bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiple combinational strategies of immunotherapy for esophageal squamous cell carcinoma: One institutional experience in Taiwan since 2016.
Authors: Chen Jo-Pai , Lu Wei-Chen , Wu Hsu , Kao Tsui-Mai , Chiang Keng-Man , Chen Hsing-wu , Kuo Sung-Hsin
Published: January 2022

328

Background: ESCC is a health burden in Taiwan due to smoking and drinking habits. In R/M setting, the prognosis is worse. In 2021, KN590 study(pembrolizumab with chemotherapy in CPS≥10%), CM648 study(nivolumab with chemotherapy or nivolumab with ipilimumab in TPS≥1%), and ESCORt-1st study(camrelizumab with chemotherapy in TPS≥1%) have all been shown to get survival benefits compared with chemotherapy alone in front-line setting. Further immunotherapy combinations with targeted therapies and subsequent therapy options after anti-PD1 failure deserve more investigation. Methods: From early 2016 to late 2021, 26 advanced ESCC patients had ever received immunotherapy-containing regimens in Yun-lin Branch of National Taiwan University Hospital. We have reviewed basic characters, ICIs regimens, and treatment response of these patients. Results: 3 patients under progression during front-line KN590 got PR by subsequent afatinib(2) or lenvatinib(1) use. So, the overall response rate of advanced ESCC to immunotherapy-containing regimens was 59%(17/29) and disease control rate was 72%(21/29). Conclusions: Afatinib has multiple immuno-modulatory effects. AP or NA is an effective regimen in Taiwan, where double cancers, like HNSCC and ESCC, are popular due to smoking, drinking, and bêtel-nuts chewing. Following KN590 good efficacy was also seen in our institution and afatinib with anti-PD1 could be introduced in CT-unfit patients. In unresectable and/or oligometastatic ESCC, induction triple therapy may lead to conversion chemoradiation, even to final surgery. EGFR or VEGFR TKI with immunotherapy might also be a subsequent recue regimen after front-line anti-PD1 failure.[Table: see text]
Evaluation of near-Infrared fluorescence-conjugated peptides for visualization of human epidermal receptor 2-overexpressed gastric cancer.
Authors: Jeong Kyoungyun , Kong Seong-Ho , Bae Seong-Woo , Park Cho Rong , Berlth Felix , Shin Jae Hwan , Lee Yoon-Sang , Yun Hye Won , Koo Eunhee , Suh Yun-Suhk , Park Do Joong , Lee Hyuk-Joon , Yang Han-Kwang
Published: January 2022

338

Background: HER2 is highly overexpressed in many kinds of cancers with a poor prognosis. Recently, near-infrared (NIR) fluorescence-based imaging is a growing field for both pre-clinical and clinical application. In this study, we aimed to synthesize Human Epidermal Receptor2 (HER2)-specific near-infrared (NIR) fluorescence probes and evaluate their applicability in cancer-specific image-guided surgeries using an animal model. Methods: An NIR dye emitting light of 800 nm (IRDye800CW, Li-COR, USA) was conjugated to trastuzumab and HER2-specific affibody using click mechanism. HER2 affinity was assessed by the surface plasmon resonance technique. HER2 positive/negative gastric cancer cell lines (NCI-N87 and SNU-601) were subcutaneously implanted into female BALB/c-nu (6 to 8 weeks old) mice. The biodistribution and fluorescence signal intensity were measured by Lumina II (Perkin Elmer, MA, USA) and a laparoscopic NIR camera (InTheSmart, Seoul, Korea) after injecting the probes intravenously. Results: Trastuzumab-IRDye800CW showed higher affinity to HER2 (K(D) = 2.093(3)pM) than unconjugated trastuzumab(K(D) = 25.75pM). The significant signal of fluorescence was targeted to the HER2-positive tumors at 24hr after injection, while no or low signal retention was observed in negative group. The peak appears at 24hr after injection. On the other hand, small difference of affinity was shown between HER2-target affibody-IRDye800CW (K(D) = 4.71nM) and unlabeled pure affibody(K(D) = 1.42nM). The renal clearance of HER2-target affibody conjugated with IRDye800CW was so fast that we could not detect the signal. Conclusions: Our results suggest that trastuzumab conjugated with IRDye800CW can be a feasible tool to monitor HER2 status in pre-clinical cancer imaging. Moreover, this probe can provide complementary means for assessment of HER2 expression in gastric cancer patients and/or be used to further detection of HER2-positive lesions during image-guided surgery.
Transcriptomic analyses of esophageal cancer patients with brain metastases.
Authors: Aguirre Luis E. , Yao Jiqiang , Mesa Tania , Wloch Marek , Yoder Sean J. , Brass Shawn , Cen Ling , Fontaine Jacques , Pimiento Jose Mario , Mehta Rutika
Published: January 2022

