bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical activity of avapritinib in ≥ fourth-line (4L+) and PDGFRA Exon 18 gastrointestinal stromal tumors (GIST).
Authors: Heinrich Michael C. , Jones Robin L. , von Mehren Margaret , Bauer Sebastian , Kang Yoon-Koo , Schoffski Patrick , Eskens Ferry , Mir Olivier , Cassier Philippe , Serrano Cesar , Tap William D. , Trent Jonathan C. , Rutkowski Piotr , Patel Shreyaskumar , Chawla Sant P. , Meiri Eyal , Zhou Teresa , Roche Maria , George Suzanne
Published: February 2020

826

Background: Targeting oncogenic KIT and PDGFRA mutations revolutionized treatment of patients (pts) with advanced GIST; however, nearly all pts succumb to resistant disease. Avapritinib is a potent and selective kinase inhibitor with broad activity against oncogenic KIT/PDGFRA mutants, including PDGFRA D842V and other primary or secondary resistance mutations. Results from the phase 1 NAVIGATOR (NCT02508532) study of avapritinib in pts with advanced GIST are presented. Methods: Adult pts with unresectable PDGFRA D842V or other mutant GIST who progressed on imatinib and ≥1 other tyrosine kinase inhibitor (TKI) were treated with oral, daily, continuous avapritinib. Adverse events (AE) and response by mRECIST 1.1 per central radiology were assessed. Overall population safety (30-600 mg starting doses) and efficacy in the response-evaluable 4L+ and PDGFRA Exon 18 (Ex 18) populations treated at the MTD (400 mg)/RP2D (300 mg) were analyzed. Results: As of 16 Nov 2018, 237 pts [172 KIT, 62 PDGFRA Ex 18 [56 D842V, 6 non-D842V), 2 PDGFRA N659K, 1 missing] were enrolled including 111 in the 4L+ population (primarily KIT, median 4 prior TKI) and 43 in the Ex 18 population (median 1 prior TKI). The 4L+ ORR was 22% [1 CR, 23 PR (1 pending)], and 52 SD with mDOR of 10.2 months (95% CI: 7.2–NE). The Ex 18 ORR was 86% [3 CR, 34 PR (1 pending)] and 5 SD; mDOR was not reached (95% CI: 11.3–NE). Most AEs were grade 1–2, most commonly nausea (63%), fatigue (58%), anemia (49%), periorbital edema (42%), diarrhea (40%), vomiting (40%), decreased appetite (38%), increased lacrimation (33%), peripheral edema (33%) and memory impairment (most common cognitive AE, 29%). 10% of pts discontinued due to a related AE. Grade 3–4 related AE ≥ 2% were anemia, fatigue, hypophosphatemia, hyperbilirubinemia, neutropenia, and diarrhea. Conclusions: Avapritinib has important clinical activity in pts with advanced GIST who have no effective therapies. The ORR and DOR of avapritinib in 4L+ exceeds that of approved 2nd and 3rd line therapies and shows impressive activity in D842V and other Ex 18 mutant PDGFRA GIST. Results suggest avapritinib has the potential to change the treatment paradigm of pts with advanced GIST. Clinical trial information: NCT02508532.
The role of circulating tumor DNA (ctDNA), tumor markers (TMs), and patient-reported outcomes (PROs) in predicting treatment response in patients with metastatic gastrointestinal (GI) cancer.
Authors: Parikh Aparna Raj , Fish Madeleine , Van Seventer Emily E. , Fosbenner Kathryn , Kanter Katie , Allen Jill N. , Clark Jeffrey William , Giantonio Bruce , Weekes Colin D. , Klempner Samuel J. , Franses Joseph Wang , Roeland Eric , Goyal Lipika , Wo Jennifer Yon-Li , Hong Theodore S. , Fetter Isobel , Siravegna Giulia , Horick Nora K. , Corcoran Ryan Bruce , Nipp Ryan David
Published: February 2020

833

Background: Changes in ctDNA and serum TMs (CEA and CA19-9) can serve as predictors of response to systemic therapy in GI cancer patients (pts). Similarly, PROs correlate with survival and treatment response. We present a preliminary analysis of ctDNA, TMs, and PROs in predicting treatment response. Methods: We are enrolling 200 pts in a prospective study with metastatic pancreatic (PDAC), colorectal (CRC), gastroesophageal (GE), and biliary cancers. We are collecting ctDNA, TMs (CEA for all tumor types; CA19-9 for PDAC, GE, biliary), and PROs (FACT-G for QOL [higher scores indicate better QOL]; ESAS-r and PRO-CTCAE for symptoms; and PHQ-4 [consists of GAD-2 and PHQ-2 for anxiety and depression]; higher ESAS-r, PRO-CTCAE, and PHQ-4 scores reflect greater symptom burden) at baseline and 4 weeks. ctDNA is benchmarked against somatic tissue alterations, and serially assessed by digital droplet PCR. We correlated median percent change from baseline to 4 weeks for ctDNA, TMs, and PROs with treatment response (clinical benefit [CB], progressive disease [PD]). Results: From April to August 2019, we have enrolled 38/45 (84.4%) eligible pts (median age = 64 years; 36.8% female). Among these 38 pts, tumor types are PDAC (36.8%), CRC (31.6%), GE (28.9%), and biliary (2.6%). 18/38 pts were evaluable for ctDNA. Change in ctDNA was -94.5% in pts with CB (n = 10) and -19.5% in pts with PD (n = 8; p = 0.025). No correlation was observed between CEA and treatment response (p = 0.367). Change in CA19-9 was -1.5% for pts with CB and +47% for pts with PD (p = 0.019). Changes in PRO-CTCAE (p = 0.345), GAD-2 (p = 0.697), and ESAS scores (p = 0.743) did not differ between pts with CB and PD. However, changes in PHQ-2 (CB 0% v. PD +22.5%; p < 0.001), PHQ-4 (CB -8.5% v. PD +5%; p = 0.015), and FACT-G (CB +30% v. PD +5%; p = 0.049) were significant. Conclusions: Preliminary analysis suggests that ctDNA and PROs demonstrate promising utility for early prediction of treatment response, with favorable performance relative to standard TMs. Further analyses of larger pt numbers in this ongoing study may clarify the use and integration of these measures to better predict pt outcomes.
Depression among older adults with gastrointestinal (GI) malignancies: Results from the Cancer and Aging Resilience Evaluation (CARE) registry.
Authors: Godby Richard , Al-Obaidi Mustafa , Smith Crystal Young , Kenzik Kelly , McDonald Andrew Michael , Paluri Ravi Kumar , Gbolahan Olumide B. , Bhatia Smita , Williams Grant Richard
Published: February 2020

