bluuebunny/crossref_metadata_2025 huggingface dataset:
Utilization of liquid biopsy for advanced gastrointesinal malignancies in a community oncology practice.
Authors: Gupta Niraj K. , Zhang Crystal Siyu , Singh Kirpal , Glass Timothy , Patel Nikhil , Aburajab Murad , Al-Satie Mazen , Crawford Christopher , Anand Aneesha , Tian Jianmin , Rowe Michael , Cantafio Alex , Alkimawi Khalid , Gorantala Kalyan , Swingley Amanda , Puri Sonia , Yousef Mohamad , Shiyab Ala , Harshberger Carolyn , Saxe Jonathan ,   ASCO Oncology
Published: January 2021

127

Background: Liquid biopsy (LB) offers a non-invasive alternative for obtaining genomic signature of malignancies to develop a tailor-made treatment plan. We evaluated the feasibility and impact on clinical management of liquid biopsies performed on patients with advanced gastrointestinal malignancies in a community setting. Methods: A retrospective chart review of adult patients with stage-IV gastrointestinal malignancies was conducted to gather all the pertinent information, including diagnoses, treatment regimens, results of liquid biopsies and any impact on further management. Results: Data on 42 liquid biopsies performed between Aug 2018 and Mar 2020 was collected. M:F ratio was 1.4: 1. Median age was 57yrs (range 31-86). The diagnoses were; Colo-rectal Ca 22(54.7%), pancreatic 9(21.9%), gastric 2(4.7%), biliary 2(4.7%), HCC 2(4.7%), Appendix 1 (2.3%), CUP 1(2.3%) and others 3(7.1%). One (2.3%) LBs was done before first line treatment and 41(97.7%) were done after the failure of first line treatment. There was insufficient sample in the bx to do tissue-NGS for the pt. who had LB before starting treatments. Majority of LBs, 37(88%) were done after the failure of second line/later treatments compared to 5(12%) done after failing the first line treatment. Patient preference and technical challenge to obtain adequate tissue were the commonest reasons for getting the LBs. Results were available in all (100%) the cases. Median turnaround time was 8 days (range:7-13). The commonest mutations were TP53,APC, KRAS, PIK3CA, BRAF, SMAD4. BRCA-2 was identified in 1 pancreatic ca pt. MSI-H was noted in 3 patients; 2 with Colon ca, and 1 with CUP. An actionable alteration was seen in, 40 (95.2%) of the patients. A FDA approved target-matched drug was available for 27/40(67.5%) pts., if we also consider off-label usage. For those who had an alteration, but no FDA approved target-matched drug was available, 13/40 (32.5%), a clinical trial was available for all 13/13 (100%) of the pts.. 43% of those who had a FDA approved target-matched treatment available, but not approved for their disease, were able to receive the drug off-protocol. Two out of 13(15.3%) of the pts. who had a clinical trial available, were enrolled on a study. Conclusions: Liquid biopsies can be efficiently utilized in a community oncology practice. It offers an attractive option to gather genomic information of malignant cells in patients with advanced GI malignancies to be able to deliver state of the art care to all patients, including those who may not have a convenient access to a tertiary center.
Identification of transcriptomic determinants to predict the efficacy of anti-EGFR treatment of colorectal cancer patients.
Authors: Chowdhury Saikat , Shen John Paul Y.C.
Published: January 2021

130

Background: It is now well known that in colorectal cancer (CRC) activating mutations in KRAS, NRAS, and BRAF confer resistance to anti-EGFR therapy. However, only ~ 40% of patients with RASWT (KRASWT/NRASWT/BRAFWT) tumors respond to therapy. We have used transcriptomic data in addition to somatic mutations to decipher intrinsic resistance mechanisms and identify novel biomarkers of anti-EGFR response in CRC. Methods: The transcriptomic profiles of metastatic CRC patients treated with the anti-EGFR drug cetuximab plus chemotherapy (n = 193) or as a single agent (n = 80) were retrospectively obtained from two independent clinical cohorts (Okita et al., 2018; & Khambata-Ford et al., 2007). Tumor samples were further divided into RASWT and RASMut groups and subsequently in four consensus molecular subtypes (CMS) based on their transcriptomic profile. The transcriptomic profiles of cetuximab treated CRC cell lines (n = 148, Medico et al., 2015) and PDX models (n = 230, Bertotti et al., 2015) were used for validation. Results: In RASWT population of cetuximab plus chemotherapy cohort, the disease control rates (DCR) observed for cetuximab in the second line were 92% (33/36) for CMS2 and 83% (15/18) for CMS4 tumors relative to 50% (2/4) and 59% (13/22) for CMS1 and CMS3 respectively (Chi-square test p-value = 0.037). Similarly, in cetuximab single agent cohort, the DCR were 0% (0/4), 68% (15/22), and 29% (5/17) for CMS1, CMS2, and CMS4, respectively (Chi-square test p-value = 0.029). In the preclinical study of 148 CRC cell lines, 60% (12/20) of CMS2 cell lines with RASWT genes were sensitive to cetuximab, versus no sensitive cell lines from other CMS (CMS1 = 0/4; CMS3 = 0/5; CMS4 = 0/12). In the PDX study, 84% (11/13) of CMS2 tumor showed clinical benefit, followed by CMS4 with 75% (6/8) in RASWT group (CMS1 = 2/5; CMS3 = 2/4). Gene Set Enrichment Analysis (GSEA) of tumor tissue samples identified that Myc (NES = 1.32, FDR = 0.3), E2F (NES = 2.24, FDR = 0.02), and mTOR (NES = 1.54, FDR = 0.1) pathways were active in the cetuximab refractory RASWT CMS2 patients relative to cetuximab sensitive tumors. Similarly, these pathways were also activated (FDR ≤ 0.05) in cetuximab resistant RASWT cell lines and PDX models, suggesting that preclinical models are appropriate for testing of potential therapeutic combinations to overcome resistance to anti-EGFR therapy. Conclusions: Resistance to anti-EGFR therapy in extended RASWT CRC tumors is mediated in part by transcriptional activation and can be predicted by consensus molecular subtype (CMS) and quantifying transcriptional states of Myc, E2F, and mTOR pathway gene sets.
Zanidatamab (ZW25) in HER2-expressing gastroesophageal adenocarcinoma (GEA): Results from a phase I study.
Authors: Meric-Bernstam Funda , Hamilton Erika P. , Beeram Muralidhar , Hanna Diana L. , El-Khoueiry Anthony B. , Kang Yoon-Koo , Lee Keun Wook , Lee Jeeyun , Rha Sun Young , Chaves Jorge M , Oh Do-Youn , Goodwin Rachel Anne , Ajani Jaffer A. , Gray Todd , Woolery Joseph , Elimova Elena
Published: January 2021