341

Background: Brain metastases from esophageal cancer are extremely rare with an estimated incidence of 1.7% but limited survival. Some reports highlight the rich microvascular density of such tumors and their distinctive degree of HER2, HIF1-a and EGFR expression, further emphasizing the potential role of angiogenesis in their neurotropic behavior. With this in mind, we aimed to illustrate the transcriptomic landscape of brain metastases from esophageal cancers and better understand the disease biology. Methods: Following IRB approval, we collected retrospective data on patients with a diagnosis of esophageal cancer with histology-proven brain metastases treated at our institution between 2008 and 2020. We identified 10 adequate, paired samples with available tissue for RNA extraction. Expression data was generated using NanoString TS 360 panels to characterize gene signatures of interest and analyzed using GSEA_4.1.0. Results: All 10 patients were Caucasian, 90% were male. Median age was 63 years. All had adenocarcinoma with G2-G3 histology. Median follow-up was 39.4 mos (95%CI, 27.4 to 51.4). At data cutoff, 6 patients had died. Median OS was 24.6 mos. Median time from curative surgery to CNS recurrence was 8.3 mos. Ninety percent of patients developed brain metastases within 24 mos of surgery. Median time from brain metastases to death was 4.7 mos. Almost a third of patients had HER2 positive disease. 48 gene signatures were analyzed; 5 being significantly enriched between metastatic and primary site accounting for cell cycle, DNA damage repair, MYC, mTOR signaling and immortality and stemness. Out of a pool of 760, significant overlap was seen between 12 genes across the 5 signatures of interest: POLE, LIG1, FEN1 (involved in DNA repair and replication); AURKA and PLK1 (cell proliferation and triggers for G2/M transition), BUB1 (establishment of the mitotic spindle checkpoint and chromosome congression), MCM2 and MCM4 (initiation of genome replication); BRIP1 and RAD51 (critical in homologous recombinational repair); CCNE1 (cell cycle G1/S transition) and WRAP53 (dual role as p53 regulator and protein involved in telomere elongation and DNA repair). ERBB2 was similarly enriched in primary and metastatic sites. Conclusions: These preliminary data demonstrate that the genomic basis of brain metastases in esophageal cancer goes beyond EGFR/ERBB2 signaling. A complex genomic interaction is present in brain metastases as compared to primary site that offers these cells the advantage for neurotropism. To our knowledge this is the first study attempting to illustrate genomic differences between primary and matched brain metastasis sites in esophageal cancer.
Efficacy of immune checkpoint inhibitors for gastrointestinal cancers with SWI/SNF complex genetic alterations.
Authors: Nakata Akinobu , Narita Yukiya , Kumanishi Ryosuke , Nakazawa Taiko , Ogata Takatsugu , Matsubara Yuki , Kodama Hiroyuki , Honda Kazunori , Masuishi Toshiki , Taniguchi Hiroya , Kadowaki Shigenori , Andoh Masashi , Yamaguchi Rui , Tajika Masahiro , Muro Kei
Published: January 2022

346

Background: SWI/SNF chromatin-remodeling complex is encoded by multi-gene families that are recurrently mutated in cancer. Previous studies reported that tumors harboring SWI/SNF complex genetic alterations (GA) are sensitive to immune checkpoint inhibitors (ICIs), but the clinical significance of SWI/SNF complex GA in patients with gastrointestinal cancers (GICs) is unclear. Methods: We reviewed patients with metastatic GICs who underwent comprehensive genomic profiling (CGP) and received ICIs at our institution between July 2014–June 2021. SWI/SNF complex GA were defined as ARID1A, ARID1B, ARID2, PBRM1, SMARCA4, and SMARCB1 alterations. Results: Of 292 patients receiving CGP, 136 patients received ICIs, of which 10 (7.4%) had SWI/SNF GA, including 8 ARID1A (5.9%), 1 ARID2 (0.7%) and 2 SMARCA4 (1.5%) alterations. The subjects included 50 esophageal cancers, 84 gastric cancers, and 2 small intestine cancers. The patients with SWI/SNF complex GA had significantly higher proportions of microsatellite instability-high ( p = 0.004) and lower proportions of esophageal cancer ( p = 0.002), compared with patients without SWI/SNF complex GA. During the median follow-up time of 7.5 months (M), the median overall survival (OS), time-to-treatment failure (TTF), and progression-free survival (PFS) in all patients was 13.2 M ([95% confidence interval [CI] 7.7-21.8 M), 2.2 M (95%CI, 1.8-2.5 M), and 2.3 M (95%CI, 1.9-2.8 M), respectively. The patients with SWI/SNF complex GA had better OS (median, not reached vs 10.3 M; hazard ratio [HR], 0.40 [95% confidence interval [CI] 0.19–0.86]; p = 0.019) than those without SWI/SNF complex GA. The patients with SWI/SNF complex GA tended to have longer TTF (median, 4.7 M vs 2.1 M; HR, 0.67 [95%CI 0.38–1.17]; p = 0.16) and PFS (median, 5.4 M vs 2.2 M; HR, 0.70 [95%CI 0.39–1.27], p = 0.24) than those without SWI/SNF GA. The objective response rate (ORR) and disease control rate (DCR) in all patients was 13.2% (95%CI, 8.0-20.1) and 40.4% (95%CI, 32.1-49.2), respectively. The ORR and DCR of patients with SWI/SNF complex GA tended to be higher than those without SWI/SNF complex GA (ORR, 30.0% vs 11.9%; p = 0.13: DCR, 70.0% vs 38.1%; p = 0.09), with 1 complete response and 2 partial responses in the patients with SWI/SNF complex GA. Conclusions: The patients with GICs who had SWI/SNF complex GA were more likely to benefit from ICI therapy, suggesting that novel ICI-containing chemotherapies targeting SWI/SNF complex GA are needed for GICs.[Table: see text]
Tumor regression grade and overall survival following gastrectomy with neoadjuvant therapy for gastric cancer.
Authors: Savoldy Michelle A , Sinnamon Andrew J , Mehta Rutika , Pena Luis , Dineen Sean P. , Lauwers Gregory Y , Pimiento Jose Mario
Published: January 2022