92

Background: Depression among older adults with cancer is often under recognized and under treated. This study characterizes the burden of depression in older adults with GI malignancies and its relationship with geriatric assessment (GA) impairments, health-related quality of life (HRQOL), and healthcare utilization. Methods: Since September 2017, patients ≥60 years in GI oncology clinics at UAB were asked to complete a CARE GA questionnaire. We examined depression using the Patient-Reported Outcomes Measurement Information System (PROMIS) Depression 4 item short form; moderate/severe (mod/sev) depression was defined by a T-score ≥60. GA impairments, HRQOL (PROMIS Global-10), and healthcare utilization were compared between those with and without mod/sev depression using a Chi-squared or t-test. Results: A total of 462 enrolled; mean age was 69 (range 60-96), majority white (72%), males (52%), and with advanced stage (III/IV, 69.1%). Most common cancers were colorectal (36%), pancreatic (23%), or hepatobiliary (15%). Overall, 55 patients reported mild depressive symptoms (12%) and 60 (13%) were found to have mod/sev depression. Depressed participants did not differ in demographics or GI cancer type/stage. Those reporting mod/sev depression were more likely to report falls (44 v 19%, p<.001), impaired performance status (63 v 27%, p<.001), dependence in activities of daily living (ADL; 45 v 14%, p<.001), dependence in instrumental ADL (84 v 45%, p<.001), cognitive dysfunction (40 v 5%, p<.001), financial distress (37 v 23%, p=.03), anxiety (76 v 10%, p<.001), fatigue (88 v 54%, p<.001), and pain (70 v 32%, p<.001). Depressed patients reported lower physical (32 v 45%, p<.001) and mental (36 v 50%, p<.001) HRQOL sub-scores, as well as more emergency room visits (67 v 49%, p=.009), but no difference in hospitalizations. Conclusions: More than one out of eight older adults with a GI malignancy reported mod/sev depression, which was associated with impairment in several geriatric domains and overall quality of life. As depression is a pleiotropic yet treatable comorbidity, oncologists should prioritize its screening and treatment.
Avelumab and cetuximab in combination with FOLFOX in patients with previously untreated metastatic colorectal cancer (MCRC): Final results of the phase II AVETUX trial (AIO-KRK-0216).
Authors: Stein Alexander , Binder Mascha , Goekkurt Eray , Lorenzen Sylvie , Riera-Knorrenschild Jorge , Depenbusch Reinhard , Ettrich Thomas Jens , Doerfel Steffen , Al-Batran Salah-Eddin , Karthaus Meinolf , Pelzer Uwe , Simnica Donjete , Waberer Lisa , Hinke Axel , Bokemeyer Carsten , Hegewisch-Becker Susanna
Published: February 2020

96

Background: Single agent PD-1/L1 inhibition is efficacious in MCRC patients (pts) with high microsatellite instability (MSI-H). For the vast majority of MCRC pts with MS stable (MSS) phenotype the role of immunotherapy remains undetermined. Methods: The single arm phase II AVETUX trial combined mFOLFOX6 and cetuximab with avelumab (10mg/kg day 1 from cycle 2 onwards) in RAS/BRAF wildtype (local lab) MCRC pts. Primary endpoint was 12 month progression-free survival rate. Secondary endpoints included overall response rate (ORR), tolerability, overall survival and translational research evaluating tissue including PD-L1 expression (tumour/immune cells) and serial ctDNA. Efficacy analyses were done by intention to treat (ITT). Results: Overall 43 pts were enrolled. Median age was 61 (range 29-82), 14 pts (33%) were female and 39 (91%) left sided. 30 pts (70%) had liver mets and 17 (40%) liver mets only. 2 pts were MSI-H, one MSI-low and 40 MSS. Besides immediate and otherwise unexplained fever in 4 pts treatment was well tolerated and avelumab was not associated with unexpected adverse events to standard FOLFOX/cetuximab. Central tissue review found 4 pts to be ineligible due to low frequent KRAS or BRAF mutation (15-31%). Thus, ITT included 39 pts. The ORR was 79.5%, including 6 complete (CR) and 25 partial responses (PR). Further 5 stable diseases were noted, thus disease control rate was 92.3%; 2 pts had progression and 1 was not evaluable. Early tumor shrinkage (ETS) rate (≥20% after 8 weeks) was 79.5% (1 CR, 27 PR and 3 SD with ≥20% - < 30%). In MSI-H pts 1 PR and 1 SD and in the 3 low RAS mut pts 2 PR were noted. Panel sequencing was feasible with 153 mutations detected, showing an immediate ctDNA drop within 4 weeks of treatment, mirroring the high rate of early tumor response. Notably, the 4 pts with fever had a high T cell infiltration in the tumor. Final data including the primary endpoint and translational data will be presented at the meeting. Conclusions: The AVETUX regimen was feasible producing a high rate of responses in MSS pts mainly occurring within the first 8 weeks. The noted ORR/ETS of 79.5% warrants further evaluation in a randomized trial. Clinical trial information: NCT03174405.
mFOLFOXIRI with or without cetuximab as conversion therapy in patients with RAS/BRAF wild-type unresectable liver metastases colorectal cancer: The FOCULM study.
Authors: Hu Huabin , Wang Kun , Wang Wei , Qiu Meng , Lin Rongbo , Zhang Haibo , Liu GuangJian , Wan Yunle , Kang Liang , Wang Hui , Zhou Zhiyang , Li Fangqian , Huang Yan , Zhang Jianwei , Cai Yue , Wu Zehua , Ling Jiayu , Huang Meijin , Deng Yanhong
Published: February 2020