164

Background: For patients with human epidermal growth factor receptor 2 (HER2)-overexpressing GEA, trastuzumab in combination with chemotherapy is the only approved HER2-targeted therapy, and they have limited treatment options after progression. Zanidatamab, a HER2-targeted bispecific antibody, has shown durable anti-tumor activity with good tolerability in a range of HER2-expressing cancers. Methods: In this 3-part Phase 1 study (NCT02892123), zanidatamab (10 mg/kg QW, 20 mg/kg Q2W, or 30 mg/kg Q3W) is administered as a single agent (Parts 1 & 2; QW or Q2W) or in combination with chemotherapy (Part 3; Q2W or Q3W). Eligibility criteria includes GEA with HER2 expression as assessed by immunohistochemistry (IHC) 3+ or IHC 2+, progression after standard of care therapy, and measurable disease per RECIST 1.1 (Part 2 requirement only). Results: In Parts 1 and 2, 36 GEA patients have been treated with zanidatamab (QW [n = 5]; Q2W [n = 31]). In Part 3, 26 GEA patients have been treated (zanidatamab Q2W + (paclitaxel [n = 11] or capecitabine [n = 6]); zanidatamab Q3W + capecitabine [n = 9]). Conclusions: Zanidatamab, both as a single agent and in combination with chemotherapy, is well tolerated with promising and durable anti-tumor activity in heavily pretreated GEA patients (including prior HER2-targeted therapy). These data support further investigation of zanidatamab as a novel therapeutic for patients with HER2-expressing GEA. Clinical trial information: NCT02892123. [Table: see text]
Impact of socioeconomic status (SES) on colorectal cancer patient survival: An analysis of 890,867 patients in the National Cancer Database (NCDB).
Authors: Salem Mohamed E. , Trufan Sally Jeanne , Symanowski James Thomas , Kadakia Kunal C. , Puccini Alberto , Musselwhite Laura W. , Graves Kristi D , Hartley Marion L. , Kim Edward S. , Hwang Jimmy J. , El-Rayes Bassel F.
Published: January 2021

19

Background: SES has been associated with outcomes in cancer patients (pts). We examined associations between SES and survival of pts with colorectal cancers (CRC). Methods: The NCDB was used to examine the association of SES status with clinicopathological features and outcomes of colorectal cancer pts, categorized by the income and education level of their area of residence. Logistic regression, Cox proportional hazard model, and chi-square test were used to examine the differences between groups. Results: A retrospective analysis of 890,867 pts with CRC (right-sided 34.1%, transverse 11.9%, left-sided 46.2%, and rectal 7.8%) diagnosed between 2004 and 2016, was conducted. About half the pts were male (51.4%); 84.3% were white, 11.2% black, and 4.5% of other races. Overall, 30.8% of pts lived in the highest and 18.4% in the lowest income areas. Twenty-three percent lived in areas comprising the highest high school graduation rate areas (>93%), while 17.4% lived in the lowest (< 79%). Compared to pts living in high-income areas, pts living in the lowest income areas were more likely to be black (OR 6.2, 6.1-6.3), present at a younger age (18-30 yrs vs. >70 yrs; OR 1.28, 1.18-1.39), have T3/T4 disease at presentation (OR 1.03, 95%CI 1.02-1.04), left-sided tumors (OR 1.05, 1.04-1.06), higher Charlson-Deyo score (OR 1.34, 1.33-1.36), and have Medicaid (OR: 3.9, 3.8-4.0) or no health insurance (OR: 2.9, 2.8-3.0). Tumor location and grade, stage, age, sex, race, ethnicity, income, education, insurance status, Charlson-Deyo score, and type of treatment center were independent predictors for survival in the multivariate analysis. Pts living in the lowest income and lowest education areas had a 13% and 4% higher risk of death, respectively, compared to pts in the highest income areas and education areas. Black pts had a 7% increased risk of death. Pts with Medicaid and no insurance coverage had a 44% and 29% increased risk of death, respectively, compared to pts with private insurance. Conclusions: CRC pts living in areas of low income and low education had worse survival. Insurance status and type of treatment center also have a strong impact on survival. Sociodemographic characteristics need to be taken into account and studied further, with the aim of improving outcomes for all pts. [Table: see text]
Racial disparities negatively impact outcomes for patients with early-onset colorectal cancer independent of income or education status.
Authors: Kamath Suneel Deepak , Torrejon Nataly Valeria , Wei Wei , Tullio Katherine , Nair Kanika G. , Liska David , Krishnamurthi Smitha S. , Khorana Alok A.
Published: January 2021