355

Background: Perioperative chemotherapy is the standard of care for locoregional gastric cancers in western populations. However, the impact of response to therapy as a biomarker of cancer survival has not been fully defined. This study focuses on the pathological response to neoadjuvant chemotherapy, as measured by tumor regression grade (TRG), for gastric cancer and its impact on patient outcomes, primarily overall survival. Methods: Patients undergoing gastrectomy for nonmetastatic invasive gastric adenocarcinoma following perioperative chemotherapy (clinical T2+/N+cM0) were identified from an institutional database (2000-2021). Demographics, clinical staging including histologic grade, surgical factors and survival outcomes were included. The association between TRG and overall survival from time of surgery was assessed. OS was estimated using the Kaplan Meier method with adjustment for covariates using Cox regression. Results: One hundred seventeen patients were identified. Median age was 65 years (IQR 57–73). The majority of the patients were male (n = 64, 55%). Seventy-six patients underwent total gastrectomy, 22 subtotal gastrectomy, and 19 distal gastrectomy. Six patients (5.1%) had a TRG of 0, 18 patients (15.4%) had a TRG of 1, 25 patients (21.4%) had a TRG of 2, and 68 patients (58.1%) had a TRG of 3. Median survival overall was 40.9 months (95% CI 28.7–66.4). TRG status was not significantly different between chemotherapy regimens (doublet vs triplet, p = 0.96). Median survival was longest in the TRG 0 group (86.9 months), followed sequentially by TRG 1 (74.5 months), TRG 2 (51.5 months), and lastly, TRG 3 group with 27.0 months. Increased tumor regression (lower TRG) was significantly associated with prolonged survival (p < 0.01 by log-rank for trend). After adjustment for clinical patient factors and tumor factors, TRG remained significantly associated with overall survival (Table; TRG hazard ratio 1.62, p = 0.007). In addition to TRG status, clinical T4 tumors and diffuse histology were associated with poor survival (cT4 hazard ratio 2.09, p = 0.039, diffuse histology hazard ratio 1.82 (p = 0.071). Conclusions: In patients receiving perioperative chemotherapy for treatment of gastric cancer, response to therapy as defined by TRG is independently prognostic of survival.[Table: see text]
Characteristics and trends in treatment utilization in young-onset cholangiocarcinoma.
Authors: Reddy Sarah , Goksu Suleyman Yasin , Chowattukunnel Nivan , Hsieh David , Al Matar Salwan , Sanford Nina Niu , Beg Muhammad Shaalan , Kazmi Syed Mohammad Ali
Published: January 2022

386

Background: Although the incidence of cholangiocarcinoma is rising, little is known about the demographic and clinical characteristics of patients with young-onset cholangiocarcinoma (YOCC), diagnosed at age < 50 years. The objective of this study was to compare patients with YOCC, and patients with typical-onset cholangiocarcinoma (TOCC; diagnosed age >50 years), and to describe trends in treatment utilization and factors associated with survival in YOCC. Methods: We identified patients diagnosed with intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and hilar cholangiocarcinoma from the National Cancer Database (NCDB) between 2004 and 2016. Patients were classified as either having YOCC or TOCC. Categorical variables were compared using the chi-square test with Bonferroni correction. Multivariate survival analyses were performed using the Cox-regression model after adjusting for age, gender, race/ethnicity, comorbidity index, insurance status, laterality, definitive surgery, radiotherapy, and chemotherapy. Results: We identified 26,346 patients, of which 2,520 had YOCC (9.6%, median age 44 years) and 23,826 had TOCC (90.4%, median age 68 years). Patients with YOCC were more likely to be non-White (YOCC 35.0% vs. TOCC 27.4%, p <0.01) and had lower overall comorbidity burden. Patients with YOCC were more likely to present with stage IV disease (YOCC 50.5% vs. TOCC 43.5%, p <0.001) and have intrahepatic cholangiocarcinoma (YOCC 56.0% vs. TOCC 45.5%, p<0.001). Patients with YOCC were more likely to receive definitive surgery (YOCC 30.9% vs. TOCC 25.0%, p <0.001) radiation (YOCC 27.7% vs. TOCC 19.0%, p<0.001), and chemotherapy (YOCC 73.1% vs. TOCC 50.4%, p<0.001). In adjusted analyses, patients with YOCC had a 21% decreased risk of death compared to patients with TOCC [HR 0.79 (95% CI 0.75-0.83), p<0.001)]. This remained true for subgroups of patients with intrahepatic disease and those who underwent definitive surgery. Conclusions: YOCC constitutes a small but distinct subgroup of cholangiocarcinoma. Patients with YOCC were more likely to be non-White and present with intrahepatic cholangiocarcinoma disease. Despite being more likely to be diagnosed with advanced stage cholangiocarcinoma, patients with YOCC had better overall survival.
Natural history of patients with advanced cholangiocarcinoma and FGFR2 gene fusions/rearrangements.
Authors: Shroff Rachna T. , Avogadri Francesca , Weng Richard , Li Ai , Dambkowski Carl L. , Lamarca Angela
Published: January 2022

391

Background: Cholangiocarcinoma (CCA) is a rare malignancy associated with poor survival. Molecular profiling is important to inform treatment choices and FGFR2 fusions or other rearrangements are common, occurring in 10–16% of patients with intrahepatic CCA (iCCA). There is limited real-world data on the natural history of patients with advanced CCA and FGFR2 fusions/rearrangements receiving therapies for advanced disease. The primary objective of this retrospective, observational natural history study was to compare real-world overall survival in patients with advanced CCA and FGFR2 fusions/rearrangements vs. those with wild-type (WT) FGFR2 from the index date of diagnosis of advanced CCA to date of death. A secondary objective was to analyze overall survival in the subgroup of patients with CCA and FGFR2 fusions/rearrangements from the index date of start of second-line therapy to date of death. Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine clinico-genomic database. Data originated from approx. 280 US cancer clinics (̃800 sites of care). Patients were ≥18 years of age, had chart-confirmed advanced CCA, comprehensive genomic profiling demonstrating FGFR2 fusion/rearrangement, and had ≥2 visits within the Flatiron Health network since January 1, 2011. Results: As of May 2020, 571 patients met the inclusion criteria; 75 patients with FGFR2 fusions/rearrangements (median age 63 years; 64% female; 95% iCCA; 68% stage IV at initial diagnosis), and 496 patients with WT FGFR2 (median age 65 years; 48% female; 74% iCCA; 55% stage IV at initial diagnosis). Median overall survival from the index date of diagnosis was numerically higher, but not statistically different, for patients with FGFR2 fusions/rearrangements vs. WT FGFR2 (12.1 months [95% CI 8.5−17.1] vs. 7.1 months [95% CI 5.7−8.8]; log rank p = 0.184). 50 patients with FGFR2 fusions/rearrangements (median age 62 years; 70% female; 94% iCCA; 70% stage IV at diagnosis) received second-line therapy. Median real-world overall survival from the index date of second-line therapy was 8.5 months (95% CI 4.1−12.4 months). Conclusions: These real-world overall survival findings did not demonstrate a survival advantage for patients with CCA and FGFR2 fusions/rearrangements vs. WT FGFR2 receiving therapies for advanced disease, although a non-significant trend towards longer overall survival was observed in patients with FGFR2 fusions/rearrangements. FGFR2 status was not a significant predictor of overall survival after adjusting for potential prognostic covariates. An additional analysis is ongoing to compare overall survival from the start of second-line therapy in patients with advanced CCA and FGFR2 fusions/rearrangements vs. those with WT FGFR2.
Ramucirumab for HCC patients who experienced two or more systemic therapy: A multicenter study.
Authors: Yasui Yutaka , Kurosaki Masayuki , Tsuchiya Kaoru , Hayakawa Yuka , Hasebe Chitomi , Abe Masami , OGAWA CHIKARA , Joko Kouji , Tada Toshifumi , Nakamura Shinichiro , Furuta Koichiro , Kimura Hiroyuki , Tsuji Keiji , Kojima Yuji , Akahane Takehiro , Tamada Takashi , Uchida Yasushi , Kondo Masahiko , Mitsuda Akeri , Izumi Namiki ,   Japanese Red Cross Hospital Liver Study Group
Published: January 2022