99

Background: Conversion therapy for unresectable colorectal liver metastases (LM) can downsize tumours and create a situation where the patient has no evidence of disease (NED). We assessed the effectiveness of cetuximab plus mFOLFOXIRI or mFOLFOXIRI in this setting. Methods: FOCULM was a prospective 2:1 controlled, multicenter, phase II trial. Given no free drugs offered and the patients' affordability for cetuximab, the study design has been amended from randomization to non-randomization since September, 2016. Patients with unresectable LM were assigned to receive cetuximab (500mg/m2) plus mFOLFOXIRI (oxaliplatin 85 mg/m2, irinotecan 165 mg/m2, folinic acid 400 mg/m2, 5-fluorouracil 2800mg/m2 46h infusion, every 2 weeks) (group A) or mFOLFOXIRI (group B). Primary endpoint was the rate of NED achieved, secondary endpoints were ORR, resection rate, the rate of local and ablative treatment (LAT), OS, PFS and DpR. Results: From February 2014 to July 2019, 114 patients were enrolled at 6 centers in China and 101 patients were in the ITT population (67 group A, 34 group B). Treatment groups were generally well balanced, although more patients with ≥5 LM were in group A. The rate of NED achieved was 62.7% in group A and 38.2% in group B (P = 0.020). At a median follow-up of 19.4 months, patients in group A had significantly prolonged the mOS, increased ORR, the rate of LAT and DpR compared with those in group B (Table). Patients with NED achieved yielded a significant survival benefit, whether in group A (Not reached vs. 49.4 months; P = 0.001) or group B (Not reached vs. 25.1 months; P = 0.007). Conclusions: The addition of cetuximab to a mFOLFOXIRI in patients with RAS/BRAF wild-type unresectable LM colorectal cancer significantly improved the rate of NED achieved, ORR and OS. Clinical trial information: NCT02063529.

[Table: see text]
AGENT: An open-label phase III study of arfolitixorin versus leucovorin in modified FOLFOX-6 for first-line treatment of metastatic colorectal cancer.
Authors: Lenz Heinz-Josef , Gibbs Peter , Stintzing Sebastian , Prager Gerald W. , Nygren Peter , Papadimitriou Christos A. , Tell Roger , Yoshino Takayuki , Jonker Derek J. , De Gramont Aimery , Tabernero Josep
Published: February 2020

TPS268

Background: 5-fluorouracil (5FU), in combination with folates, is an established cornerstone of metastatic colorectal cancer (mCRC) treatment. All folates currently approved for mCRC need to be metabolically activated to [6R]-5,10-methylenetetrahydrofolic acid ([6R]-MTHF), the active thymidylate synthase co-substrate that potentiates the effect of 5FU. Arfolitixorin does not require multi-step metabolic activation, and may produce higher, and less inter- and intraindividually variable, concentrations of [6R]-MTHF than leucovorin. Methods: The phase III AGENT trial (NCT03750786) is a randomized, multicenter, parallel-group study comparing the efficacy of arfolitixorin versus leucovorin in mCRC patients treated with first-line 5FU, oxaliplatin, and bevacizumab. Patients are randomized (1:1) to the investigational arm (arfolitixorin + 5FU + oxaliplatin [ARFOX] + bevacizumab) or the comparator arm (leucovorin + 5FU + oxaliplatin [modified FOLFOX-6] + bevacizumab), and treated until disease progression based on RECIST 1.1 criteria. Recruitment is ongoing, and aims to randomize 440 patients in 18 months. Eligibility criteria include non-resectable mCRC; eligibility for 5FU, oxaliplatin, and bevacizumab therapy; ECOG PS 0 or 1. The study will be conducted across approximately 100 sites in Australia, Austria, Canada, France, Germany, Greece, Japan, Spain, Sweden, and USA. The primary endpoint is objective response rate. Key secondary endpoints are progression-free survival and duration of response. Additional secondary endpoints include overall survival, quality of life, safety and tolerability, and number of patients undergoing curative metastasis resection. A translational program will evaluate expression levels of several folate metabolism- and transportation-related genes in mCRC tumor biopsies to determine their relationship to treatment outcome. A broad array of genes will analyzed, including ATP-binding cassette C3 (ABCC3) transporter, methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), proton-coupled folate transporter (PCFT), and serine hydroxymethyltransferase 1 (SHMT1). Interim data are expected in mid 2020. Clinical trial information: NCT03750786.
A phase II study of niraparib in combination with EGFR inhibitor panitumumab in patients with advanced colorectal cancer.
Authors: Alese Olatunji B. , Shaib Walid Labib , Akce Mehmet , Wu Christina , Lesinski Gregory B. , El-Rayes Bassel F.
Published: February 2020