20

Background: The incidence of colorectal cancer (CRC) in patients under age 50 is rising for reasons that are incompletely understood. We examined the effects of health disparities and socioeconomic factors on outcomes for patients with early-onset CRC compared to older-onset CRC. Methods: Patients with CRC from 2004-2015 in the National Cancer Database were included and categorized by age under or over 50 years. Differences in demographic, disease and treatment characteristics and socioeconomic factors between younger and older patients were assessed by Chi-square test. The effect of age, race, ethnicity, insurance status, community median income and community educational attainment on overall survival (OS) were assessed using Cox models. Subgroup analyses were carried out by factors with significant interactions with race. Bonferonni correction was used when indicated. Results: The study population comprised 1,061,204 patients, 108,058 (10.2%) of whom were under age 50. The proportion of patients diagnosed under age 50 increased over time: 9.4% in 2004-2006, 10.1% in 2007-2009, 10.5% in 2010-2012 and 10.7% in 2013-2015. Compared to older patients, young patients were more likely to be Black (15.1% vs. 11.3%) or Hispanic (8.6% vs. 4.6%) and to be diagnosed with stage 4 disease (24.9% vs. 17.0%), p < 0.0001 for all. Age < 50 years was associated with improved median OS (157.4 vs. 64.2 months, p < 0.0001). ). Black patients had the worst median OS (58.3 months) compared to White (67.0 months), Hispanic (91.6 months) or Asian (104.9 months) patients, p < 0.0001. Within the subgroup of early-onset CRC patients with private insurance, Blacks had worse OS compared to White patients at multiple community income and education levels. Older CRC patients did not demonstrate the same disparities. Asian and Hispanic patients had equivalent or better OS compared to White patients regardless of insurance type, income or education level. These data are shown in the Table. Conclusions: Early-onset CRC continues to increase. Patients with early-onset CRC are more likely to be Black or Hispanic and to present with stage 4 cancer compared to older patients. Alarmingly, Black patients showed worse OS compared to White patients in all income subgroups, even with private insurance. Much more work is needed to address the environmental factors and health disparities that lead to these outcomes. [Table: see text]
Results of a phase II trial of ramucirumab plus irinotecan as second-line treatment for patients with advanced gastric cancer (HGCSG 1603).
Authors: Kawamoto Yasuyuki , Yuki Satoshi , Sawada Kentaro , Nakamura Michio , Muto Osamu , Sogabe Susumu , Shindo Yoshiaki , Ishiguro Atsushi , Sato Atsushi , Tsuji Yasushi , Dazai Masayoshi , Okuda Hiroyuki , Sasaki Takahide , Harada Kazuaki , Nakano Shintaro , Nakatsumi Hiroshi , Sekiguchi Mari , Sakata Yuh , Sakamoto Naoya , Komatsu Yoshito ,   Hokkaido Gastrointestinal Cancer Study Group (HGCSG)
Published: January 2021

217

Background: Ramucirumab (RAM) is a fully human IgG1 monoclonal vascular endothelial growth factor receptor-2 (VEGFR-2) antibody. The RAINBOW trial showed RAM plus paclitaxel (PTX) increased overall survival (OS) compared with PTX alone for advanced gastric cancer (AGC) in second-line treatment. WJOG 4007 trial demonstrated equivalent efficacy between irinotecan (IRI) and PTX. We conducted this trial to examine the efficacy and safety of RAM plus IRI combination therapy in the second-line treatment for AGC. Methods: This non-randomized, single arm, phase 2 trial was carried out at 22 institutes in Japan. AGC patients with refractory or intolerance to primary chemotherapy were eligible. RAM 8 mg/kg and IRI 150 mg/m2 combination therapy administered every two weeks were continued until progression or emergence of adverse events requiring discontinuation. The primary endpoint was progression-free survival (PFS) rate at six-month, the target was set as 16% with an expected threshold of 39%. A total of 35 cases are planned for registration. The secondary endpoints were OS, PFS, response rate (RR) and safety. This trial was registered with Japan Registry of Clinical Trials, number jRCTs011180029. Results: Between Jan 2018 and Sept 2019, 35 patients were enrolled. Median age was 70 (range, 47-80); female/male were 10/25; ECOG PS 0/1, 22/13. PFS rate at six months was 26.5% (95%C.I., 13.2-41.8%, p = 0.1353). Median PFS and OS were 4.2 (95%C.I., 2.5-5.4 months) and 9.6 months (95%C.I., 6.5-16.6 months), respectively. RR was 26% and disease control rate was 85%. Grade 3 or higher adverse events that occurred in more than 5% of patients were neutropenia (51%), leucopenia (43%), anemia (20%), anorexia (14%), febrile neutropenia (11%), diarrhea (9%), hypertension (9%), proteinuria (9%), hypokalemia (9%), hypoalbuminemia (9%), thrombocytopenia (6%), and hyponatremia (6%). No death and new safety signals with a causal relation to study treatment were observed. Conclusions: Although the primary endpoint was not achieved statistically, the results are clinically encouraging, especially take into account that more elderly patients enrolled in this trial. The combination of RAM plus IRI has anti-cancer activity and manageable safety profile in second-line treatment for patients with AGC. Clinical trial information: jRCTs011180029.
Phase Ib trial of varlitinib plus weekly paclitaxel in EGFR/HER2 co-expressing advanced gastric cancer (AGC).
Authors: Sang Yunbeom , Jung Minkyu , Kim Hyo Song , Kang Beodeul , Lee Choong-kun , Chung Hyun Cheol , Rha Sun Young
Published: January 2021