395

Background: Ramucirumab has been approved for hepatocellular carcinoma (HCC) patients whose α-fetoprotein was≥400 ng/mL as a second-line agent after sorafenib. The present study aimed to clarify the efficacy and safety of ramucirumab including patients who experienced two or more systemic treatments or whose hepatic reserve was deteriorated. Methods: We enrolled 76 unresectable HCC patients from 14 institutes. The data, regarding survival, radiological response, and adverse events were retrospectively collected. This cohort included 35 patients who received more than two molecular targeted agents and 29 Child-Pugh B or C patients. The radiological response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results: Median overall survival (OS) in the total cohort was 7.5 months (m), whereas it was 7.5 m, 9.8 m, and 6.8 m in patients who were administered ramucirumab as the second-, third-, and fourth-line therapies, respectively. The overall survival of Child-Pugh A patients (n = 47) was significantly longer than that of Child-Pugh B/C patients (n = 29) (OS 10.3 m vs. 6.7m, p = 0.04). Progression-free survival in the second-, third-, and fourth-line therapies was 3.7, 2.2, and 3.4 m, respectively. The best response identified by RECIST version 1.1 was partial response (PR) in one patient and stable disease (SD) in 25 patients, and the disease control rate (DCR) in the study was 49.1%. There were no statistically significant differences in DCR between the treatment courses. Regarding adverse events, there was no difference between the treatment courses. However, peripheral edema, the development of ascites that required the administration of diuretics (Grade ≥ 2), and diarrhea were significantly more frequent in Child-Pugh B/C patients than in Child-Pugh A patients (peripheral edema; 65.5% vs . 31.9%, p = 0.005, ascites; 62.0% vs . 19.1%, p < 0.001, diarrhea; 27.6% vs . 8.5%, p = 0.05). Conclusions: Ramucirumab was useful as a second-line therapy and feasible as a third- or fourth-line treatment for HCC.
Single-center real-world treatment and outcomes in patients with hepatocellular carcinoma receiving immunotherapy.
Authors: Habib Diane , Patel Ronak , Algaze Sandra , Iqbal Syma , Chiu Victor Yundeh , El-Khoueiry Anthony B.
Published: January 2022

401

Background: Immune checkpoint inhibitor (ICI) based therapy has emerged as a therapeutic option in hepatocellular carcinoma (HCC). Approvals were based on clinical trials with strict eligibility criteria limiting generalizability to clinical practice. Further, there is no established post ICI treatment standard. Methods: Patients (pts) with advanced HCC treated with ICI as single agent (ICI-SA) or in combination (ICI-C) across lines of therapy were included in this retrospective study. Results: The cohort consisted of 118 pts: median age 63 years (24, 88); 84% male; 35% Hispanic/Latino, 26% Asian, 19% Non-Hispanic White, 5% Black and 15% unknown. Etiology of cirrhosis: 13% Hepatitis B, 45% Hepatitis C, 16 % alcohol liver disease, 10% NAFLD and 16 % mixed/other; 73% had baseline Child Pugh (CP) A, 25% had CP-B, and 2% had CP-C; ALBI Scores were ≤ -2.60 in 32%, 2.60 < and ≤-1.39 in 48%, and ≥-1.39 in 19% pts; 62% had extrahepatic disease and/or portal invasion; AFP was ≥ 400 ng/mL in 25% of pts. 81% of pts had prior local therapy. First line systemic therapies were: TKIs in 52 pts (44%), ICI-SA in 42 (36%), ICI-C in 15 (13%), clinical trial agent (CTA) in 8 (7%) and chemotherapy in 1 (1%), with a median duration (dur) of 4 months (95% CI 2.3 to 4). Ninety one (77%) and 61 pts (52%) received ≥ 2 or 3 lines of therapy, respectively. Fifty seven pts had ICI-SA and 14 ICI-C in second line or beyond. Median dur of ICI therapy was 4 months (95% CI 3-5) for all lines. Post-ICI therapies included 11% ICI, 30% CTA and 59% TKIs. TKIs included sorafenib (46%), cabozantinib (27%), lenvatinib (15%), and regorafenib (27%). For the 118 pt cohort, mOS was 14 months (95% CI 12-19). For pts treated with ICI in first line, mOS was 11 months (0, 74); post-ICI mOS was 6 months (95% CI 3-9) and mPFS was 3 months (95% CI 2-3). Thirty one pts received a TKI post ICI; mOS for this subset was 19 months (15, 22); mOS from start of TKI post ICI was 6.5 months (4, 12). On multivariable regression analysis, ALBI score was associated with OS (HR 1.63, p=0.02, CI: 1.08-2.27). Conclusions: Pts with advanced HCC and CP-A or B cirrhosis are able to receive sequential systemic therapy including ICI. Survival outcomes in this cohort are impacted by the inclusion of patients with more compromised liver function and less restrictive pt selection compared to clinical trials. Usage of TKIs post ICI is feasible with suggestion of clinical activity but this is an area in need of prospective studies.
A phase 1 study of ABX196 in combination with nivolumab in patients with previously treated hepatocellular carcinoma (HCC).
Authors: Sigal Darren , Bhangoo Munveer Singh , Frenette Catherine T. , Lee Sunyoung S. , Fark Christine , Gineste Paul , Vissian Anais , Teyton Luc , Pearce Tillman E. , Kaseb Ahmed Omar
Published: January 2022

