Pancreatic Ductal Adenocarcinoma Pts Research Articles

Interim results of the randomized phase 2 cohort of study FW-2020-01 assessing the efficacy, safety and pharmacodynamics of CM24 in combination with nivolumab and chemotherapy in advanced/metastatic pancreatic cancer.

LBA4143 Background: The novel monoclonal antibody CM24 blocks the activity of Carcinoembryonic Antigen Cell Adhesion Molecule 1 (CEACAM1), known to have key roles in cancer progression, immune evasion, and metastasis. We present the interim efficacy and safety data from the global multi-center, open label, randomized Phase 2 study (NCT 04731467) in patients (pts) with advanced/metastatic pancreatic ductal adenocarcinoma (PDAC) who progressed after 1st line therapy, treated with CM24, nivolumab (nivo) and chemotherapy vs. chemotherapy (CH). Methods: Patients with advanced/metastatic PDAC progressing after 1 prior line of systemic therapy including fluoropyrimidine/irinotecan or gemcitabine/nab-paclitaxel, having ≥1 measurable lesion, ≥18-year-old, ECOG ≤1 and adequate organ function were randomized 1:1 based on the class of prior CH received. Randomization was either to the experimental groups (EX) receiving CM24 (20mg/kg, q2wk), nivo (240mg/kg, q2wk) with one of the following CH regimens, liposomal irinotecan, 5 fluorouracil and leucovorin (Nal-IRI; q2wk) or gemcitabine/nab-paclitaxel (gem/nab; q1wk x3) or the control groups (C) with one of the CH regimens alone. This is a Bayesian design with an overall planned sample size of 60 pts with Overall Survival (OS) as the primary endpoint. Secondary endpoints include progression free survival (PFS), objective response rate (ORR) and disease control rate (DCR). An interim estimate of PFS HR, ORR and DCR based on data cut-off date of 21 Feb 2024 is reported. The analysis compares the EX vs. the respective C arm using log-rank test stratified by CH regimen. Results: A total of 63 PDAC pts were evenly randomized across the study arms. At data cut-off date, a total of 18 pts, 9 per treatment regimen remain on treatment. The median follow-up time for the Nal-IRI regimen is 6.3 months (95% CI: 5.5-8.4) and 5.2 months (95% CI: 4.0-6.7) for the gem/nab regimen. Median PFS ORR and DCR for the Nal-IRI EX arm were 3.8m (1.9-5.1; HR 0.70; p=0.213), 18.8% and 62.6%, and for the Nal-IRI C arm 1.9m (1.8-5.6), 6.3% and 40%, respectively (Table). Data for the gem/nab regimen and OS data for both regimens are not mature. Overall Grade ≥3 AE rate was 50% in the Nal-IRI EX arm and 13% in the C arm. The most common treatment-emergent grade ≥3 AEs EX vs. C were diarrhea (18.8% vs 6.7%), fatigue (18.8% vs 6.7%) and anemia (6.3% vs 0%). Conclusions: The interim analysis suggests that the combination of CM24/nivo/Nal-IRI/5FU/LV has a manageable safety profile with a longer PFS supported by higher ORR and DCR. OS Data continues to mature and will be reported once available. Clinical trial information: NCT04731467 . [Table: see text]

Safety and efficacy of IBI343 (anti-claudin18.2 antibody-drug conjugate) in patients with advanced pancreatic ductal adenocarcinoma or biliary tract cancer: Preliminary results from a phase 1 study.