TPS269

Background: Panitumumab (Pmab) is a recombinant monoclonal antibody that binds specifically to the human epidermal growth factor receptor (EGFR), and is indicated for metastatic colorectal carcinoma (mCRC). EGFR inhibition induces synthetic lethality with poly ADP ribose polymerase inhibitors (PARPi) by attenuating DNA repair pathways. This susceptibility to PARPi-induced cell death by EGFR inhibition is associated with deficient Non-homologous end joining (NHEJ), and Homologous recombination (HR) mediated DNA repair and persistence of DNA damage. Furthermore, efficacy of PARPi (such as niraparib) is highly correlated with platinum sensitivity. Cancer cell sensitivity and resistance to both PARPi and platinum have been associated with loss and restoration of HR DNA repair, indicating similar mechanisms of anticancer activity and resistance. Platinum sensitivity in CRC could therefore predict for anticancer properties of PARPi when utilized in the setting of synthetic lethality. Combining PARP and EGFR inhibition has the potential to confer synergistic benefit, while ameliorating resistance mechanism to PARPi. This study aims to evaluate the activity of the combination of niraparib and Pmab in RAS wildtype (WT) mCRC. Methods: Eligible patients for the trial include advanced, RAS WT mCRC who have been intolerant of, progressed on, or failed at least one line of systemic chemotherapy. Those currently on first line oxaliplatin-containing regimen are allowed on the trial if they have remained stable or better (PR or CR) for at least 4 months on that line of treatment, and are being considered for maintenance therapy as standard of care. Patients must also be 18 years old, ECOG PS 0-1 and measurable disease per RECIST 1.1. A safety run-in cohort of 6 eligible patients, and additional 20 patients with the same inclusion criteria will be enrolled. Pmab dose - 6 mg/kg IV on days 1 & 15 of each 28-day cycle; Niraparib - 200mg or 300mg (based on body weight and platelet count) orally continuously. Primary endpoint: clinical benefit rate (CR +PR + SD). Biomarker analysis includes skin biopsies evaluated for p-Caspace-3, PARP, p-MAPK, Ki-67, and p27. The study was activated in Sept. 2019. Clinical trial information: NCT03983993.
Immunotherapy with Y90-radioembolization for metastatic colorectal cancer (iRE-C).
Authors: Kasi Pashtoon Murtaza , Toskich Beau M , Chandrasekharan Chandrikha , Prabhakar Dhivya , Sharif Saima , Berg Daniel James , Miller Ann , Chan Carlos Hou Fai , Laroia Sandeep
Published: February 2020

TPS276

Background: Immune checkpoint inhibitors have revolutionized the treatment of a number of cancers. In colorectal cancers, their efficacy is limited to mismatch repair deficient or microsatellite stability-high (dMMR/MSI-High) tumors only. These constitute only 4-5% of all metastatic colorectal cancers (mCRC). Novel approaches are needed to make immunotherapy a viable option for mismatch repair proficient or microsatellite stable (pMMR/MSS) tumors. Increasing exposure of neo-antigens to the immune system could be one potential strategy to enhance the response of immunotherapy. Yttrium 90-radioembolization (Y90-RE) in combination with immunotherapy may work synergistically to enhance efficacy of each other. Additionally, radiation can potentially make the tumor microenvironment conducive to effector T-cell recruitment and function. Therefore, we hypothesize and propose the clinical trial of combining immunotherapy with Y90-RE as a feasible and safe strategy that will improve outcomes in patients with mCRC with liver-predominant metastases. Methods: This clinical trial will be conducted as a single-center, open-label, Phase I/II trial to evaluate initially the feasibility and safety of Y90-RE in combination with a fixed dose of immunotherapy (durvalumab) in subjects with liver-predominant, mCRC (Table). It will be offered in the refractory setting. The trial will be performed in 18 subjects with mCRC with liver metastasis and the safety of immunotherapy (durvalumab) with Y90-RE will be investigated in an accelerated titration design. This would allow a maximum tolerated dose with the minimum number of subjects. Correlative studies pertaining to serial circulating tumor DNA (ctDNA - liquid biopsies) testing as well as immune-panel based profiling will be performed alongside pre- and post-biopsies to study changes in the tumor microenvironment. Clinical trial information: NCT04108481.

[Table: see text]
A randomized study evaluating tailoring of advanced/metastatic colorectal cancer (mCRC) therapy using circulating cell-free tumor DNA (ctDNA) (TACT-D).
Authors: Raghav Kanwal Pratap Singh , Wang Xin Shelley , Xiao Lianchun , Dasari Arvind , Morris Van K. , Johnson Benny , Shen John Paul Y.C. , Parseghian Christine Megerdichian , Kee Bryan K. , Shureiqi Imad , Fogelman David R. , Wolff Robert A. , Raymond Victoria M. , Odegaard Justin I. , Lanman Richard B. , Overman Michael J. , Kopetz Scott
Published: February 2020

TPS277

Background: Identifying non-responders to expensive salvage therapies with modest benefits and substantial treatment related adverse events (TRAEs) (e.g. regorafenib/TAS102 in mCRC) is necessary to maximize benefits and limit toxicities. Serial ctDNA sequencing is reliable for tracking tumor dynamics and appears to predict resistance to therapy earlier than radiographic progression. Methods: TACT-D is a randomized study (N = 100) to validate the ability of changes in ctDNA (ΔctDNA) to predict resistance early and in limiting toxicities. We hypothesize that increase in ctDNA (measured by variant allele fraction) at 2 weeks (wk) into treatment can predict resistance earlier than standard radiographic means [at 8-12 wk] and detecting resistance early can enable prompt change in therapy resulting in reduction of TRAEs. Pts with mCRC eligible for either regorafenib/TAS102 are randomized 2:1 to either standard of care (SOC) or ctDNA arm. On SOC arm, treatment is given as per current paradigm i.e. for 8 wk and then restaging. On ctDNA arm, decision to continue therapy is based on ctDNA change between baseline and 2 weeks [ΔctDNA = ctDNA (C1D15 – C1D1)]. Increase in ctDNA triggers early radiographic staging (4 wk). Treatment is continued for disease stability/regression and discontinued for progression. Study has 2 co-primary endpoints: 1) Association of Δ ctDNA and radiographic progression [62 pts on SOC arm, have 94% power (2-sided α 0.05) to detect difference of 95% vs. 58% in progressive disease between pts with increase vs decrease in ctDNA] and 2) Compare proportion of pts experiencing TRAEs within 4 months between study arms [67 in SOC arm and 33 in ctDNA arm have 82% power (2-sided α 0.05) to detect a 30% decrease in toxicity]. Key secondary endpoints include: patient-reported outcomes (MD Anderson Symptom Inventory and PRO-CTCAE), OS, clinical events of special interest (hospitalizations/ER visits/medical interventions such as blood transfusions/IV hydration), clinical trial referral and cost effectiveness. Study is now actively accruing pts (NCT03844620). Funding: MD Anderson Cancer Center, Houston, TX & Guardant Health Inc., Redwood City, CA. Clinical trial information: NCT03844620.
Phase II study of nanoliposomal irinotecan (nal-IRI) with 5-fluorouracil (5-FU)/folinic acid (FA) in refractory advanced high-grade neuroendocrine cancer (HG-NEC) of gastroenteropancreatic (GEP) or unknown origin.
Authors: Gupta Medhavi , Choi Minsig , Ramirez Robert A. , Attwood Kristopher , Mukherjee Sarbajit , Iyer Renuka V.
Published: February 2020