429

Background: ABX196, a synthetically modified α-galactosylceramide (α-GalCer), activates invariant NKT (iNKT) cells and produced anti-tumor activity in Hepa 106 xenograft HCC models. Pre-administration of anti-PD1 antibodies prevented α-GalCer-induced iNKT cell anergy and may also enhance iNKT cell-induced T cell response. We report on a phase 1 study evaluating the combination of ABX196 plus nivolumab (N) in HCC patients previously treated with at least 1 line of prior systemic therapy. Methods: In a 3+3 dose escalation design, intramuscular ABX196 was dosed at 0.1, 0.2, or 0.4 µg 120 mins after N infusion on day 1 of every other 28-day cycle. N (240mg) was administered intravenously on day 1 and 15 of each cycle. Key objectives were to assess safety, MTD, and signs of clinical benefit. Study endpoints included incidence and severity of AEs, laboratory parameters, DLTs, ORR, and PFS. Results: 10 patients (8 males, 2 females) were enrolled: median age, 66y (49-76y); median # of prior systemic therapies, 2 (1-3), including 9 patients with prior immune checkpoint inhibitor (ICI) therapy; median # of ABX196 doses, 2.5 (1-8). There were 76 AEs (95% G1/G2) and 1 non-treatment related SAE. Common non-serious AEs included diarrhea (6), malaise/fatigue (6), AST/ALT increase (6), and only 1 injection site reaction. Maximum administered dose was 0.4 μg; MTD not reached. Clinical benefit was observed in 5 patients (50%) including 1 patient with a PR (ORR 10%) and 4 patients with SD (40%). Of these 5 patients, 3 had viral hepatitis. Median PFS for all patients was 113.5 days (49-450 days), but for those with clinical benefit it was 276 days (172-450 days). Conclusions: ABX196 plus N was very well tolerated without any DLTs or treatment emergent SAEs. In this small but heavily pre-treated HCC population, ABX196 plus N demonstrated promising signals of clinical benefit, including in patients with previous ICI therapy. These results support further clinical development of ABX196 in the front-line HCC setting. Clinical trial information: NCT03897543. [Table: see text]
Efficacy and safety of anlotinib with or without PD-1 blockades in the treatment of advanced primary hepatocellular carcinoma (HCC): A real-world exploratory study.
Authors: Chen Xiao-Qi , Zhao Yun-Xia , Zhang Chuan-Lei , Wang Xin-Ting , Yuan Chang-Wei , Ji Ai-Ying , Chen Xin-Ju
Published: January 2022

432

Background: Half of the new cases and deaths of HCC was observed in China all over the world in 2020. However, the prognosis of traditional treatments for patients (pts) with HCC was dismal currently. Small-molecule anti-angiogenesis targeted drugs and PD-1 blockades were proved to demonstrate potential efficacy in advanced primary HCC. Anlotinib was a novel oral multi-targeted tyrosine kinase inhibitor for tumor angiogenesis and proliferation, which had been licensed for treatment of considerable malignancies in China. However, the real-world evidence of anlotinib and PD-1 blockades in HCC was still scanty currently. Consequently, the aim of this study was to investigate the efficacy and toxicity of anlotinib with or without PD-1 blockades in the treatment of advanced primary HCC in real-world. Methods: Pts with advanced primary HCC who received at least 2 cycles of anlotinib (8̃12mg, po, d1̃14, q3w) were recruited in this study. Clinical efficacy and survival data was summarized, adverse events were documented retrospectively. The tumor response was assessed by investigator according to RECIST version 1.1 using CT scans. The primary endpoint was objective response rate (ORR), secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Results: From Jul 2019 to May 2021, a total of 28 eligible pts were screened. Among them, 12 pts received anlotinib as first-line treatment, 9 pts as second-line treatment and 7 pts as third-line treatment and above. In best overall response assessment, there were 5 CR (17.8%), 2 PR (7.1%), 13 SD (46.4%), 7 PD (25.0%) and 1 NE (3.5%). ORR was 25.0% (95%CI: 10.7̃44.9%) and DCR was 71.4% (95%CI: 55.3̃86.8%). At the data cut-off date, 15 pts discontinued treatment due to disease progression, the preliminarily prognostic results indicated that the median PFS of the 28 pts was 4.93 months (95%CI: 1.60̃8.26), and the median OS was 13.21 months (95%CI: 10.77̃15.65). Specifically, 14 pts combined with PD-1 blockades treatment, ORR was 28.6% (95%CI: 8.4̃58.1%) and DCR was 71.4% (95%CI: 41.9̃91.6%). The remaining 14 pts failed to receive PD-1 blockade combination therapy with the ORR of 21.4% (95%CI: 4.7̃50.8%) and DCR of 71.4% (95%CI: 41.9̃91.6%). The safety profile suggested that the most common drug-related adverse events were decreased appetite, fatigue, thrombocytopenia, hypertension, diarrhea, anemia, hand-foot syndrome, proteinuria and bleeding. The common grade 3 adverse event was bleeding (10.7%). Conclusions: Present study indicated that anlotinib-related regimens in the treatment of advanced primary HCC exhibited potential efficacy and manageable adverse events in real-world setting. The conclusion should be validated in more pts included subsequently.
Regorafenib in patients with unresectable hepatocellular carcinoma (uHCC) in routine clinical practice: Exploratory analysis of overall survival (OS) in the prospective, observational REFINE study.
Authors: Finn Richard S. , Kudo Masatoshi , Klümpen Heinz-Josef , Lim Ho Yeong , Merle Philippe , Ikeda Masafumi , Masi Gianluca , Frenette Catherine T. , Kim Yoon Jun , Gerolami René , Kurosaki Masayuki , Numata Kazushi , Pisarenko Julia , Ozgurdal Kirhan , Qin Shukui
Published: January 2022

