Citations

Abstract Background: The inhibitory immune pathway, consisting of the receptor programmed cell death 1 (PD-1) and its ligands, PD-L1 and PD-L2, plays a vital role in the maintenance of peripheral tolerance. Therapies with monoclonal antibodies targeting PD-1 and its ligands are associated with remarkable response rates in various cancers. Imugene is proposing to develop an anti-PD-1 immunotherapy using a vaccine approach to treat patients with tumors that over-express PD-L1. The hypothesis is that a polyclonal-induced B-cell antibody response will be more effective or as effective with improved safety over current monoclonal antibody therapy. IMU-201, is a B-cell epitope (amino acids 92-110 from PD-1) linked to a promiscuous T cell epitope (amino acid residues 288-302 from measles virus fusion protein) via a 4-amino acid linker (G-P-S-L), combined in an aqueous phase vaccine to be emulsified in Montanide ISA 720 VG, to form the drug product. Study Design: IMU-201-101 is a 2-part open-label dose escalation/dose expansion study of IMU-201. Part 1 will dose escalate IMU-201 as monotherapy and in combination with Standard of Care (SOC) treatment to evaluate safety, tolerability and immunogenicity and assess the optimal biologic dose (OBD) of IMU-201. Part 2 will expand the number treated with IMU-201 at OBD in combination with SOC treatment. OBD is defined as the dose resulting in the best safety/tolerability and immunogenicity and will be determined after all dose cohorts have completed Day 29 of Part 1. A total of approximately 30 adult patients aged 18 years with NSCLC expressing PD-L1 will be enrolled in the study at sites in North America and Australia. In Part 1, three cohorts (25, 125 and 250 µg of IMU-201) of 3-6 participants per cohort are anticipated to establish the Optimum Biological Dose (OBD) of IMU-201 as monotherapy (mOBD). After establishing mOBD, combination dose escalation will combine IMU-201 with SOC treatment which may include ICI, chemotherapy or their combination, to establish combination OBD (cOBD). The starting dose for combination dose escalation will be one dose level below mOBD. The same dosing schedule of IMU-201, DLT criteria, and dose escalation rules will be used to establish mOBD and cOBD. In Part 2, the number of patients treated in combination with IMU-201 at cOBD will be expanded to 12 patients. Patients will receive IMU-201 at Baseline/Day 1, Day 15 and Day 29. Dosing with IMU-201 will continue at Day 64 (± 7 days) and every subsequent 63 days (± 7 days) until progressive disease or complete response. Therapy may continue beyond progression if the treating physician feels that the patient is deriving benefit. Primary Objectives: To evaluate the safety/tolerability and immunogenicity of IMU-201 as monotherapy and in combination with SOC treatment. To identify OBD of IMU-201 as monotherapy and in combination with SOC treatment. To evaluate changes in immunological, biochemical and additional radiological markers of tumor progression in patients treated with IMU-201 as monotherapy and in combination with SOC treatment. To evaluate changes in humoral and cellular immunogenicity data including PD-1 specific antibodies (IgG, IgM), vaccine-specific cytokine levels and regulatory and effector T and B cells. Citation Format: Pravin Kaumaya, Tanios Bekaii-Saab, Tri Phan, Mark T. Marino, Nick Ede, Anthony Good. IMU-201-101 - an open-label, multi-center, dose escalation/expansion, phase 1 study of IMU-201 (PD1-Vaxx), a B-cell immunotherapy, in adults with non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT128.