TPS636

Background: The incidence of GEP HG-NEC is increasing and the prognosis is poor. Etoposide–platinum (EP) combination is considered the standard (std) therapy (Rx), but survival is less than 1 year. There is an unmet need for an optimal 2nd line Rx in these patients (pts). Nal-IRI has shown efficacy in small cell lung cancer (pathologically similar to HG-NEC) and in 2nd line pancreatic adenocarcinoma. In a retrospective study, HG-NEC pts with progression on 1st line EP when treated with 2nd line FOLFIRI (FA+5-FU+ IRI) had a good response and a tolerable safety profile (Hentic et al, 2012). Based on this data and the fact that no std 2nd line Rx option exists in HG-NEC, we are evaluating the efficacy of nal-IRI+ 5-FU/FA in a prospective single-arm multicenter study. Methods: Advanced GEP or unknown origin HG-NEC pts with progressive disease/intolerance to 1st line Rx with EP or temozolomide/capecitabine; ECOG PS 0-2 would receive nal-IRI 70 mg/m2, FA 400 mg/m2 followed by 5-FU 2400 mg/m2 on D1 & 15 of 28-days cycle. Rx to continue till disease progression or unacceptable toxicity. Tumor assessment by CT/MRI per RECIST 1.1 q6 wks. Primary end point is to measure ORR (CR+PR). Secondary endpoints include PFS, TTP, OS, safety and QOL changes. Assuming a historic ORR of 15% with std Rx, 37 pts (upto 41 pts considering non-evaluable pts) are required to show an ORR of 30% at a power of 80% at 1-sided significance of α = 0.1. In stage 1, n1= 18 pts will be enrolled. If 3 or more responses are seen, an additional n2= 19 pts to be enrolled. If 8 or more responses are observed of the n = 37 evaluable pts, the Rx would be considered promising for further study. Genomic mutational profiling to be conducted on pre-study tumor samples and correlated with circulating tumor DNA (CT DNA). CT DNA level, assessed serially, will be correlated with Rx response and disease recurrence. We plan to accrue over 3 years at 3 sites. As of August 2019, 1-patient has been enrolled. The trial is funded by Ipsen Pharmaceuticals and the North American Neuroendocrine Tumor Society through the Clinical Investigator Scholarship. Clinical trial information: NCT03736720.
A pilot study of intratumoral SD-101 (toll-like receptor 9 agonist), nivolumab, and radiotherapy for treatment of chemotherapy-refractory metastatic pancreatic adenocarcinoma.
Authors: Chen Justin , Huynh Jasmine , Monjazeb Arta , Cho May Thet , Kim Edward Jae-Hoon
Published: February 2020

TPS782

Background: Pancreatic adenocarcinoma is an aggressive disease projected to be the second leading cause of cancer-related death. A majority of patients have advanced disease on diagnosis. Combination chemotherapy is first-line for advanced disease but limited by toxicity and median survival under 1 year. SD-101 is a toll-like receptor 9 agonist that is injected intratumorally to increase immunogenicity in the tumor microenvironment. Localized radiation can further enhance this via antigen release and potential abscopal effects. Immunotherapy has revolutionized care for various solid organ malignancies but not yet for pancreatic cancer. Therefore, the combination of SD-101, localized radiation, and checkpoint inhibitor is a promising therapeutic strategy for metastatic pancreatic adenocarcinoma. Methods: Six patients with chemotherapy-refractory, liver-metastatic pancreatic adenocarcinoma will be evaluated for combination SD-101, radiation, and nivolumab. SD-101 is injected intratumorally into a liver metastasis on days 1, 8, 15, 29 with optional dosing days 43 and 57. Localized radiation (6-10 Gy per fraction) to the injected lesion will be given on days 1, 3, 5, 8, and 10. Nivolumab will be given at 240 mg every 2 weeks starting day 2 until progression or unacceptable toxicity. Blood samples will be collected at baseline and at regular intervals while on treatment. Biopsies will be obtained at baseline and on day 29. Primary objectives are to evaluate safety and tolerability, defined so if ≥5 patients reach day 29 without experiencing grade ≥3 treatment-related toxicity. Secondary objectives include preliminary efficacy as defined by disease control rate, duration of response, progression-free survival, and overall survival. Exploratory objectives include objective response rate and biomarker correlatives (T-cell clonality, tumor mutational burden, tumor infiltrative immune cell subsets, and immune-related gene expression profile). Blood and biopsy specimens will be analyzed using flow cytometry, qRT-PCR, RNA sequencing, and whole exome sequencing including immunohistochemistry on biopsy specimens. Clinical trial information: NCT04050085.
TRYbeCA-1: A randomized, phase III study of eryaspase in combination with chemotherapy versus chemotherapy alone as second-line treatment in patients with pancreatic adenocarcinoma (NCT03665441).
Authors: Hammel Pascal , Berardi Rossana , Van Cutsem Eric , Feliu Jaime , Greil Richard , Wasan Harpreet Singh , Metges Jean-Philippe , Nygren Peter , Osterlund Pia J. , Noel Marcus Smith , Seufferlein Thomas , Creemers Geert-Yan , Gupta Anu , Salesse Sophie , Biswas-Baldwin Nigel , Dion Hedy , Youssoufian Hagop , Garzon Felix Tomas , El-Hariry Iman , Hidalgo Manuel
Published: February 2020