3037 Background: Prognosis for advanced pancreatic ductal adenocarcinoma (PDAC) and biliary tract cancer (BTC) remains poor, with limited treatment options available. Expression of claudin18.2 (CLDN18.2) has emerged as a potential target for anti-cancer treatment. Herein, we report preliminary safety and efficacy results of IBI343, an antibody-drug conjugate (ADC) consisting of anti-CLDN18.2 monoclonal antibody conjugated to exatecan (topoisomerase I inhibitor), in patients (pts) with advanced PDAC or BTC in a phase 1 study. Methods: Eligible pts who failed or were intolerant to standard treatment were enrolled. IBI343 were intravenously administered at 6 mg/kg or 8 mg/kg Q3W. In dose escalation, pts were enrolled regardless of CLDN18.2 expression. In dose expansion, pts were required to have CLDN18.2 expression ≥40% (1+/2+/3+ staining intensity by immunohistochemistry). Primary endpoint was safety. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and progression free survival (PFS) assessed by investigator per RECIST v1.1. Results: As of December 19, 2023, 35 pts (1 pt in dose escalation and 34 pts in dose expansion) were enrolled from China and Australia (males: 57.1%, median age: 58.0 years, ECOG PS 1: 71.4%, stage IV: 91.4%, median lines of prior treatment: 2) including 28 PDAC pts and 7 BTC pts. Pts received IBI343 at 6 mg/kg (n=17) or 8 mg/kg (n=18). Median duration of treatment was 7.0 weeks (range: 3.0-23.6) with 23 (65.7%) pts still on treatment. In all pts, treatment-related adverse events (TRAEs) occurred in 28 (80.0%) pts including grade ≥3 TRAEs in 9 (25.7%) pts. Common TRAEs (≥20%) were anemia (42.9%), neutrophil count decreased (28.6%), nausea (25.7%), vomiting (25.7%) and white blood cell count decreased (22.9%). Serious TRAEs occurred in 4 (11.4%) pts. TRAEs leading to dose interruption and treatment discontinuation occurred in 7 (20.0%) pts and 1 (2.9%) pt respectively. No TRAE led to death. Safety profiles of IBI343 in PDAC and BTC were comparable with the whole study cohort and no new safety signal was observed. As of January 15, 2024, 25 pts at 6 mg/kg and 8 mg/kg were efficacy evaluable. Partial response (PR) was observed in 7 pts (5 PDAC and 2 BTC). The ORR was 28.0% (95%CI: 12.1-49.4) and DCR was 80.0% (95%CI: 59.3-93.2). In evaluable pts at 6 mg/kg with CLDN18.2 expression ≥60% (1+/2+/3+, n=13), 5 pts had PR with ORR of 38.5% (95%CI: 13.9-68.4) and DCR of 84.6% (95%CI: 54.6-98.1). Among 10 PDAC pts in this subgroup, ORR was 40% (95%CI: 12.2-73.8). DoR and PFS data were immature. More updated data on safety and efficacy will be presented at the meeting. Conclusions: IBI343 was well tolerated with favorable safety profiles and encouraging efficacy in CLDN18.2-positive PDAC and BTC. Clinical trial information: NCT05458219 .

KRAS mutation status in the prediction of pancreatic tumor response after neoadjuvant systemic therapy and magnetic resonance-guided SBRT.

709 Background: Stereotactic body radiotherapy (SBRT) has been incorporated into multi-modality treatment of locally advanced and borderline resectable pancreatic ductal adenocarcinoma (PDAC). For non-metastatic inoperable PDAC patients (pts) who receive magnetic resonance-guided SBRT (MRgSBRT), baseline features that predict for treatment response remain unsettled. In localized PDAC, multiple studies have investigated the KRAS oncogene as a prognostic factor with mixed findings. In this single institution retrospective study of PDAC pts treated with MRgSBRT, we hypothesized that KRAS mutation status would be predictive of meaningful clinical outcomes. Methods: From an IRB approved dataset of PDAC pts treated with MRgSBRT between 2016 and 2022, 39 pts with non-metastatic inoperable pancreatic cancer, known KRAS mutation status, ≥ 3 months of neoadjuvant systemic therapy (NST), and at least 3 months post-RT follow up were extracted for analysis. Baseline demographics, tumor and treatment characteristics, and clinical endpoints including conversion to resectability, best imaging response per RECIST v1.1, pathologic response (PR) per TRG-CAP, and overall survival (OS) after MRgSBRT were collected. Objective response (ORR) on both imaging and pathology was defined as complete response (CR) + partial response (PR); disease control (DC) was defined as CR + PR + stable disease (SD). Logistic regression was used to assess correlation between baseline variables and ORR. Cox proportional hazard models were utilized to determine association with OS. Results: Out of 39 pts, 21 (53%) were KRAS-mutated (KRAS-mt) and 18 (47%) were KRAS wild-type (KRAS-wt). Median age was 62, 54% were male, only 1 pt had ECOG > 1, and CA 19-9 at diagnosis was 197. Median duration of NST was 9 cycles, and common agents included Gemcitabine and Abraxane (21%); FOLFIRINOX (28%); a combination of the two regimens (41%); or other NSTs (10%). Median MRgSBRT dose fractionation was 50 Gy (range 35 – 50) in 5 fractions; all fractions underwent adaptive optimization. Thirty pts (77%) experienced DC on imaging, 16 (43%) had ORR, and 12 (31%) were converted to resectable following MRgSBRT. Cohort median OS was 12.3 months, and pts who had surgery had a non-significant median OS advantage (18 vs 12 months; p=0.19). KRAS-mt was associated with worse ORR (p=0.04; AUC=0.73) and decreased OS (HR: 2.15; p=0.03). In a clinical model incorporating baseline characteristics (age, ECOG, radiographic staging, CA 19-9 level, and KRAS), only KRAS predicted OS (HR: 3.02 for KRAS-mt; p=0.01). KRAS-mt status was also predictive of OS among pts who underwent surgery (HR: 5.24 for KRAS-mt; p=0.04). Conclusions: For localized PDAC pts inoperable at diagnosis who received NST followed by MRgSBRT, KRAS was the only significant predictor of ORR and OS, highlighting the need for further treatment intensification in KRAS-mt pts.