227

Background: EGFR and HER2 are over-expressed in gastric cancer, and activation of EGFR signaling in HER2-overexpressing gastric cancer can confer resistance to HER2-directed treatment like trastuzumab. Varlitinib (also known as ASLAN001) is a small-molecule, adenosine triphosphate competitive inhibitor of the tyrosine kinases - EGFR, HER2, and HER4. We present phase 1b results of the phase1b/2 study to evaluate the safety and efficacy of varlitinib in combination with weekly paclitaxel in EGFR/HER2 co-expressing AGC patients as a second-line treatment. (KCT0003583). Methods: An open-label phase Ib trial was conducted using a 3+3 design. AGC patients who had failed first-line fluoropyrimidine-containing chemotherapy, with evidence of both EGFR and HER2 overexpression by IHC (≥1+), were enrolled. The primary objective was to assess the dose limiting toxicity (DLT) and recommended phase 2 dose (RP2D) of varlitinib [Dose 1: 300 mg BID, Dose -1: 300mg intermittent dose] and weekly paclitaxel (80 mg/m2 D1,8,15) every 4 weeks along with evaluation of anti-tumor activity. Results: From July 2019 to May 2020, 9 patients were enrolled at Dose 1 level of varlitinib 300mg bid and 6 patients were evaluable for safety per protocol. Two patients did not finish DLT period: one patient withdrew after 1 week and one patient received palliative surgery for panperitonitis caused by gastric cancer metastasis. One patient had major violation in IP administration as the patient took varlitinib intermittently. Among the 6 evaluable patients, there was 1 DLT of G4 AST/ALT elevation and G3 hyperbilirubinemia, which resolved after 3 weeks. The most common treatment related adverse events (TRAEs) were neutropenia (n=5), all of which were grade ≥ 3, but no lasting more than 7 days. Grade 2 TRAEs included rash (n=2), mucositis (n=2) and peripheral sensory neuropathy (n=2). After a median follow-up of 3.0 (range, 1.9~ 6.2) months, the best responses were stable disease in 4 patients. Currently, 4 patients are ongoing. Conclusions: The combination of varlitinib 300mg bid and weekly paclitaxel 80mg showed manageable safety profiles and determined as RP2D. Currently, multi-site phase 2 part is now underway. Clinical trial information: KCT0003583.
Clinical and molecular characteristics of early-onset versus average-onset esophagogastric cancer.
Authors: Lumish Melissa Amy , Sabwa Shalom , Maron Steven Brad , Ku Geoffrey Yuyat , Ilson David H. , Won Elizabeth , Li Jia , Joshi Smita Suhas , Gu Ping , Strong Vivian E. , Molena Daniela , Jones David Randolph , Sihag Smita , Coit Daniel G. , Yoon Sam S. , Tang Laura H. , Hechtman Jaclyn Frances , Janjigian Yelena Y. , Cercek Andrea
Published: January 2021

250

Background: While the rate of esophagogastric (EG) cancer is declining, early onset (EO) gastric cancer prior to age 50 is rising. It is unknown whether EO-EG cancer represents a distinct entity. This study investigates the clinical and molecular characteristics of EO compared with average onset (AO)-EG cancers. Methods: We reviewed clinical and molecular features of gastric (G), esophageal (E) and gastroesophageal junction (GEJ) cancer in patients treated at MSKCC between 2005 and 2018. We defined early onset as age < 49, based on the age cutoff for urgent endoscopy referral. Clinical symptoms at diagnosis, primary tumor location, histology, HER2 and MSI status and molecular alterations were compared using Fisher’s exact test. Benjamini-Hochberg method was used to decrease the false discovery rate. Results: We analyzed 738 pts with EG cancer (age < 49 n=151; age >50 n=587). Race and sex were different with more Asian (19% vs. 9%), fewer Caucasian (62% vs. 81%) ( P<0.001) and more female patients (40% vs. 29%, P=0.014) in the EO group. Time from symptom onset to diagnosis was longer in the EO group (median (IQR) 144 d (66-276) vs. 75 d (34-136), P=0.009), though stage did not differ ( P=0.49). Patients with EO-EG cancer had less weight loss ( P<0.001), but no other distinct presenting symptoms. Primary disease site was different with more gastric in the EO group (66% vs. 55%, P=0.04). Signet-ring histology was more common in the EO group (11% vs. 3%; P=0.0009). ERBB2 amp and MSI-H were similar, with a trend toward more MSI-H in the AO group (ERBB2 amp P=0.88, Q=0.830; MSI-H P=0.0157, Q=0.056). The most frequent somatic alterations were similar in EO vs. AO pts, including TP53 (68% vs. 70%, P=0.370, Q=0.825), CDH1 (15% vs. 11%, P=0.139, Q=0.825), RHOA (6% vs. 5%, P=0.395, Q=0.825). There was a trend toward more ARID1A (19% vs. 7%, P<0.01, Q=0.250) and FBWX7 (5% vs. 2%, P=139, Q=0.825) mutations in the AO group. Conclusions: Presenting symptoms, stage, histology, HER2 and MSI status are similar in patients with EO vs. AO-EG cancer. There is a trend in EO toward longer time to diagnosis, gastric primary site of disease, signet-ring histology and fewer ARID1A and FBWX7 mutations. Expanded clinical and molecular data will be presented. [Table: see text]
Cross-sectional adherence with the multitarget stool DNA test for colorectal cancer screening in a large, national study of insured patients.
Authors: Miller-Wilson Lesley-Ann , Finney Rutten Lila J , Van Thomme Jack , Ozbay Burak , Limburg Paul J.
Published: January 2021

27

Background: Colorectal cancer (CRC) is the second most deadly and fourth most frequently diagnosed cancer in the United States. Early detection can improve CRC outcomes, but overall screening rates (62%) remain below the 80% goal set by the National Colorectal Cancer Roundtable. Multiple options are endorsed for average-risk CRC screening, including the multi-target stool DNA (mt-sDNA) test, which includes patient and provider navigation support. Cross-sectional adherence with the mt-sDNA test was previously reported in a large Medicare population (71%). In the current study we investigated cross-sectional adherence with the mt-sDNA test in a broader, national sample of insured patients. Methods: Aggregate data from Exact Sciences Laboratories LLC (ESL; Madison, WI) were retrospectively analyzed in compliance with HIPAA requirements. Study participants included individuals ages 50 years and older who were covered by commercial insurance or Medicare, had a valid mt-sDNA test order placed between January 1–December 31, 2018, and received a test kit shipped from ESL. Cross-sectional adherence, defined as successful completion and return of the test kit within 365 days of the shipment date, was assessed overall and by patient- and provider-level factors. Results: In total, 1,420,460 participants met the study criteria (61.2% women; mean age 65.7 years). Overall cross-sectional adherence was 66.8%. Adherence was 72.1% in participants with Traditional Medicare, 69.1% in participants with Medicare Advantage, and 61.9% in participants with commercial insurance (p<0.001). Adherence increased by participant age (p<0.001): 60.8% for ages 50-64, 71.3% for ages 65-75, and 74.7% for ages 76+ years. For Traditional Medicare patients, ages 65-75, adherence was 73.6%. Participants with mt-sDNA tests ordered placed by gastroenterologists had a higher adherence rate (78.3%) than those with orders placed by primary care clinicians (67.2%) (p<0.001). Adherence rates were highest among patients with ordering providers in the Pacific region (71.4%) and West North Central region (70.1%), and lowest in the Mid-Atlantic region (65.7%), New England (65.2%), West South Central region (64.6%), and Puerto Rico and US territories (60.7%). Conclusions: Novel data from this large, national sample of insured patients demonstrate high cross-sectional adherence with the mt-sDNA test (66.8%), supporting the substantial contribution this guideline-endorsed option plays in average-risk CRC screening. At the patient-level, adherence increased with patient age, and was highest in those covered by Traditional Medicare. Provider-level stratification showed the highest adherence for mt-sDNA tests ordered by gastroenterologists. This study adds to data regarding the impact of accompanying navigation support and at-home convenience of mt-sDNA on screening completion rates.
Longitudinal evaluation of quality of life (QoL) in patients (Pts) with FGFR2-driven cholangiocarcinoma (CCA) treated with pemigatinib.
Authors: Valle Juan W. , Bibeau Kristen , Cho Yohan , Ren Haobo , Féliz Luis , Lihou Christine Francis , Abou-Alfa Ghassan K.
Published: January 2021