Abstract Immunotherapy targeting immune checkpoints has become a common approach for many types of cancer but currently there are no reliable biomarkers to predict and monitor treatment response. Immunohistochemical staining of PD-L1, which was initially developed as a companion diagnostic, is problematic due to tumor heterogeneity, variations in specimen preparation and multiple scoring schemes. There is, therefore, a critical need for a better biomarker to guide the use of immunotherapy to improve clinical outcomes. We previously reported that higher levels of Bim and CX3CR1/granzyme B in CD8+ T cells were associated with increased response to PD-1 blockade therapy in patients with melanoma; high levels of Bim were also prognostic of poor survival in melanoma patients. In this study, we investigated the roles of Bim and CX3CR1/granzyme B in patients receiving PD-1 blockade therapy (i.e. pembrolizumab) for small bowel adenocarcinoma as part of planned correlative analysis of the ACCRU clinical trial, NCT02949219. Patients with unresectable or metastatic biopsy-proven small bowel adenocarcinoma (excluding ampulla of Vater and appendix) who had at least one prior line of systemic chemotherapy were eligible for the trial. Pembrolizumab (200 mg) was administered over 30 minutes intravenously every 3 weeks until unacceptable toxicity, disease progression, or patient refusal. All patients underwent peripheral blood collection at baseline prior to initiation of treatment and then after 3 cycles of treatment. Levels of Bim and CX3CR1/granzyme B in circulating T cells were quantified by flow cytometry using patients' peripheral blood mononuclear cells. Data was analyzed via Cox proportional hazards model, Wilcoxon Rank-Sum test, and Kaplan Meier curves using SAS 9.4. A total of 35 eligible patients were included in the analysis. Three patients had confirmed response (all partial responses) and 10 had stable disease as their best overall response. Seven patients had disease progression around the second blood draw. The median time from baseline to the second blood draw was 9 weeks. Lower levels of Bim in CD8+CD11ahi T cells at baseline on the percentage scale were associated with treatment response (median 54.5% vs. 79.5%; p=0.0087) and disease control (partial response plus stable disease; median 71.2% vs. 81.3%; p=0.0104) but higher levels led to worse progression-free survival (hazard ratio=1.05, 95% confidence interval 1.01-1.08; p=0.0051). In addition, positive changes in CX3CR1/granzyme B in CD8+CD11ahi T cells from baseline were associated with better overall survival (median 20.2 months vs. 3.7 months, p=0.0086). The levels of PD-1 and Ki-67 in CD8+CD11ahi T cells were not associated with treatment response or survival. In conclusion, Bim and CX3CR1/granzyme B are biomarkers that associate with response and survival benefits respectively of PD-1 blockade therapy. This preliminary data calls for a larger-scale, prospective study to validate their predictive and prognostic utilities. Citation Format: Mojun Zhu, Henan Zhang, Nathan R. Foster, Haidong Dong, Tanios S. Bekaii-Saab, Brandy L. Jaszewski, Patrick M. Boland, Michael J. Overman, Katrina Pedersen, Robert R. McWilliams, Academic and Community Cancer Research United (AACRU). Bim and CX3CR1/granzyme B in circulating CD8+ T cells are predictive biomarkers for PD-1 blockade therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4467.

Abstract Background It is unclear whether results from recent trials of resectable pancreatic ductal adenocarcinoma (PDAC) are generalizable to older patients, who are underrepresented. We aimed to evaluate outcomes of surgery and of neoadjuvant and adjuvant therapy in older patients with resectable PDAC. Patients and Methods We included patients aged ≥65 years with upfront resectable PDAC from a prospectively maintained pancreatic cancer registry from 2007 to 2016. Patients were stratified into ages 65–75 and 75+ years. Overall survival (OS) was assessed in treatment comparisons: (A) surgery (n = 636) versus nonsurgical (n = 178), (B) neoadjuvant therapy (n = 139) versus upfront surgery (n = 497), and (C) adjuvant therapy (n = 379) versus surgery alone (n = 118). We compared neoadjuvant (n = 139) versus adjuvant therapy (n = 379) in an exploratory analysis. Results Nine hundred and three patients had a median age of 73.7 (range, 65–96.6) years. Median OS was 26.6 versus 11.9 months (adjusted hazard ratio [HRadj], 0.4; 95% confidence interval [CI], 0.31–0.52; p < .001) in Comparison A groups, 30.7 versus 25.8 months (HRadj, 0.69; 95% CI, 0.49–0.96; p = .03) in Comparison B groups, and 26.9 versus 17.4 months (HRadj, 0.62; 95% CI, 0.44–0.88; p = .008) in Comparison C groups, respectively. OS benefit in these treatment comparisons was present in age group 75+ with HRadj 0.24 (95% CI, 0.16–0.36; p < .001) in Comparison A and HRadj 0.52 (95% CI, 0.27–1; p = .049) in Comparison B, but not in Comparison C with HRadj 0.68 (95% CI, 0.43–1.08; p = .1). Statistically comparable median OS of patients who received neoadjuvant or adjuvant therapy stratified by age groups was observed. Conclusion Older patients with resectable PDAC who received surgery, neoadjuvant therapy, or adjuvant therapy appeared to have improved survival outcomes compared with those who did not receive such treatment. Implications for Practice Older patients with resectable pancreatic ductal adenocarcinoma (PDAC) in general are underrepresented in large clinical trials and less well studied in terms of the role of surgery, neoadjuvant therapy, and adjuvant therapy. This study collected data on older patients with resectable PDAC from a prospectively maintained single-institutional pancreatic cancer registry of a tertiary referral center from 2007 to 2016. It was found that, with multidisciplinary evaluation, older patients with resectable PDAC who received surgery, neoadjuvant therapy, or adjuvant therapy appeared to have improved survival outcomes compared with those who did not receive such treatment. These results are of substantial importance to practitioners who treat older patients, who are traditionally underrepresented in most clinical trials.