TPS783

Background: Second-line treatment options for advanced pancreatic adenocarcinoma are currently limited. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs) is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. We have recently reported the outcome of a randomized Phase 2b study inpatients with advanced pancreatic cancer whose disease progressed following first-line treatment. Eryaspase in combination with gemcitabine monotherapy or FOLFOX combination therapy improved overall survival (OS) and progression free survival (PFS). The safety profile of eryaspase was acceptable. The results of this Phase 2b study provided a rationale for initiating this confirmatory Phase 3 pivotal trial (TRYbeCA-1). Methods: TRYbeCA-1 is a randomized, open-label Phase 3 trial (N = ~500) of eryaspase combined with chemotherapy in patients with adenocarcinoma of the pancreas who have failed only one prior line of systemic anti-cancer therapy for advanced pancreatic cancer and have measurable disease. Patients are randomized in a 1:1 ratio to receive gemcitabine/Abraxane or irinotecan-based therapy (FOLFIRI [FOLinic acid-Fluorouracil-IRInotecan regimen] or irinotecan liposome injection/5-fluorouracil/leucovorin) with or without eryaspase, administered as IV infusion on Day 1 and Day 15 of each 4-week cycle. Key eligibility criteria include performance status 0 or 1; stage III-IV disease; documented evidence of disease progression; available tumor tissue; and adequate organ function. The primary endpoint is OS. Key secondary endpoints include PFS and objective response rate, safety, quality of life, pharmacokinetics and pharmacodynamics, and biomarker research. A hazard ratio in OS of 0.725 is being targeted which represents a conservative estimate based on the Phase 2b data and is viewed as being highly clinically relevant. An IDMC will be established to review safety at regular intervals andto review efficacy data at the planned interim and final analyses. Clinical trial information: NCT03665441.
PCRT16-001: Phase II study of PEGPH20 plus pembrolizumab for patients (pts) with hyaluronan (HA)-high refractory metastatic pancreatic ductal adenocarcinoma (mPDA).
Authors: Chiorean E. Gabriela , Ritch Paul S. , Zhen David Bing , Poplin Elizabeth , George Ben , Hendifar Andrew Eugene , Dragovich Tomislav , Coveler Andrew L. , Stoll-D'Astice Amy C. , Edwards Stephanie , Rosenthal Adam , Thorsen Shelley M. , Hingorani Sunil R.
Published: February 2020

TPS785

Background: PDA is characterized by invasiveness and therapeutic resistance in part due to a desmoplastic stroma and an immunosuppressive microenvironment ( Provenzano PP, Hingorani S. Br J Cancer 2013). PD1/PD-L1 inhibitors have no single agent activity in PDA, except for pts with mismatch repair defects. There is high need to overcome resistance to immune targeted therapies and develop biomarkers for pts selection. Stromal HA poses a physical barrier and protects tumor cells from immune surveillance ( Kultti A, et al Biomed Res Int 2014). By remodeling the tumor stroma, PEGPH20 allows infiltration of cytotoxic T lymphocytes, and improves delivery of chemotherapy and PD1/PD-L1 antibodies ( Singha NC, et al Mol Cancer Ther 2015). mPDA pts refractory to 1st line therapy have median overall survival (OS) of 6 mos. We hypothesize that stroma remodeling with PEGPH20 sensitizes PDA to immune therapy, and stroma and immunologic biomarkers will identify pts most likely to benefit. In this trial we will evaluate the efficacy, safety and translational biomarkers of PEGPH20 plus pembrolizumab in HA-high refractory mPDA. Methods: Eligible pts have ECOG PS 0-1, ≤ 2 prior therapies for mPDA, life expectancy ≥ 12 wks, able/willing to have tumor biopsies at baseline and after 6 wks of treatment. PEGPH20 dosing is 3 µg/kg iv QW and pembrolizumab 200 mg iv Q3W (2-4 hrs after PEGPH20 on wk 1) in 3-wk cycles. All pts receive prophylactic low molecular weight heparin. Primary endpoint: progression-free survival (PFS). Secondary endpoints: safety, OS, response rates. Translational endpoints: flow cytometry of peripheral and intratumoral immune cells, T-cell receptor sequencing, immune transcriptome, immune subsets IHC, circulating cytokines, serial plasma and tumor HA levels. For the primary endpoint of PFS, with a sample size of 31 evaluable pts, a one-sided α-level of 0.05, assuming 12 mos of accrual and 6 mos of follow-up, this study has 80% power to detect a difference between the null hypothesis median PFS 3 mos, versus the alternative hypothesis median PFS 6 mos. The study was activated in May 2019 and is open to accrual; 6 pts were enrolled as of 24Sept 2019. Clinical trial information: NCT03634332.
Trends in PRO reporting in clinical trials leading to cancer immunotherapy drug approvals from 2011 to 2019.
Authors: Safa Houssein , Tamil Monica , Diab Adi , Semaan Adele , Chahoud Jad
Published: February 2020