276

Background: CCA is associated with poor prognosis and reduced QoL. In the phase 2 FIGHT-202 study (NCT02924376) of the selective oral FGFR1–3 inhibitor pemigatinib, 35.5% and 46.7% of pts with previously treated advanced CCA and FGFR2 fusions/rearrangements (RE) had a complete or partial response (CR/PR) and stable disease (SD), respectively; 14.9% had progressive disease (PD) [Abou-Alfa et al., Lancet Oncology 2020;21:671-684]. QoL was an exploratory endpoint. Methods: Pts received pemigatinib 13.5 mg once daily (21-day cycle; 2 weeks on, 1 week off). QoL was assessed longitudinally by best overall response (BOR) per RECIST with the EORTC-QLQ-C30 and the biliary tract cancer-specific EORTC-QLQ-BIL21 questionnaires. QoL scores and longitudinal changes from baseline (BL) were analyzed using descriptive statistics. Treatment-related changes in QoL were a priori expected to be evident by cycle 6 day 1 (week 16). Results: Of 107 pts with FGFR2 RE, 100 (93%) were evaluable for QoL, including36, 48, and 15 with CR/PR, SD, and PD, respectively. From BL to week 16, QLQ-C30 overall health status was maintained in pts with CR/PR and SD and worsened in pts with PD (Table). Emotional functioning remained stable and similar in pts with CR/PR and SD but worsened in pts with PD. All subgroups showed decline in role and social functioning. Pts with CR/PR and SD experienced decreases in QLQ-BIL21 pain and anxiety; all subgroups showed increases in QLQ-BIL21 treatment side effects. Conclusions: In these pts with advanced CCA, those with an SD as BOR had a similar pattern of changes in QoL as those with CR/PR to pemigatinib. Changes in QoL were directionally more favorable in pts with CR/PR or SD than pts with PD. Clinical trial information: NCT02924376. [Table: see text]
The dose-optimisation of lenvatinb for patients with unresectable hepatocellular carcinoma in clinical practice: A retrospective analysis of real-world evidence in China.
Authors: Zhang Lan , Wang Yanhong , Ge Ningling , Gan Yu-Hong , Ren ZhengGang , Chen Yi ,   Liver Cancer Institute, Zhongshan Hospital, Fudan University
Published: January 2021

280

Background: Lenvatinib has become available as first-line therapy in patients with unresectable hepatocellular carcinoma (u-HCC). Although 8mg or 12mg/day is the standard starting dose according to weight, the high rate of adverse events (AEs) leading to dose reduction often limits its application. Various dosing schedules are used clinically to alleviate toxicities in practice. This study evaluated the safety and antitumor activity of two dosing strategies for lenvatinib administrations. Methods: Patients administered lenvatinib for u-HCC between April 2018 and July 2019 were enrolled. The dose-escalation strategy was conducted as follow, starting dose 4mg/day orally with biweekly escalation (As common AE always occurred within 2 weeks after administered), per 4 mg increment, to 8 or 12mg finally per body weight if no significant drug-related (no more than G2) adverse events occurred. Patients with a standard-dose strategy (8/12mg/day orally per body weight) were also included for comparison.Objective response rate(ORR) and progression-free survival (PFS) were assessed according to RECIST1.1 criteria. Dose-reduction rate was recorded and treatment-related adverse events (TRAE) was evaluated according to the CTCAE 5.0. Results: Totally 56 patients were included (37 in dose-escalation group and 19 in standard-dose group). The mean weight was 64.79±1.66 kg in dose-escalation group and 58.76±2.45 kg in standard-dose group, BCLC stage C proportion was 51.4% and 63.2%, Child-pugh B proportion was 16.2% and 5.3% respectively. Baseline demographic parameters were comparable between two groups (P>0.05). There was no significant difference in response rate (32.43% vs 42.1%, P=0.335), disease control rate (86.4% vs 84.2%, P=0.686) and PFS (P=0.631). The proportion of patients who reached the full dose (per weight) was also similar (48.6% vs 63.2%, p=0.399). Dose reduction rate was significantly higher in standard-dose group than dose-escalation group (36.8%vs 13.5%,p=0.044). Although, no difference in grade 3/4 adverse events was found between two groups (P=0.083), patients in standard-dose group(36.8%,7/19) have a higher incidence trend of G3/4 AEs than those of dose-escalation group(16.2%,6/37). Conclusions: The dose-escalation strategy may be an alternative approach to prolong lenvatinib treatment period, with comparable efficacy and more tolerance. More data are needed to confirm the long-term efficacy and safety of the dose-escalation strategy.
Post hoc analysis in patients (pts) with unresectable hepatocellular carcinoma (uHCC) who progressed to Child-Pugh B (CPB) liver function in the phase III REFLECT study of lenvatinib (LEN).
Authors: Huynh Jasmine , Cho May Thet , Kim Edward Jae-Hoon , Ren Min , Robbins Carol , Amaya-Chanaga Carlos , Vogel Arndt
Published: January 2021