433

Background: Regorafenib improved OS versus placebo in patients with uHCC who progressed on prior sorafenib in the RESORCE trial (Bruix J, 2017). An interim analysis of the observational REFINE study supported the safety and effectiveness of regorafenib in patients with uHCC in real-world clinical practice (Lim HY, 2021). Here we present an exploratory analysis of OS in REFINE by prior treatment. Methods: REFINE is a multicenter study that enrolled patients with uHCC for whom a decision to treat with regorafenib is made by the treating physician prior to enrollment according to the local health authority approved label. The primary objective of this study is safety, including the incidences of treatment-emergent adverse events (TEAEs) and dose modifications due to TEAEs (NCI-CTCAE v4.03). The secondary endpoints include OS, progression-free survival, and treatment duration. Results: Of the 1,031 patients enrolled, 1,008 were evaluable for interim analysis. At baseline, median age was 66 years (range 21–94); 62% of patients were Barcelona Clinic Liver Cancer stage C; 62% had Child–Pugh A disease; and 83% had an Eastern Cooperative Oncology Group performance status of 0 or 1. In total, 99% of patients received prior treatment: 96% had prior sorafenib, 9% had ≥1 prior immunotherapy (most common: nivolumab [50%] and pembrolizumab [21%]), and 6% had a multikinase inhibitor other than sorafenib (lenvatinib [62%]). The majority of patients experienced TEAEs (91%) and drug-related TEAEs (73%). Median OS was 12.9 months (95% confidence interval [CI] 11.4, 14.6). Subgroup analyses of OS by prior treatment are shown (Table). Conclusions: REFINE reflects the changing treatment landscape and supports the safety and effectiveness of regorafenib in real-world patients with uHCC who had prior systemic treatment other than sorafenib, including immunotherapy. This interim analysis suggests that patients who received regorafenib in the second line had longer OS than patients who received regorafenib in the third line and beyond. Clinical trial information: NCT03289273. [Table: see text]
Indirect treatment comparison of futibatinib with chemotherapy and pemigatinib in cholangiocarcinoma with FGFR2 fusions/rearrangements.
Authors: Borad Mitesh J. , Paine Abigail , Wacheck Volker , He Yaohua , Kazerooni Reza , Salimi Tehseen , Bridgewater John A.
Published: January 2022

440

Background: Futibatinib, an irreversible FGFR1–4 inhibitor, is being investigated for the treatment of advanced intrahepatic cholangiocarcinoma (iCC) with FGFR2 fusions/rearrangements. We conducted an indirect treatment comparison to evaluate efficacy outcomes with futibatinib for advanced iCC patients from the FOENIX-CCA2 trial (NCT02052778) relative to published data for chemotherapy and FGFR inhibitors. Methods: A systematic literature review was conducted to identify clinical trials for FGFR inhibitors published 01/2015-02/2021, with additional targeted searches for chemotherapy data. A simulated treatment comparison was conducted using individual-level patient data from FOENIX-CCA2 and published aggregate data from comparator trials, applying regression models to adjust for between-trial differences in baseline characteristics. Population-adjusted Cox regression models were used for base case time-to-event outcomes (progression-free survival [PFS], overall survival [OS], duration of response [DOR]) and binomial-logistic regressions for binary outcomes (objective response rate [ORR]). Results: Two studies of FGFR inhibitors among previously treated patients with FGFR2 fusions/rearrangements were identified with sufficient data for analysis: FOENIX-CCA2 (n=103) and FIGHT-202 (n=107, pemigatinib). Two studies were identified for chemotherapy in this setting (an analysis of prior systemic therapy in the FIGHT-202 cohort [n=53] and a natural history study using a clinicogenomic database [n=71]). Comparisons of futibatinib with chemotherapy showed significantly lower risk of progression or death with futibatinib (table). Comparisons of futibatinib with pemigatinib showed similar outcomes between treatments (table), however, there was a numerical advantage for futibatinib in all efficacy parameters. Conclusions: Data suggest that futibatinib provides longer survival vs chemotherapy among previously treated advanced iCC patients with FGFR2 fusions/rearrangements. No statistically significant differences were observed in efficacy outcomes between futibatinib and pemigatinib, although numerical trends favored futibatinib. Molecular detail such as improved activity against co-mutated tumours and resistance mutations may explain such trends. [Table: see text]
Phase II study of gemcitabine with oxaliplatin (GEMOX) in heavily treated patients with advanced hepatocellular carcinoma after failure of sorafenib treatment (PEACH).
Authors: Lee Choong-kun , Kim Han Sang , Choi Hye Jin
Published: January 2022