Contribution of neoadjuvant chemotherapy and radiation therapy (intensity-modulated radiation therapy with concurrent chemotherapy versus stereotactic body radiation therapy alone) on tumor volume regression in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma: A single institution experience.

707 Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with a minority of patients (pts) eligible for curative resection. Pts with borderline resectable or locally advanced (BR/LA) PDAC frequently receive neoadjuvant chemotherapy (NAC) +/- radiation therapy (RT) to improve resectability. Here, we report the individual contribution of NAC and RT (either intensity modulated RT + concurrent chemotherapy (IMRT+CC) or stereotactic body RT (SBRT) alone) on tumor regression by measuring tumor volumes. Methods: We performed a single institution retrospective review of PDAC pts who underwent resection between 2011-2021 and were part of a tumor biobank registry. Tumor measurements were performed at baseline, post-NAC, and post-RT by five independent, blinded abdominal radiologists. Analyses were performed using paired t-tests, two-proportion z-tests, log-rank tests, and Mann-Whitney U test. Results: We identified 49 BR/LA pts who received NAC followed by RT who had complete pre- and post-treatment imaging. Fifteen pts received IMRT+CC and 28 received SBRT. The effect of NAC on tumor volumes (-29.2% vs -26.3%, p=0.66; mean percent change) and maximum diameter (-9.2% vs -12.0%, p=0.58) was similar within the IMRT+CC and SBRT groups. Both IMRT+CC (-7.12 cm3, p=0.003) and SBRT (-2.70 cm3, p=0.001) resulted in significant tumor regressions. IMRT+CC achieved a significantly greater overall mean percent change in tumor volume (-53.4% vs -28.8%, p=0.024) and maximum diameter (-30.4% vs -16.2%, p=0.020) compared to SBRT. Pts receiving IMRT+CC or SBRT had similar tumor volumes (10.88 vs 11.74 cm3, p=0.87, respectively) and maximum diameter (3.45 vs 3.17 cm, p=0.48) prior to RT. IMRT+CC resulted in improved tumor volume response (>30% regression; 80.0% vs 46.4%; p=0.033) but not an improved response rate by RECIST criteria (46.7% vs 21.4%; p=0.085). Mean resected tumor volumes (by pathological review) for those receiving IMRT+CC (n=9) and SBRT (n=23) were 4.34 vs 13.1 cm3 (p=0.049). The R0 (86.7% vs 85.7%, p=0.93) and N0 (73.3% vs 53.6%, p=0.21) resection rates between the two groups were similar. Compared to SBRT, IMRT+CC resulted in an improved recurrence free survival (RFS; 2.36 vs 1.31 years; p=0.026), but did not meet statistical significance for an overall survival benefit (mOS; 2.85 vs 2.03 years, p=0.19). Conclusions: We found that IMRT+CC yielded superior radiographic volumetric regression and improved RFS but did not significantly impact mOS. Correspondingly, resected tumors from patients treated with IMRT+CC were smaller than those obtained from patients treated with SBRT. The role of IMRT+CC and SBRT in PDAC remains to be clearly defined.