AbstractLutetium-177-dotatate (177Lu-dotatate), a form of peptide receptor radionuclide therapy, was approved by the U.S. Food and Drug Administration for the treatment of advanced somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors (NETs) in 2018 based on the promising results of the NETTER-1 trial for grade 1–2 midgut NETs. Here, we present a patient with a grade 3 pancreatic neuroendocrine tumor and BRCA1 germline mutation who had a significant response to 177Lu-dotatate.

e16771 Background: AbGn-107 is an ADC directed against AG-7 antigen, a Lewis A-like glycol-epitope expressed in 24-61% of gastric (G), colorectal (CRC), pancreatic (PDA), and biliary (BIL) cancers. Based on promising antitumor activity of AbGn-107 in both in vitro and in vivo preclinical studies, we performed a Phase Ia trial in patients with the aforementioned GI malignancies. Methods: Standard 3+3 dose escalation was used. Key eligibility included locally advanced or metastatic G, CRC, PDA, or BIL cancer, previously treated, ECOG PS 0-1; positive AG-7 expression was not required. Two dosing intervals were tested: AbGn-107 administered i.v. Q4 weeks (at doses ranging from 0.1-1.2 mg/kg) and Q2 weeks (at doses from 0.8-1.0 mg/kg). Dose limiting toxicities (DLT) were based on grade 3/4 hematologic and non-heme AEs occurring during the initial 4-week rx window. Patients were treated until disease progression or unacceptable toxicity, with tumor assessments Q8 weeks. 1o objectives: safety and MTD; 2o objectives: PK, immunogenicity, and efficacy defined by ORR (RECIST 1.1). Results: 35 patients were enrolled across 6 dose levels (median age 61.5 yo (range 40 – 81); G (0)/CRC (12)/PDA (20)/BIL (3); median # lines of prior rx = 3 (range 1-7). Safety: 5 patients experienced Grade 3 or 4 neutropenia, all at higher dose levels, inc. 1 episode of febrile neutropenia. Other frequent drug-related AEs, mostly grade 1/2, inc. fatigue (29%), nausea (20%), and diarrhea (14%). DLTs included grade 4 CK elevation (n = 1) at 0.8 mg/kg Q4W and grade 3 arthralgias (n = 1) at 1.2 mg/kg Q4W. Based on safety profile and PK data, 1.0 mg/kg Q2W was selected as the dose schedule for cohort expansion phase. Efficacy: Median duration of treatment = 56 days (range, 8 – 225 days). Six pts have demonstrated a minor response by RECIST (range, -1.3 to -21.1%); 4 pts (all PDA) have had durable dz control > 180 days. Conclusions: Overall, AbGn-107 appears well-tolerated with encouraging prelim signs of efficacy in unselected pts with heavily pre-treated advanced GI cancers. Updated safety and efficacy data will be provided at the time of the meeting for the cohort expansion phase of this study (currently open across multiple sites in U.S. and Taiwan), in which subjects with G, CRC, PDA, and BIL cancers are pre-screened for high levels of AG-7 tumor expression. Clinical trial information: NCT02908451 .