105

Background: Patient-reported outcomes (PROs) are a primary tool to evaluate the effect of a given drug on the health-related quality of life from a patient’s perspective and to maximize the value of patient-centeredness in drug development and approval. In this study, we aimed to evaluate the current trend in reporting, analysis and interpretation of PRO data. Methods: We conducted a systematic review of the FDA archives, identifying all cancer immunotherapy drug approvals between the years 2011 and 2019. We then retrieved the clinical trials that respectively led to these drug approvals from PubMed and ClinicalTrials.gov. We systematically screened for PROs and assessed their analytic tools and interpretation methods that were collected from the published journal articles and their study protocols. If one FDA approval was supported by more than one clinical trial, we included all studies in our review. An FDA approval was considered to include PROs if they were reported in at least one of the supporting trials. Results: Thirty-seven clinical trials leading to 35 immunotherapy drug approvals were identified. More than half (54%) did not publish any PROs. While PROs were reported in the primary clinical outcomes manuscript of 4 trials (11%) and in a secondary separately published paper for 13 trials (35%). The median time between the primary and secondary papers was 22 months (range: 5 - 40). In the 17 published PROs, the hypothesis was broad in 12 (71%), not reported in 4 (24%) and specific in only 1 (6%). Ten (59%) were reported as exploratory endpoints, five (29%) as secondary endpoints, and two (12%) did not specify the PRO reporting in their endpoints. The most common PRO instruments were EQ-5D (71%) and QLQ-C30 (65%). Control for type I error was needed but not done in 15 (88%). Fourteen (82%) described an approach for dealing with missing PRO assessments. None reported on significant differences based on race and ethnicity of participants. Conclusions: Suboptimal reporting and delays in publication of PROs occur regularly in cancer immunotherapy trials. Increased efforts are needed to enhance standardization and quality reporting of PROs to maximize the value of this data in cancer immunotherapy drug approval.
Alternative measure of therapy impact (TXI): Length of sojourn on treatment—Value of early restaging imaging for prediction of response to nivolumab among patients with advanced cancer.
Authors: Janicek Milos Josef
Published: February 2020

106

Background: Cross-sectional Imaging (CI) plays an essential role in early assessment of patients on immune checkpoint inhibitors (ICIs), yet often remains inconclusive in the setting of advanced disease, prior cancer treatment, toxicity, and cancer unrelated findings. We propose a robust, reproducible imjScore based on measurable tumor response on the first two re-staging scans that may predict TXI. We are testing prognostic value of early imaging, time lag of ICIs effect, against Duration of clinically effective treatment as a Measure of Treatment Impact. Methods: Retrospective review of CI studies in 92 patients with advanced stage solid tumors treated with Nivolumab (Nivo) during 6/2015-8/2018 at BMC on standard clinical protocols. Time on therapy (TOTx) was used as a surrogate marker of therapy impact. Modified imRECIST score utilizing ∑ of 5 discrete cancer lesions at baseline, 1st, and 2nd CI since initiation of Nivolumab were adjusted for TOTx. Our imjSCORE averages "predicted days on therapy" from best fit function of tumor change/day [%] at each time point vs. TOTx and ratios between 1st and 2nd scan. Results: Median TOTx was 70 days (range 1-1029). Differences in imRECIST scores derived from two early restaging CI studies adjusted for TOTx were able to identify with high statistical significance two groups of "SHORT" vs "LONG" sojourn on Nivolumab around Median of 70 days. Early Progression curve was associated with shorter benefit of Nivo; Pseudo-progression curve showed significantly shorter sojourn on Nivolumab compared to initial Regression or Stable score curves (P < .002). Conclusions: The imjScore may differentiate with high likelihood patients with short versus long sojourn on Nivo as a novel measure of TXI. Our CI-based imjSCORE validates early imaging with a response curve and standardized analysis of the 1st and 2nd post-treatment scans. If validated with other ICIs, this scoring tool may allow early prediction of ICIs treatment response and clinical outcome. Further correlation with clinical biomarkers may lead to development of predictive nomograms of "short" versus "long" TXI.
A cell-based platform to potentiate oncolytic virus: Potential approach for cancer therapies.
Authors: Nguyen Duong , Gomez Alberto , Alamillo Ashley , Neuharth Forrest , Minev Ivelina , Herrmann Thomas , Haertl Barbara , Schneider Laura Edith , Minev Boris , Draganov Dobrin , Santidrian Antonio F.
Published: February 2020

21

Background: Oncolytic virotherapy has been pursued by multiple companies and institutions with few candidates reaching the clinic and demonstrating limited efficacy. The therapeutic potential of oncolytic viruses can be severely restricted by innate and adaptive immune barriers. To overcome this obstacle, we load and protect tumor selective CAL1 oncolytic vaccinia virus into adipose-derived stem cells (AD-MSC) to generate a new therapeutic agent called SNV1(SuperNova1). Methods: SNV1s were generated by incubating AD-MSC with CAL1 virus. SNV1 was analyzed for its ability to kill cancer cell lines and protect virus in the presence of active neutralizing antibodies and complement. In animals, SNV1 was intratumorally injected in various xenograft and syngeneic models. Viral biodistribution was also evaluated by PCR. Immune infiltration were analyzed using flow cytometry. Results: Compared to the naked virus, SNV1 showed improved protection against the humoral barriers and efficient eradication of various human cancer cell lines in vitro. Intratumoral SNV1 treatment showed statistically significant and potentiated tumor growth inhibition compared to control or CAL1 naked virus treatment in all tested models (prostate, breast, melanoma, colon, and prostate cancers). Importantly, local administration of SNV1 induced systemic therapeutic effects. Five days after SNV1 administration, tumor infiltrating lymphocytes (TILs) from both treated and untreated tumors showed increased CD4 and CD8 T-cell populations. As well as decreased frequency of Tregs, and improved effector to Treg ratios, which was associated with inhibition of tumor growth at the treated tumor site and also at distant untreated sites. Ongoing and persistent virus infection could be detected in the treated tumor as late as 15 days after administration. Conclusions: This study demonstrates the ability of our cell-based platform to protect and potentiate oncolytic vaccinia virus by circumventing the innate and adaptive immune barriers, resulting in enhanced oncolytic virotherapy. These findings provide fundamental rationale for the development of cell-based platforms to maximize the therapeutic potential of various oncolytic viruses.
AVM0703 as a novel stand alone or combination therapy for lymphoma.
Authors: Taylor Margaret , Rylatt Colleen , Lee-Diaz Stephanie , Ashok Arya , Jarzyna Peter , Parthasarathy Vaishnavi , Poulin Kendra , Zahid Yumna , Deisher Theresa
Published: February 2020