Preliminary results from ERAS-007 plus palbociclib (palbo) in patients (pts) with KRAS/NRAS mutant (m) colorectal cancer (CRC) or KRASm pancreatic ductal adenocarcinoma (PDAC) in HERKULES-3 study: A phase 1b/2 study of agents targeting the mitogen-activated protein kinase (MAPK) pathway in pts with advanced gastrointestinal malignancies (GI cancers).

3558 Background: The RAS/MAPK pathway is dysregulated in a broad range of cancers including CRC and PDAC, resulting in downstream activation of ERK1/2. ERAS-007 is a novel, orally bioavailable inhibitor of ERK. Palbo is an oral CDK4/6 inhibitor that inhibits cellular proliferation, an essential feature of tumor growth. Both in vitro & in vivo data exploring the combination of ERAS-007 and palbo in a panel of CRC and pancreatic CDX and/or PDX models have shown promising activity to support the potential combinatorial clinical benefit in RASm CRC and PDAC pts. Methods: HERKULES-3 is a Phase 1b/2 study to assess safety, tolerability, PK, and preliminary clinical activity of ERAS-007 combinations targeting the MAPK pathway in pts with advanced GI cancers. Within this study, we are currently evaluating the safety, tolerability, and PK of escalating doses of ERAS-007 twice daily-once a week (BID-QW) (75, 100 mg) in combination with palbo once daily (QD) (75, 100, 125 mg) in pts with KRASm/NRASm CRC or KRASm PDAC. Results: As of 30 November 2022, 30 pts were dosed with the combination of palbo and ERAS-007. Treatment emergent AEs (TEAEs) occurring in ≥20% pts were diarrhea (40%), nausea (40%), anemia (33%), vision blurred (27%), fatigue (23%), and neutrophil count decreased (20%). ERAS-007 treatment related AEs (TRAEs) were reported in 19 pts (63%), with the most frequently reported as diarrhea (40%), nausea (33%), and vision blurred (27%). Grade (Gr) ≥3 TEAEs were reported in 12 pts (40%), including 3 related to ERAS-007 (neutrophil count decreased, diarrhea and dermatitis acneiform). Neutrophil count decreased and anemia were the only Gr 3 events reported in ≥2 pts. No Gr 4 events were reported. Two Gr 5 events unrelated to any drugs (hemorrhage intracranial and malignant pleural effusion) and one Gr 5 event (anemia) related to palbo were reported. Two pts discontinued ERAS-007 due to TEAEs (Gr 5 malignant pleural effusion and Gr 2 neutrophil count decreased). Three pts reported 4 DLTs: 1 pt at 75mg ERAS-007 & 125mg palbo (Gr 3 maculopapular rash & Gr 4 sepsis), 1 pt at 100mg ERAS-007 & 100mg palbo (Gr 3 dermatitis acneiform), and 1 pt at 100mg ERAS-007 & 125mg palbo (Gr 3 thrombocytopenia). Based on preliminary PK, no clinically relevant PK interactions were identified between ERAS-007 and palbo. The evaluation of clinical activity is ongoing. Conclusions: ERAS-007 in combination with palbo in pts with KRASm/NRASm CRC or KRASm PDAC shows expected preliminary safety with reversible and manageable AEs. The highest dose evaluated and cleared by the safety review committee to date is ERAS-007 100 mg BID-QW in combination with the approved monotherapy dose of palbo 125 mg QD. Clinical trial information: NCT05039177 .

A phase 1b, open-label, two-part safety, tolerability, and efficacy study of a soluble beta-glucan (odetiglucan) in combination with a CD40 agonistic monoclonal antibody (CDX-1140) in patients with metastatic pancreatic adenocarcinoma whose disease did not progress during first-line (1L) chemotherapy.