298

Background: The treatment landscape for pts with uHCC has recently expanded. However, there is an unmet need for effective treatment options in CPB pts. LEN is approved first-line in uHCC based on the REFLECT study (Child-Pugh A [CPA] pts were allowed, per inclusion criteria). In a prior analysis of REFLECT, pts treated with LEN benefited irrespective of baseline liver function (ALBI grade 1 or 2; Child-Pugh score 5 or 6). To determine outcomes in pts with reduced liver function, we report a post hoc analysis of key efficacy and safety results in LEN-treated pts from REFLECT who progressed to CPB and those who did not within the first 8 weeks of treatment. Methods: In REFLECT, pts with uHCC were randomized 1:1 to LEN (per bodyweight: 12 mg/day for ≥60 kg; 8 mg/day for < 60 kg) or sorafenib (400 mg twice daily) in 28-day cycles. This analysis assessed ORR. Landmark analyses (starting at week 8) of PFS, time-to-progression (TTP), and OS in CPB pts and in pts who remained CPA at 8 weeks post-randomization were also conducted. Tumors were assessed by mRECIST by independent imaging review. Safety was also assessed from baseline. Results: This subgroup analysis included LEN-treated pts (n = 60) who progressed to CPB within the first 8 weeks of treatment (CPB pts) and 413 pts who did not (CPA pts). At baseline, 26.7% and 73.1% of pts had an ALBI grade of 1 and 73.3% and 26.9% of pts had an ALBI grade of 2 in CPB and CPA pts, respectively. ORR was 28.3% (95% CI 16.9–39.7) for CPB pts and 42.9% (95% CI 38.1–47.6) for CPA pts. A landmark analysis showed a median PFS of 3.7 mos (95% CI 1.8–7.4) for CPB pts and 6.5 mos (95% CI 5.6–7.4) for CPA pts from the week 8 timepoint. Landmark analyses at week 8 also showed that the median TTP was 5.6 mos (95% CI 3.5–9.3) for CPB pts and 7.3 mos (95% CI 5.6–7.4) for CPA pts; the median OS was 6.8 mos (95% CI 2.6–10.3) for CPB pts and 13.3 mos (95% CI 11.6–16.1) for CPA pts per week 8 landmark analyses. As expected, efficacy appeared to be greater in CPA pts versus CPB pts; however, OS of 6.8 months in CPB pts after the week 8 landmark is notable. Moreover, median duration of treatment was 3.2 mos for CPB pts and 6.9 mos for CPA pts, thereby suggesting CPB pts can remain on LEN. The incidence of grade ≥3 treatment-related AEs (TRAEs) was 71.7% in CPB pts and 54.7% in CPA pts. TRAEs leading to discontinuation occurred in 18.3% of CPB pts and 7.5% of CPA pts. Conclusions: In this post hoc analysis of pts in REFLECT, we examine the key efficacy and safety results for LEN-treated pts who progressed to CPB by week 8. This post hoc analysis is limited by its descriptive nature; however, the results indicate that further study of LEN in CPB pts with uHCC is warranted. Clinical trial information: NCT01761266.
Real-world outcomes of patients with intrahepatic cholangiocarcinoma treated with trans-arterial radioembolization: Results from the CIRSE Registry for SIR-Spheres Therapy (CIRT), a large European prospective multi-center observational study.
Authors: Helmberger Thomas , Arnold Dirk , Balli Tugsan , Golfieri Rita , Pech Maciej , Ronot Maxime , de Jong Niels , Sangro Bruno
Published: January 2021

308

Background: Trans-arterial radioembolization (TARE) is a treatment option for patients with intrahepatic cholangiocarcinoma (ICC). The CIRSE Registry for SIR-Spheres Therapy (CIRT) is the first European prospective multi-centre observational study designed to evaluate the clinical outcomes of patients treated with TARE with SIR-Spheres Y90 resin microspheres for ICC in the multi-institutional real-life clinical setting. The study was conducted by the Cardiovascular and Interventional Radiological Society of Europe (CIRSE). Methods: Patients were enrolled prospectively between Jan 2015 and 31 Dec 2017. Eligible patients were adults treated with TARE with Y90 resin microspheres for ICC. Data on baseline characteristics and treatment intention/clinical context and dosimetry were collected, as well as follow-up data (every 3 months; for 24 months after treatment), including overall survival (OS), (hepatic) progression-free survival [(h)PFS], safety and Global Health Status (GHS, using the European Organisation for the Research and Treatment of Cancer QLQ-C30). Results: 120 patients were included from 18 sites in 8 European countries. Median age was 63 years (range: 29-86) and 54.2% were male. Median tumour to liver percentage was 12.8%. Median prescribed activity was 1.32 GBq for whole liver treatments (n = 49), 1.20 GBq for right lobe treatments (n = 56) and 0.82 GBq for left lobe treatments (n = 51). 97.5% of the delivered activity was within 90% of the prescribed activity. TARE treatment as a first line (L1) global strategy was applied in 39.1%, 27.4% as second line (after systemic therapy). Treatment intention was predominantly palliative (69.2%) or tumour shrinkage (20.8%). Median OS was 14.7 months (95% confidence interval (CI) 10.9 – 17.9). Median PFS was 5.7 months (95% CI 3.9 – 7.5), whereas hPFS was 6.2 months (95% CI 4.1 – 8.5). Mean GHS was 59.3 at baseline, 61.0 after 3 months, 56.0 at 6 months, 54.4 at 9 months and 63.0 after 1 year. Severe adverse events (grade 3 and 4) were found in 13 (10.8%) patients: (abdominal pain 3.3%, fatigue 1.7%, gastrointestinal ulceration 0.8%, gastritis 0.8%, radiation cholecystitis 0.8%, radiation-induced liver disease 1.7%, other 5.8%). Detailed subgroup analyses are currently being performed. Updated data describing OS, PFS and hPFS for L1 TARE vs TARE after systemic chemotherapy, as well as prognostic factors for OS, PFS and hPFS will be shown. Conclusions: The results from this large prospective multi-centre observational study shows that in the real-world context, TARE is applied early and successfully in the treatment pathway. TARE is shown to be an effective and safe treatment with no meaningful deterioration of quality of life. Clinical trial information: NCT02305459.
Alliance/CALGB 80802: Impact of hepatitis C (HCV) on doxorubicin (DO) + sorafenib (S) versus S in patients (pts) with advanced hepatocellular carcinoma (aHCC).
Authors: El Dika Imane H. , Geyer Susan Michelle , Nixon Andrew B. , Innocenti Federico , Shi Qian , Jacobson Sawyer B. , Yaqubie Amin , Lopez Juan C. , Huang Binhui , Tang Yi-Wei , Wen Yujia , Schwartz Lawrence Howard , Bertagnolli Monica M. , Meyerhardt Jeffrey A. , O'Reilly Eileen Mary , Venook Alan P. , Abou-Alfa Ghassan K.
Published: January 2021