42

Background: Chemotherapy remains a vital part of cancer treatment. There is an urgent need to reduce the toxicities associated with chemotherapy-based treatments especially in the pediatric and young adult population where the risk for chemo-induced secondary cancers is high. AVM0703 is a new treatment option that can be used as a stand-alone or in combination with chemo for relapsed/refractory lymphoma patients. AVM0703 is effective at lymphoablating while sparing red blood cells, platelets, and hematopoietic stem cells. AVM0703 is a novel patent-pending formulation of a repurposed drug without the toxic excipients unlike existing formulations. AVM0703 has anti-tumor activity in an immunocompetent mouse model of B-cell lymphoma (A20) as both a stand-alone treatment and in combinations with current therapeutics. Methods: Wild-type BALB/c mice were implanted with A20 tumor cells suspended in a 50% Matrigel mixture and implanted subcutaneously. Palpable tumors were visible within seven days. Mice were dosed with either high-dose AVM0703 alone, or in combination with intraperitoneal cyclophosphamide and fludarabine. Mice were then monitored for tumor growth and changes in body weight. Results: Mice dosed repeatedly with AVM0703 survived 20 days longer than mice dosed with placebo and displayed no significant toxicity or body weight loss. In a separate study, mice treated with 2 doses of Cy/Flu had a loss of tumors similar to 1 dose of AVM0703 + 1 dose of Cy/Flu. Additionally, when compared to standard treatments like CHOP, in the same A20 lymphoma model, the AVM0703 + Cy/Flu combination had better tumor efficacy than 2 cycles of CHOP. Unlike 2XCHOP treatment, which induced greater than 30% body weight loss and death of 18% of the mice due to drug toxicity, the AVM0703 + Cy/flu combination had no observed toxicity or body weight loss. Conclusions: AVM0703 can reduce the number of chemotherapy cycles without affecting efficacy and decrease the toxicities associated with chemo and will help to provide a better quality of life for patients.
Correlation between immune-related adverse events and outcomes in nivolumab/ipilimumab combination therapy for metastatic melanoma.
Authors: Rauwerdink Daan , Frederick Dennie T. , Sharova Tatyana , Boland Genevieve Marie
Published: February 2020

58

Background: Systemic immune checkpoint blockade therapy anti-PD1 nivolumab combined with anti-CTLA-4 ipilimumab is an effective therapy for metastatic melanoma. The treatment, however, has a high frequency of immune related adverse events. Interestingly, immune-related adverse events in anti-PD1 and anti-CTLA4 monotherapy have been associated with an improved overall survival in melanoma. Whether immune-related events correlate with enhanced outcomes in ipilimumab/nivolumab combination therapy is unknown. Methods: Clinical data from patients diagnosed with untreated cutaneous stage IV melanoma receiving ipilimumab/nivolumab combination therapy between 2015-2018 at the Massachusetts General Hospital (MGH) and have been analyzed retrospectively. Tumor response was measured using RECIST criteria. Primary endpoints were frequencies and characteristics of immune-related adverse events, overall survival, and response to therapy. Results: A total of 57 patients received ipilimumab/nivolumab combination therapy. During a mean follow-up period of 26 months, 28 (49%) patients completed the therapy. Immune-related adverse events were observed in 45 (79%) patients, with rash (28%), colitis (23), hepatitis (21%) and fever (21%) being the most frequent. Overall survival was 29 months in patients with immune-adverse related events and 14 months in the group without any adverse events (p-value < 0.01). The onset of hypophysitis correlated with tumor response (p = 0.02) and hepatitis showed a trend in a correlation to response of therapy (p = 0.06). Conclusions: Our study demonstrates the association between improved overall survival and the onset of immune-related adverse events in ipilimumab/nivolumab combination therapy. A trend correlated with improved outcomes and onset of immune-related adverse events was seen in hepatitis and was significantly associated with hypophysitis, however these results must be interpretated carefully as larger studies must confirm our findings. Despite small study size, we are the first to describe an association between immune-related adverse events in ipilimumab/nivolumab combination therapy.
Inflammation and cell proliferation signatures: Implications for response to immune checkpoint inhibition therapies.
Authors: Glenn Sean , Pabla Sarabjot , Kato Shumei , Van Roey Erik , Conroy Jeffrey M. , Wang Yirong , Nesline Mary , Burgher Blake , Giamo Vincent , Andreas Jonathan , Lenzo Felicia L. , Kurzrock Razelle , Morrison Carl
Published: February 2020

67

Background: Progress in unraveling the complex tumor immune microenvironment (TIME) has aided our understanding of the host immune response to ICI therapies. To gain further insight, we associate a 160-gene tumor inflammation signature (TIS) with cell proliferation status and response to ICI. Methods: 242 FFPE tumor samples from lung, RCC and melanoma were evaluated by RNA-seq to measure expression levels of 394 immune related genes. TIS (weak, moderate, strong) and cell proliferation status (poor, moderate, high) were determined by algorithmic analysis of selected gene pathways. All cases were evaluated for association with ORR to ICIs using RECIST criterion. Furthermore, 13 pre-post ICI treated biopsy pairs were studied to understand the dynamics of these signatures following treatment. Results: In both weakly and moderately inflamed tumors, ORR was highest in moderately proliferative tumors 32.6% (15/46) and 37.8% (14/37), respectively (Table). Surprisingly, in strongly inflamed tumors, both highly and moderately proliferative tumors had a high response rate of 55% (11/20) and 43.2% (16/37), whereas poorly proliferative tumors have a significantly lower response rate of 12.5% (3/24; p= 0.03). 6 of 13 pre-post ICI treated cases demonstrated increased inflammation post treatment, with 83% (5/6) demonstrating concurrent decrease in cell proliferation. Conclusions: Together, TIS and cell proliferation predict response to ICI in NSCLC, RCC and melanoma. The data suggests that in strongly inflamed and highly proliferative tumors, the cell proliferation signal could be attributed to antigen stimulated T-cell proliferation, whereas in other categories of inflammation, moderately proliferative tumors contain signal from both immune cells and tumor cells. Further studies are required to determine the relationship between these signatures in hot and cold tumors. [Table: see text]