TPS4201 Background: Metastatic pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal disease with a 5-year overall survival (OS) rate of 3%. Standard of care treatment is continuous cytotoxic chemotherapy which produces modest improvements in OS but is also associated with significant toxicity raising the need for novel treatment paradigms. Although immunotherapy has yet to produce clinical benefit for most patients with PDAC, preclinical modeling demonstrates its potential and show that combinations of myeloid agonists can trigger robust synergistic anti-tumor activity against PDAC tumors that are otherwise resistant to immunotherapy including immune checkpoint blockade (anti-CTLA4, anti-PD1). In this study, odetiglucan (OD), a novel beta glucan pathogen associated molecular pattern (PAMP), will be combined for the first time with CDX-1140, a fully human Ig2K agonistic monoclonal CD40 antibody in the maintenance setting after an induction phase of cytotoxic chemotherapy. OD and a CD40 agonist directly promote the activation and maturation of antigen presenting cells and shift the suppressive TME to enhance T-cell responses through non-redundant myeloid signaling pathways. We hypothesize that the combination of OD and CD40 agonist therapy has the potential to trigger anti-tumor immunity in PDAC and thus, extend and deepen responses to 1L cytotoxic chemotherapy. Methods: A two-part Phase 1b study of metastatic PDAC pts who have evidence of response or stable disease following 16-24 wks of chemotherapy is being conducted. Part A uses a 3+3 design; pts will receive OD 4 mg/kg QW + CDX-1140 1.5 mg/kg Q3W. Following a dose-limiting toxicity observation period, the dose will be held at 1.5 mg/kg or decreased to 0.72 mg/kg Q3W. Once preliminary safety is established, the cohort will be expanded to 15 pts. Part B pts will receive OD 4mg/kg + CDX-1140 at the dose identified in Part A Q3W. The study will enroll 30 pts. Main eligibility criteria: Metastatic PDAC having durable stable disease or response to 1L chemotherapy; serum ABA ≥20 µg/mL, and no prior anti-CD40 mAb or immunomodulatory treatment exposure. Primary endpoints are MTD, RP2D, and safety. Secondary endpoints include DOR, PFS, ORR, and OS and exploratory endpoints include evaluating immune pharmacodynamic responses in peripheral blood and tumor. Safety parameters will be listed and summarized using descriptive statistics. ORR will be tabulated by overall frequency; DOR, TTF, PFS and OS will be summarized and presented using Kaplan-Meier and waterfall plots. 5 US sites will participate. Clinical trial information: NCT04834778 .

Prognostic role of a novel clinical-nutritional index in pancreatic ductal adenocarcinoma: The Pancreatic Adenocarcinoma Nutritional-Clinical Index (PANCIN).

697 Background: Impaired nutritional status is often associated with Pancreatic Ductal Adenocarcinoma (PDAC) and poor prognosis. Little is known on the prognostic role of nutritional variables in PDAC patients (pts) receiving chemotherapy (CT). Methods: Locally advanced or metastatic PDAC pts enrolled at our Institute in a prospective observational study (PAC-MAIN) and treated with 1st-line CT between April 2019 and July 2021 were included in the analysis. Clinical and nutritional variables entailed biohumoral parameters, bioimpedance vector analysis (BIVA)- and Computed Tomography-derived body composition. Progression-free and Overall survival (PFS and OS) were calculated from CT start to progression or death. A Multivariate Cox proportional-hazards model for PFS prediction was generated by backward selection of features with a p-value (p) ≤ 0.06. The resultant index, named PANCIN, was calculated as linear combination of the covariates (Xi are the N) and the b Cox coefficients (bi), according to the formula: PANCIN = ∑Ni=1 bi Xi Kaplan–Meier test was performed to assess the ability of PANCIN to stratify pts according to its median value for PFS and OS prediction. Results: 74 pts were included in the study. The variables retained in the model were: serum Vitamin B12 (pg/ml) [Hazard Ratio (HR)= 1.001, 95% Confidence Interval (CI) 1.0004-1.0016, p=0.002]; BIVA-derived Body Cell Mass (%) [HR= 0.94, 95% CI 0.887-1.002, p=0.058]; ECOG Performance Status (0 vs 1-2) [HR= 3.25, 95% CI 1.048-10.077, p=0.041]; Albumin (g/L) [HR= 0.91, 95% CI 0.86-0.97, p=0.002]; FAACT Score [HR= 1.041, 95% CI 1.006-1.077, p=0.022]. Median PFS was 15.3 (95% CI 7.6-21.8) and 5.8 months (95% CI 2.7-9.0) for pts with PANCIN < or ≥ -1.7768 median value respectively [HR= 3.7, 95% CI 1.9-7.0, p=0.0001]. Median OS was 23.8 (95% CI 12.6-33.3) and 10.0 months (95% CI 5.7-12.7) for pts with PANCIN < or ≥ -1.7768 respectively [HR= 4.1, 95% CI 2.1-7.9, p<0.0001]. Conclusions: PANCIN is a novel nutritional-clinical index able to predict outcome of advanced PDAC pts receiving CT. If furtherly validated, it may represent a stratification tool both in clinical practice and in prospective trials. Our findings also support the relevance of a baseline comprehensive nutritional assessment, to define tailored nutritional interventions.[Table: see text]