325

Background: Alliance/CALGB 80802 randomized phase III trial evaluated DO+S vs. S in pts with aHCC, and showed no improvement in median OS. Multi-drug resistant pathway mitigation by the Ras/Raf/MEK/ERK pathway and bFGF-mediated activation of Raf-1 promotes the formation of antiapoptotic Raf-1 and ASK1 complex, induced by anthracyclines. S efficiently blocks NS5A-recruited c-Raf mediated HCV replication and viral gene expression. Once inhibited by S, VEGF expression of HepG2 may limit HCV cellular entry. Release of Raf-1-Ask-1 dimer and inhibition of Raf-1 via S putatively differ in the presence or absence of DO. We hypothesize treatment with S reduces HCV titer levels (TL) and influence pts’ outcome. Methods: In 80802 HCV pts, TL were evaluated in both arms at baseline and post-baseline at Day 1 of Cycles 2, 3, and every 2 cycles and at progression or discontinuation of therapy. HCV undetectable (HCV-UN) levels were defined as < 50 copies/mL. TL were evaluated in relation to OS and PFS. HCV RNA levels were measured by TaqMan PCR and by genotype. Results: Of 356 pts, 83 were HCV+ with more Black/African American (25/50 = 50%) vs. White (54/239 = 23%) or other race groups (4/67 = 6%) (p < 0.0001). HCV titer data were available on 54 pts (S: 28, DO+S: 26). At baseline, 12 pts (S: 7, DO+S: 5) were HCV-UN, and post-baseline HCV TL did not significantly differ between treatment arms; one patient in each arm went from detectable (HCV-D) to HCV-UN. Post-baseline, 40 pts were HCV-D vs. 14 who were HCV-UN (S+DO: 8, S: 6 pts). Except for the two pts who became HCV-UN, baseline HCV-D vs. HCV-UN titers was similar to that status post-baseline. PFS and OS between HCV-D and HCV-UN both at baseline and post-baseline are delineated in the table. Conclusions: We observed that S did not influence HCV TL. Pts treated with DO+S vs. S had worse PFS if they had HCV-UN, and further that higher levels of HCV titers at baseline were associated with significantly improved PFS. Given the small sample size, these findings warrant further prospective evaluation. Support: U10CA180821, U10CA180882, U24CA196171; Bayer, Bristol-Myers-Squibb, and Sanofi. https://acknowledgments.alliancefound.org . Clinical trial information: NCT01015833. [Table: see text]
Safety and efficacy of combination of GT90001, an anti-activin receptor-like kinase-1 (ALK-1) antibody, and nivolumab in patients with metastatic hepatocellular carcinoma (HCC).
Authors: Hsu Chiun , Chang Yi-Fang , Yen Chia-Jui , Lu Li-Chun , Zhu Xiaoyan , Xu Yuwei , Zhou Qiaoxia , Dong Xunwei , Tong Youzhi
Published: January 2021

326

Background: GT90001, a fully human anti-ALK-1 mAb (IgG2) that may inhibit ALK-1/ TGF-β signaling and tumor angiogenesis, has shown good single-agent safety profile in humans. This study aimed to assess the safety and efficacy of GT90001 in combination with nivolumab in patients with advanced HCC who had progressive disease after or were intolerant to first-line sorafenib or lenvatinib therapy (NCT03893695). Methods: We did a phase I/II, open-label, single arm, dose de-escalation and expansion trial of GT90001 in combination with nivolumab in patients with histologically or cytologically confirmed HCC with Child-Pugh class A, ECOG performance status of 0 or 1 at three sites in Taiwan. Patients previously treated with immune checkpoint inhibitors were excluded. Stage 1 (dose de-escalation cohort) tested 3 doses of GT90001 (7 (starting dose), 4.5, and 3 mg/kg every 2 weeks) plus nivolumab 3 mg/kg every 2 weeks in 6 subjects at each dose level. Dose-limiting toxicity (DLT) was defined as any treatment-emergent grade 3-4 adverse events (AEs) (CTCAE V5.0) in the first 28 days of treatment. Stage 2 (expansion cohort) tested the combination regimen in 14 patients until loss of clinical benefit or unacceptable toxicity. The primary efficacy endpoint was investigator-assessed objective response as per RECIST v1.1. Results: Between July 9th, 2019 and June 26th, 2020, twenty eligible patients were treated. No DLT was observed in stage 1, and GT90001 7.0 mg/kg + nivolumab 3.0 mg/kg every 2 weeks were given in stage 2. The pharmacokinetics of GT90001 and nivolumab were similar to those observed in monotherapy. As of June 26, 2020, 20 patients were evaluable for safety. The common AEs (occurring to more than 20%) included platelet count decreased, rash, fatigue, dizziness, peripheral edema, and constipation. Three patients had treatment-related serious AEs (renal dysfunction, autoimmune hepatitis, hyperamylasemia). Nine patients had GT90001 dose interruption due to AEs and the most common reasons were platelet count decrease (3 patients). No patient discontinued the treatment due to AEs. The median duration of follow-up was 3.7 months (range 0.6-11.1). An objective response assessed was observed in 7 patients (43.75%) out of 16 evaluable patients, all were partial response and 4 of them had confirmed responses. The disease control rate (complete response + partial response + stable disease) was 56.2%. Updated efficacy data will be presented at the congress. Conclusions: The combination of GT90001 with nivolumab showed a manageable safety profile, and no new safety signals were identified. The promising preliminary antitumor activities show the potential of GT90001 combined with nivolumab as second-line treatment for advanced HCC. Clinical trial information: NCT03893695.
Role of ctDNA to predict risk of recurrence following potentially curative resection of biliary tract and pancreatic malignancies.
Authors: Lamarca Angela , McNamara Mairead Geraldine , Hubner Richard , Valle Juan W.
Published: January 2021