e16686 Background: Genetic alterations in the FGFR pathway are emerging as promising therapeutic targets in CCA. The clinical and molecular features of patients (pts) with CCA harboring FGFR genetic alterations are reported here. Methods: A retrospective chart review was performed in pts with CCA who were found to have an FGFR alteration on tumor molecular profiling as part of routine care between 9/2007 and 12/2019. Data on demographics, risk factors, pathology, molecular characteristics, systemic therapies, radiographical response, time on treatment, and overall survival (OS) were collected in a multi-center collaborative effort across seven academic centers. Results: Among 135 pts with FGFR-altered CCA, the median age at diagnosis was 57 years old (range = 25-92 years), and 80 (59.3%) pts were female, 129 (95.6%) had intrahepatic CCA, and 6 (5.6%) had chronic HBV. At presentation, 28.2% of pts had resectable disease, including 65.0% with Stage I-II, 22.5% with Stage III, and 5.0% with Stage IV. At the time of initial diagnosis, CA19-9 was < 35U/mL in 42.6% of pts. Bone metastases were observed in 41 (30.6%) pts with advanced disease. FGFR2 fusions were the most common FGFR alteration (68.2%), followed by FGFR2 mutations (21.5%), FGFR3 mutations (3.7%), FGFR2 rearrangements (1.5%), FGFR1 amplification (1.5%), and FGFR2 amplification (1.5%). The most common FGFR2 fusion partners were BICC1 (28.3%), SORBS1 (4.4%), POC1B (3.3%), and TACC2 (3.3%). The median lines of palliative systemic therapies received was 3 (range = 0-8), and 40/135 (29.6%) pts received a liver-directed therapy. For the 55 (59.8%) pts with FGFR2 fusions who received gemcitabine/cisplatin as first-line palliative systemic therapy, the median time on treatment was 6.2 months (95% CI: 4.1-9.3). The median OS from time of initial diagnosis was 36.1 months (95% CI: 28.3-51.6) in the FGFR2 fusion positive cohort. Among the 92 pts with FGFR2 fusions, 70 (76.1%) pts received an FGFR inhibitor on a clinical trial; 12 (17.1%) were subsequently treated with a second FGFR inhibitor, and 58.3% stayed on the second FGFR inhibitor for ≥4 months. Pts with a BICC1 fusion partner (n = 16) had an overall response rate of 42.9% on FGFR-selective inhibitors compared to 30.8% in non-BICC1 fusion partners (n = 54). Conclusions: Pts with CCA harboring FGFR alterations were found to have a high rate of normal CA19-9, high rate of bone metastases, and short median time on treatment on first-line palliative gemcitabine/cisplatin. Additional comparative studies are necessary to evaluate these findings.

TPS4661 Background: Liposomal irinotecan administered with 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA for metastatic pancreatic ductal adenocarcinoma (mPDAC) following progression with gemcitabine-based therapy. A phase 1/2 study in previously untreated locally advanced/metastatic PDAC showed promising anti-tumor activity with liposomal irinotecan 50 mg/m2 free base + 5-FU 2400 mg/m2 + LV 400 mg/m2 + oxaliplatin (OX) 60 mg/m2 on days 1 and 15 of a 28-day cycle (Wainberg et al. Ann Oncol 2019;30 Suppl 4: SO-005). Herein, we present the design of the phase 3 NAPOLI-3 study investigating the efficacy and safety of this regimen as first-line therapy in patients with mPDAC. Methods: NAPOLI-3 (NCT04083235) is a phase 3, open-label, randomized, global study in adults with histologically/cytologically confirmed pancreatic adenocarcinoma not previously treated in the metastatic setting. Patients are required to have one or more metastatic tumors measurable with computed tomography/magnetic resonance imaging and an Eastern Cooperative Oncology Group performance status score of 0–1. Site activation began in Dec 2019 and enrollment is ongoing. Random allocation (1:1) of 750 patients is planned to liposomal irinotecan + 5-FU/LV + OX (regimen as per phase 1/2 study) or nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 on days 1, 8 and 15 in a 28-day cycle. The primary endpoint is overall survival (OS). Secondary endpoints (progression-free survival [PFS] and overall response rate assessed with Response Evaluation Criteria in Solid Tumors v1.1 criteria) will be compared only if the primary endpoint shows superiority for liposomal irinotecan + 5-FU/ LV + OX over nab-paclitaxel + gemcitabine. Safety assessments include adverse-event monitoring. Patients will continue treatment until disease progression, unacceptable toxicity or study withdrawal, and will then be followed for survival every 2 months until death or study end (when all patients have died, withdrawn consent or are lost to follow-up). Clinical trial information: NCT04083235 .