Exploring optimal therapeutic management of STAGE IA PDAC in the era of neoadjuvant chemotherapy.

712 Background: Neoadjuvant chemotherapy (NAT) is currently recommended for non-metastatic pancreatic ductal adenocarcinoma (PDAC). Data on the optimal NAT duration and the proper post-surgical chemotherapy (PSC) are lacking, especially for patients (pts) who yielded a pathological stage IA. Methods: We retrospectively analyzed the outcome of PDAC pts resected between 2015 and 2020 at our institution after NAT yielding a pathologic stage of PDAC ypT1N0. Pts were analyzed basing on NAT duration (aim 1) and PSC indication (yes/no) and type (aim 2). The primary endpoint was median event-free survival (EFS) for aim 1 and median disease free-survival (DFS) for aim 2. As per secondary endpoints, overall survival (OS) and the prognostic role of clinical and pathological variables was assessed (baseline CA19.9 level; pre-operative Ca19.9 level, basal vascular involvement, grading, perineural invasion, R1 resection). Results: During the study period a total of 756 pts were resected, 363 (48%) after NAT. Of them, 72 pts (20%) achieved a pathological ypT1N0 (ypIA). Among this group 16 pts (22%) showed a T1a-T1b, 62 pts (86%) had a G1/G2 tumor, 60 pts (83%) had a R0, 36 pts (50%) had a perineural invasion and 33 (46%) had a tumor regression grade marked or completed. For aim 1 we compared 34 pts (47%) treated with NAT for not more than 4 months (Group A1) and 38 pts (53%) treated for at least 4 months (Group B1). Baseline, biochemical and radiological variables were similar between the 2 groups. No statistical difference was found in EFS (Group A1: median 46 months/ Group B1: median not reached). For aim 2 we compared 10 pts (14%) who received the same chemotherapy regimen in NAT and PSC (Group A2), 35 pts (49%) who received a different chemotherapy regimen in NAT and PSC (Group B2) and 27 (14%) pts who did not receive any PSC (Group C2). PSC were gemcitabine/nab-paclitaxel (10%) and mFOLFIRINOX (90%) in group A2, whereas gemcitabine/nab-paclitaxel (17%), mFOLFIRINOX (3%), gemcitabine (51.5%), capecitabine (17%), gemcitabine/capecitabine (8.5%), PEXG (3%) in group B2. DFS were 24 months for group B2, whereas median was not reached for group A2 e C2 (p=0.006). No statistical difference was found in OS among the groups. At multivariate analysis only grading (G3) emerged as independent factor for poor prognosis. Conclusions: In ypIA pts NAT duration and or type seem to be unrelated to the outcome. PSC performed with alternative and depotentiated chemotherapy as compared to NAT, seem to be related to a higher rate of disease recurrence. Poor differentiated/G3 tumors is confirmed as independent risk factor for poor survival in this population.

