and 17 pts in the safety analysis. In best overall response assessment, there were 55.6% PR (5/9) and 33.3% SD (3/9). ORR was 55.6% (95% CI: 21.2̃86.3), and DCR was 88.9% (95% CI: 51.8̃99.7). The overall incidence of KN046 related treatment-emergent adverse events was 64.7%, with 29.4% were grade 3 TRAE. The most common KN046 related treatment-emergent adverse events (≥10%) were alanine aminotransferase increased (n = 5, 29.4%), nausea (n = 3, 17.6%), rash (n = 3, 17.6%), aspartate aminotransferase increased (n = 2, 11.8%), diarrhoea (n = 2, 11.8%), hyperphosphataemia (n = 2, 11.8%), pyrexia (n = 2, 11.8%), vomiting (n = 2, 11.8%). Conclusions: Combining KN046 with nab-paclitaxel and gemcitabine as first-line treatment for unresectable locally advanced or metastatic PDAC patients is safe and feasible, and lays the foundation for subsequent clinical trials. Clinical trial information: NCT04324307.
Treatment with pembrolizumab in combination with the oncolytic virus pelareorep promotes anti-tumor immunity in patients with advanced pancreatic adenocarcinoma.
Authors: Mahalingam Devalingam , Chen Siqi , Xie Ping , Kalyan Aparna , Kircher Sheetal Mehta , Kocherginsky Masha , Xu Jiahui , Maurer Victoria , Viveiros Pedro Antonio Hermida de , Vagia Elena , Wilkinson Grey A , Coffey Matthew C. , Mulcahy Mary Frances , Benson Al Bowen , Zhang Bin 
Published: June 2021

4144 Background: Pelareorep is an intravenously delivered oncolytic reovirus that can induce a T-cell-inflamed phenotype in pancreatic ductal adenocarcinoma (PDAC). In prior studies, tumor tissue analysis from patients treated with pelareorep shows pelareorep replication, increased T cell infiltration, and upregulation of PD-L1. We hypothesized that pelareorep in combination with pembrolizumab in patients with PDAC would lead to improved responses and anti-tumor immunological changes within peripheral blood and tumor biopsies in responding patients. Methods: PDAC patients who progressed after first-line treatment received pelareorep at a dose of 4.5x1010 TCID50 IV on Days 1, 2, 3 & 8 of Cycle (C) 1, and Days 1 & 8 with C2 onwards. Pembrolizumab was administered on Day 1 of each 21-day cycle at 200 mg IV. The primary objective was overall response rate by RECIST v 1.1 criteria. Secondary objectives included evaluating immunological changes within tumor tissue and peripheral blood, performed by multi-plex immunohistochemistry and spectral flow cytometry (Cytek), respectively. Results: Thirteen patients were enrolled. Disease control was achieved in 33% of the 12 efficacy-evaluable patients. One patient achieved a partial response (PR). Three additional patients achieved stable disease (SD). On-treatment tumor biopsies, collected during C1, showed pelareorep replication, increased infiltration of CD8+ T cells and PD-L1+ cells, and decreased expression of VDAC1, a mitochondrial gatekeeper for tumor promotion, relative to archival tissue. Reduced infiltration of Foxp3+ regulatory T cells (Treg) was observed in patients showing tumor response. Peripheral blood was collected at day 1 of each cycle and on C1 day 8. Relative to pretreatment samples, the number of CD8+ effector memory T cells and B cells tend to increase while the number of Treg cells declined in C2 onwards in patients with tumor response. Furthermore, these patients had increased expression of the mitochondrial protein TOMM20 in CD8+ T cells and decreased expression of PD-1 and the H3K27me3 epigenetic mark in Treg. Treatment was well tolerated with most treatment-related adverse events, including flu-like symptoms, being grade 1 or 2. Conclusions: The combination of pelareorep and pembrolizumab showed a manageable safety profile and modest efficacy in an unselected PDAC population. Additional correlation analyses between treatment efficacy and immunological changes will be presented. The anti-tumor activity of pelareorep and checkpoint blockade therapy is being evaluated further in additional ongoing studies. Clinical trial information: NCT03723915.