TPS4116 Background: Chemotherapy in combination with targeted agents are standard-of-care options for patients for mCRC with response rates >50% in first line. In the second line setting, efficacy of chemotherapy and targeted agents are much lower with response rates of 5% for FOLFIRI (5-fluorouracil, leucovorin, irinotecan) + bevacizumab (anti-VEGF). New treatment options are urgently needed in particular for the 50 % of patients harboring a KRAS mutation. PLK1 is a serine/threonine kinase, master regulator of the mitotic checkpoint and cell division. PLK1 is overexpressed in CRC and its overexpression is associated with poor prognostic. A genome wide RNAi screen identified PLK1 as a synthetic lethal target in KRAS mutant CRC cells, inducing cell cycle arrest and apoptosis upon inhibition. Onvansertib is an oral, highly selective PLK1 inhibitor that demonstrates single agent and synergistic activity with irinotecan in preclinical CRC models. Additionally, KRAS mutated vs wild-type cells showed higher sensitivity to onvansertib. PLK1 inhibition is a potential target in KRAS-mutated mCRC, and the combination of onvansertib + FOLFIRI + bevacizumab may provide a new second-line treatment option. Methods: The primary objective of this single-arm Phase 1b/2 study is to assess the safety and preliminary efficacy of onvansertib in combination with FOLFIRI and bevacizumab in the second line setting for KRAS-mutated mCRC patients. For the Phase 1b segment, a standard 3 + 3 dose-escalation design is used to determine the maximum tolerated dose or recommended phase 2 dose (RP2D) of onvansertib. As of January 24, 2020, enrollment in the second dose level is ongoing. Efficacy will be determined by objective response rate (ORR) according to RECIST v1.1 (primary endpoint), progression-free survival and reduction in KRAS allelic burden in liquid biopsies (secondary endpoints). In the phase 2, based on a one-sided one sample log-rank test with 10% Type I error, there will be at least 90% power to detect an improvement in ORR from 5% to 20% with 26 patients. Exploratory endpoints include genomic studies of circulating tumor cells and ctDNA to evaluate altered pathways that correlate with patient clinical response. Clinical trial information: NCT03829410 .

Objectives: Survival benefit of combination over single-agent chemotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC) was demonstrated in younger patients in clinical trials. The authors aimed to evaluate whether this survival benefit of combination chemotherapy is present in elderly patients with metastatic PDAC. Materials and Methods: The authors identified elderly patients (age 65 y or older) with stage IV PDAC and extracted available clinical information from a prospectively maintained institutional pancreatic cancer registry from 2007 to 2016. The primary endpoint was overall survival. Cox proportional hazards regression was used for multivariable survival analyses. Survival outcomes for the entire cohort and by age group I (elderly, 65 to 75 y) and age group II (very elderly, older than 75 y) were assessed. Results: A total of 606 patients were included with a median age of 73.8 years. Among them, 239 patients (39%) received combination chemotherapy and 152 patients (25.1%) received single-agent chemotherapy as first-line treatment. Combination chemotherapy was associated with significantly longer median overall survival compared with single-agent chemotherapy (10.9 vs. 7.5 mo, P<0.001) with hazard ratio 0.62 (95% confidence interval, 0.47-0.81; P=0.001) after adjusting for age, sex, comorbidity, Eastern Cooperative Oncology Group (ECOG) performance status, and carbohydrate antigen 19-9 level. Analyses by age groups indicated that very elderly patients (age group II) benefited from combination chemotherapy compared with single-agent chemotherapy with hazard ratio 0.56 (95% confidence interval, 0.31-1; P=0.049), comparable with the age group I (P age-treatment interaction=0.81). Conclusion: Elderly patients, even those older than 75 years, with metastatic PDAC benefited from combination chemotherapy.