336

Background: The potential role of ctDNA to identify residual disease after potentially curative resection has been suggested in some malignancies; its role in resected pancreatico(P)-biliary(B) malignancies is unknown. Methods: Patients diagnosed with PB malignancies underwent molecular profiling (ctDNA) using FoundationMedicine Liquid (72 cancer-related genes) following potentially curative resection. Baseline patient characteristics and molecular profiling outcomes, including mutant allele frequency (MAF) for pathological alterations were extracted. Primary objective: prevalence of ctDNA identification and its correlation with recurrence (relapse-free survival (RFS) and relapse rate). Results: Total of 11 individuals had ctDNA analysed following potentially curative resection for PB malignancies: 8 B (4 extra-hepatic cholangiocarcinoma (eCCA), 2 ampulla, 1 intrahepatic cholangiocarcinoma (iCCA), 1 gallbladder cancer (GBC)) and 3 P. Baseline characteristics: 6 female (54.55%), median age 71.59 years (range 39.98-81.19). Most were pT2 (45.45%), pN0 (54.55%) and R0 (63.64%). Following surgery, 6 patients were started on adjuvant chemotherapy; at the end of follow-up (data cut-off 25/6/2020; median follow-up 11.15 months (range 5.45-13.52); 5 relapsed (45.45%) and 2 died (18.18%). Estimated median RFS was 11.43 months (95% CI 2.28-not reached); median overall survival was not reached. No sample failed ctDNA analysis; presence of ctDNA was identified in 3/11 (27.27%) of the samples; 2 and 1 samples had 2 and 1 pathological alterations identified, respectively: ALK fusion (1 sample; GBC), TP53 mutation (2 samples; eCCA and GBC), CHEK2 mutation (1 sample; pancreas), IDH2 mutation (1 sample; eCCA). Mean maximum MAF was 1.47 (2 in biliary; 0.43 in pancreas). Variants of unknown significance were identified in 72.73% of the samples (87.5% in B; 33.33% in P; p-value 0.152). None of the baseline characteristics explored correlated with presence of ctDNA. There was a trend towards increased relapse risk in the patients with ctDNA present following potentially curative surgery; Cox regression for RFS [HR 2.64 (95% CI 0.36-19.31); median RFS 11.44 months (95% CI 2.28-not reached) vs 10.87 (95% CI 2.21-not reached)]; relapse rate 37.5% (ctDNA absent) vs 66.67% (ctDNA present); statistical significance was not reached (p-value 0.340 and p-value 0.545, respectively). Conclusions: This pilot study demonstrates the feasibility of testing for ctDNA following potentially curative resection in PB malignancies. Presence of ctDNA may be associated with increased relapse risk; further studies are required to increase sample size and assess clinical implications.
Phase Ib/II study of pembrolizumab with lanreotide depot for advanced, progressive gastroenteropancreatic neuroendocrine tumors (PLANET).
Authors: Morse Michael , Halperin Daniel M. , Uronis Hope Elizabeth , Hsu David S. , Hurwitz Herbert , Bolch Emily , Warren Dana , Haley Sherri , John Lisa , Moyer Ashley , Rushing Christel N. , Niedzwiecki Donna
Published: January 2021

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Background: Pembrolizumab has antitumor activity in a subset of GEP-NETs patients. We hypothesized that the lanreotide, by its antitumor effects and reduction of serotonin, a modulator of immunity, would synergize with pembrolizumab in low/intermediate grade GEPNETs. Methods: GEP-NETs patients who had progressed on a prior somatostatin analogue received lanreotide 90mg sq and pembrolizumab 200mg IV every 3 weeks until progressive disease or intolerable toxicity. The primary endpoint was ORR at any time on study and secondary endpoints were PFS and OS. Results: 22 patients were treated (F/M 10/12; Caucasian/AA/other 10/7/5; GI/pancreatic 14/8; median Ki67 5%, median time since diagnosis 5.3 yrs (IQR 2.3-7.9 yrs)). Prior octreotide LAR/lanreotide/both was administered to 20/1/1. Patients had a median of 2 prior systemic therapies (range 1-9) and six had prior locoregional therapy and 3 external beam radiotherapy. Of the 12 tumors analyzed thus far, 4 had detectable PD-L1 expression and 11 had detectable TILs. A median of 6 pembrolizumab doses (range 2-15) and 7 lanreotide doses (range 2-15) were administered. Six patients experienced treatment related SAEs (abdominal pain, pneumonitis, colitis, and hyperglycemia, all related to the pembrolizumab). Selected treatment related adverse events included: Hypothyroidism 23%, colitis 9%, hyperglycemia 14%, and pneumonitis 5%. Best response by RECIST 1.1 was SD/PD/Not available:39/52/9% and by irRECIST was 43/48/9%. Median PFS was 5.4 months (95% CI 1.7-8.3 mo). The median overall survival at a median follow-up of 15 months was not reached. Peripheral blood immunologic correlates will be reported subsequently. Conclusions: In a population of GEP-NET patients, progressing on a median of 2 prior therapies, including prior somatostatin analogue therapy, a minority of whom had PD-L1 expressing tumors, the combination of lanreotide and pembrolizumab produced stable disease in approximately 40% of patients. No new safety signals were identified. Clinical trial information: NCT03043664.