456

Background: Recent advances in treatment of advanced hepatocellular carcinoma (HCC) includes novel immunotherapy and anti-angiogenic tyrosine kinases. However, there is no treatment option for the heavily treated HCC patients, and the role of cytotoxic chemotherapy regimens, such as oxaliplatin based doublets, are unknown. We aimed to investigate the antitumor activity of gemcitabine and oxaliplatin in advanced HCC patients who failed sorafenib treatment. Methods: This prospective single-arm, single-center phase II trial was conducted in Yonsei Cancer Center, Korea. Gemcitabine 1000mg/m2 IV D1 and oxaliplatin 100mg/m2 IV D1 were given every 2 weeks to Child Pugh Class A or B7 HCC patients who progressed after or cannot tolerate sorafenib treatment. Patients with HCC of >60% liver occupation or portal vein invasion at the main portal branch (Vp4) were excluded. The primary endpoint was progression-free survival (PFS) rate at 6months and the secondary endpoints included PFS, overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety profile, and exploratory molecular biomarker analysis. Results: Total of 32 patients were treated between May 2015 and July 2019 with median follow up of 10.2 months. Most of the patients were ECOG PS 1 (93.8%), B-viral (90.6%), and BCLC-C (96.9%). Patients had multiple distant metastatic sites including lung (81.2%) and lymph node (34.3%). Patients were heavily treated with 25% of patients treated as fourth-line and 18.7% of patients treated as fifth-line or later. The PFS rate at 6 months was 15.6%. Median PFS was 3.87 months and median OS was 10.5 months. 9.4% of the patients achieved partial response, and DCR was 65.6%. Median number of treatment cycles were 6 (range, 3 to 25). Treatment-related AE (≥G3) occurred in 15 patients (46.9%) including 5 patients (15.6%) with asthenia, 5 patients (15.6%) with sensory neuropathy, and 4 patients (12.5%) with thrombocytopenia. Conclusions: Gemcitabine and oxaliplatin for sorafenib failed, heavily treated advanced HCC were tolerable and showed modest efficacy. Although novel agents are currently adopted in clinics to treat advanced HCC, gemcitabine and oxaliplatin could be considered as later-line treatment option for heavily treated HCC patients. Exploratory molecular biomarker analysis results will be presented.
Tumor treating fields (TTFields) in combination with sorafenib inhibit hepatocellular carcinoma in vitro and in vivo.
Authors: Potter Wyatt , Davidi Shiri , Jacobovitch Sara , Shteingauz Anna , Tempel-Brami Catherine , Zeevi Einav , Dor-On Eyal , Schneiderman Rosa S , Voloshin Tali , Tzchori Itai , Haber Adi , Giladi Moshe , Kinzel Adrian , Weinberg Uri , Palti Yoram
Published: January 2022

464

Background: Hepatocellular carcinoma (HCC) is a highly malignant liver cancer and a leading cause of cancer related mortality. Sorafenib was the first approved systemic treatment for HCC, and remains one of few front-line treatments for this malignancy. Tumor treating fields (TTFields) are low intensity (1-3 V/cm), intermediate frequency (100-500 kHz), alternating electric fields that exert antimitotic effects on cancerous cells. Results of the phase 2 HEPANOVA study of TTFields (150 kHz) plus sorafenib for advanced HCC support investigation of TTFields in a randomized controlled phase 3 study. The current research aimed to describe the in vitro and in vivo efficacy of this combination and to elucidate details regarding the underlying mechanism of action. Methods: In vitro examinations were performed in HepG2 and Huh-7D12 human HCC cell lines, to which TTFields at a frequency of 150 kHz were applied using the inovitro system. Autophagy was examined by western blot and fluorescence detection of microtubule-associated protein light chain 3 (LC3) levels, an accepted autophagy marker. The effect of TTFields in combination with sorafenib was evaluated using cytotoxic, clonogenic, and apoptotic assays. In vivo, SD rats were inoculated orthotopically into the left hepatic lobe with N1S1 HCC cells. 7 days later, TTFields or sham (heat) were applied to the abdominal region of the rats, continuously for 6 days. Daily intraperitoneal injections of sorafenib (10 mg/kg/day) or vehicle were performed during this time. To determine tumor volume growth, MRI images were acquired before and after treatment. Levels of autophagy and apoptosis were examined in tumor sections by immunohistochemistry for LC3 and cleaved PARP, respectively. Results: Application of TTFields induced autophagy in HCC cells. TTFields delivery was cytotoxic to the cells, reduced their colony forming ability, and induced apoptosis while combination with sorafenib elevated these effects. In vivo, tumor volume increased 6-fold in control animals vs 1.6-fold in animals treated with TTFields plus sorafenib. This effect was accompanied by significantly elevated levels of cleaved PARP and LC3 within the tumors of treated relative to control rats. Conclusions: The results demonstrate induction of autophagy and apoptosis in HCC following treatment with TTFields. Concomitant application of TTFields with sorafenib enhanced efficacy via a mechanism that may involve overwhelming autophagy, in vitro and in vivo.
The CCK-B receptor: A novel target for therapy of hepatocellular carcinoma.
Authors: He Aiwu Ruth , Gay Martha D , Cao Hong , Chen Wenqiang , Kallakury Bhaskar , Smith Jill P
Published: January 2022

466

Background: Today, the fastest growing cause of cancer-related death is hepatocellular carcinoma (HCC). Treatment with immune checkpoint antibodies has shown promise in HCC, but the response is still low at about 15%-20% as monotherapy. Our research laboratory discovered that the cholecystokinin-B receptor (CCK-BR) becomes over-expressed in the injured/ inflamed liver and is up-regulated in HCC. The primary aim of this study is to evaluate the effects of a CCK-BR antagonist, proglumide, alone and in combination with a PD-1 antibody (PD-1 Ab) on survival in HCC tumor-bearing mice and the tumor infiltrating T-cells. The secondary aim was to evaluate the frequency of CCK-BR expression in human HCC. Methods: RNA was extracted from murine RIL-175 HCC cells and subjected to qRT-PCR for gene expression of CCK-BRs, gastrin, and PD-L1. C57BL/6 mice (N = 40) were injected with RIL-175 HCC cells (100,000) subcutaneously. After one week when the mice had palpable tumors, they were divided into 4 groups (N = 10ea) of equal tumor size. Treatment included: controls-untreated drinking water; proglumide (0.1mg/ml) in drinking water; PD-1Ab (50µg, ip, days 7, 14, 21 with untreated water); and combination therapy with PD-1 Ab (as above) and proglumide water. Mice were euthanized when tumors reached a diameter of 20mm according to IACUC guidelines. Tumors were stained with a CD8 antibody to evaluate CD8+ tumor infiltrating T-cells. CCK-BR protein expression in human liver tissues and human HCC was evaluated by immunohistochemistry using a tissue microarray (US Biomax). Results: RIL-175 murine HCC cells exhibited increased expression of CCK-BR, gastrin, and PD-L1 by qRT-PCR. Survival of mice treated with the combination of proglumide and the PD-1 Ab was double that of the control mice and greater than proglumide or PD-1 Ab monotherapy. Compared to tumors of control mice, tumors of mice receiving proglumide monotherapy exhibited a 5-fold increase in CD8+ cells (P = 2.5x10-8), and there was a 12-fold increase in CD8+ T-cells in tumors of mice treated with the combination therapy (P = 4.7x10-17). In the human liver tissue microarray, immunoreactivity for the CCK-BR was negative in the normal human liver tissues and increased with the grade of HCC tumor (P = 0.0045) with 84.6% of grade-3 human HCC tissues staining positive for CCK-BR. Conclusions: The CCK-BR may provide a novel target for therapy in HCC. Treatment with the CCK-BR antagonist, proglumide, in combination with a PD-1 Ab appears to be synergistic improving the survival of mice by increasing the number of intratumoral CD8+ T-cells.
Molecular profiling to identify potential therapeutic targets in hepatocellular carcinoma.
Authors: Kundranda Madappa N. , Routh Josh , Kemkes Ariane C. , Turner Michelle , Therala Nishitha , Hall David W. , Flannery Cynthia A. , Evans Mark C. , De La O Jean-Paul , Thakkar Snehal Govind
Published: January 2022

471

Background: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is often diagnosed at an advanced stage with limited effective therapies. The advent of comprehensive genomic molecular profiling has the potential to identify novel therapeutic options in the treatment of HCC. In this descriptive clinical utility study, we evaluated the utility of the Oncotype MAP Pan-Cancer Tissue (MAP) test to identify potential therapeutic options, including clinical trials. Methods: Between October 2018 and October 2020, we identified 41 samples from patients with HCC submitted for MAP testing. The MAP test uses tumor tissue to identify single nucleotide variants, indels, copy number alterations, and select structural variants and fusions by next-generation sequencing (NGS) of a 257 gene panel. Tumor mutational burden and microsatellite instability are also determined. A custom immunohistochemical (IHC) panel is also performed. Results from NGS and IHC are run against a proprietary knowledgebase of genomic and proteomic data that includes FDA approvals, NCCN Recommendations and published biomarker data on potentially targetable alterations. Eligibility for ongoing clinical trials is determined using the NCI database. Results: Of the 41 samples, 37 (90%) met minimum tissue requirements (3mm2 and 15% tumor cellularity) for DNA sequencing. Of these 37 samples, 36 (97%) were successfully sequenced for NGS testing. Median turnaround time from the date of accessioning to the date of laboratory report was 5 days (interquartile range (IQR) 4-6 days). The most frequently identified genomic variants characterized as pathogenic, or unknown significance, were TP53, CTNNB1 and FAT1 genes. Thirty-two samples (86%) had a genomic alteration that could potentially direct treatment. Six samples (16%) had findings directing to an approved treatment for HCC, 4 (11%) had findings for an approved treatment of a different tumor type, and 22 (59%) had findings for one or more clinical trials. Conclusions: The Oncotype MAP Pan-Cancer Tissue test identified molecular variants that could be used to inform treatment decisions in 86% of HCC samples, including 16% to an approved HCC therapy. The Oncotype MAP test may be considered as another tool in the management of advanced HCC patients.
Plasma hPG80 (circulating progastrin) as a novel prognostic biomarker for hepatocellular carcinoma at early to intermediate stages (BCLC 0 to B).
Authors: Prieur Alexandre , Dupuy Marie , Iltache Sarah , Assenat Eric
Published: January 2022

472

Background: Alpha-fetoprotein (AFP) is the most widely used biomarker for hepatocellular carcinoma (HCC) prognosis. However, AFP is not useful in establishing a prognosis for patients with a tumor in the early stages. hPG80 (circulating progastrin) is a tumor promoting peptide present in the blood of patients with various cancers including HCC, even at early stages. In this study, we evaluated the prognostic value of plasma hPG80 in patients with HCC at early and intermediate stages. Methods: A total of 79 HCC patients including 44 BCLC from 0 to A and 35 BCLC B managed with local or systemic treatments, (“Liverpool” biobank) were enrolled prospectively and analyzed retrospectively. hPG80 was quantified using DxPG80 Lab kit (ECS-Progastrin) with a limit of detection at 1 pM and AFP was quantified using Cobas E411 in the blood of HCC patients. An optimal cutoff value of hPG80 was identified at 4.5 pM by calculating the minimal p-value based on the log-rank method. For AFP, a cutoff of 100 ng/mL was used as for liver transplantation (Notarpaolo, 2016). The prognostic impact of hPG80 and AFP levels on patient overall survival (OS) was assessed using Kaplan-Meier curves and log-rank tests. Results: hPG80 was detected in 36 of 44 (81.8%) HCC patients at stages BCLC 0 to A and 29 of 35 (82.9%) at stage BCLC B by contrast to AFP present in only 5 (11.4%) and 9 (25.7%) patients respectively. The median of hPG80 was 5.7 pM (IQR: 1.7-22.4 pM) at stages BCLC 0 to A, 6.0 pM (IQR: 1.5-22.2 pM) at stage BCLC B and significantly different from a non-HCC age-range matched control group cohort (median value: 1.5 pM, IQR 0.6-3.2 pM, p < 0.0001). When combining BCLC 0 to B, the median OS for hPG80+ patients (n = 46) was significantly shorter than that of hPG80- patients (n = 33) (25 months versus undefined, HR: 3.07, 95% CI: 1.46-6.43; p = 0.0064). AFP+ patients were also significantly correlated with poorer OS (17.5 months versus undefined, HR: 3.16, 95% CI: 1.06-9.47; p = 0.0030). Then, we evaluated the prognostic significance of hPG80 in combination with AFP levels. hPG80+ patients with AFP > 100 ng/mL (n = 46) had a worse OS than that of patients with AFP < 100 ng/mL patients (n = 33) (15.8 months versus undefined, HR: 6.38, 95% CI: 1.74-23.41; p = 0.0052). Conclusions: Our findings show that hPG80 could serve as a new prognostic biomarker for HCC patients at early to intermediate stages. These results will need to be confirmed in a prospective study, but it opens the possibility to use hPG80 as a biomarker for HCC patients at early stage at a time they can be treated to be cured.