DNA damage repair (DDR) germline mutations (GMs) in pancreatic ductal adenocarcinoma (PDAC): A mono-institutional retrospective study.

10587 Background: GMs in DDR genes, in particular BRCA1/2, are associated with increased risk of cancer, including PDAC. Their identification is crucial for the clinical relevance, the best treatment choice, and the family implications in cancer prevention. However, there are few data regarding the epidemiology and the prognostic role of DDR GMs in PDAC patients (pts). The aim of our study is to determine the prevalence of DDR GMs, their correlation with clinicopathological features and their prognostic role. Methods: Unselected PDCA pts, assessed by BRCA1/2 GM analysis or multigenic panel at our Institution, were retrospectively analyzed. We divided the overall population into three groups based on GMs: pts with pathogenic variants (PVs), pts with variants of uncertain significance (VUS) and pts with no alterations. Clinicopathologic characteristics and treatment data were collected. The incidence of DDR GMs variants and their association with overall survival (OS) were evaluated. Univariate and multivariate analyses for OS were performed. Results: From September 2019 to August 2021, 200 PDAC pts were tested for DDR GMs: all pts were evaluated for BRCA 1/2; 140 pts were tested for further DDR GMs by a multigenic panel. Twenty-five pts (12.5%) had PVs, 45 (22.5%) pts had VUS and 130 (65%) pts had no GMs. BRCA 1-2 PVs were found in 10 pts (5%). Out of 91 pts with metastatic disease, the rate of PVs BRCA1/2 was 8.8%. Among 140 pts tested with multigenic panel, further PVs included: 7 (5%) ATM, 5 (3.6%) MUTYH, 1 (0.7%) TP53, 1 (0.7%) BARD1, and 1 (0.7%) MSH6. The most frequent VUS were: CHECK2 (5%), APC (3.6%), ATM (3.6%) and BRCA2 (3.6%). Regarding cancer family history, a statistically significant difference was reported between the 3 group (76% in PV pts, 82% in VUS pts and 60% in pts with no GMs; p 0.01). No difference was found concerning age (p 0.69), stage at diagnosis (p 0.31) and platinum-exposure (p 0.27). Out of 189 evaluable pts, median OS was 23 months. A significant difference in OS was observed in the 3 groups (30 months in PVs pts, 14 months in VUS pts and 24 months in pts with no GMs, p 0.0006). No factor, including the presence or the type of GMs, age, stage and family history, was significantly associated with OS at the multivariate analysis. Conclusions: In our study, we observed a high incidence of DDR GMs PV (12.5%), beyond BRCA 1/2, regardless of age, stage and family history. Despite retrospective nature of our analysis, small population, and single-institution evaluation, our findings confirm the importance of genetic testing for BRCA1/2 and, where available, of a multigenic test in all PDAC pts, due to the therapeutic implications and cancer risk prevention in patients relatives. The prognostic role of DDR GMs and the impact of VUS remain unclear.

Circulating tumor DNA profile in pancreatic ductal adenocarcinoma (PDAC) and potential targeted therapy.

4152 Background: Despite huge efforts patients (pts) with advanced PDAC, still have a dismal long-term prognosis. The lack of available good-quality tissue samples for next generation sequencing (NGS) prevents from finding actionable alterations that could guide personalized treatments. Circulating tumor DNA (ctDNA) provides a non-invasive method for obtaining molecular information with therapeutic potential. Here, we present prospective data of ctDNA sequencing in pts with PDAC. Methods: We collected a single blood sample from advanced PDAC pts at any line of treatment (Tx) and at least 10 days apart from their last therapy. The samples were analyzed by Guardant360 plasma-based NGS, a standardized assay which covers microsatellite instability [MSI] evaluation and analysis of all four types of somatic alterations in 74 genes. Alterations were reported either as pathogenic or non-pathogenic. We classified each gene alteration according to the different OncoKB therapeutic levels of evidence [LE]. Additionally, we gathered the dates of both blood collection and molecular report. In case the molecular report showed no tumor-related alterations, it was interpreted as either absence of detectable mutations or low ctDNA levels, which would translate low disease burden or pts responding to therapy. Demographic and clinical data have been accessed from the medical records. Results: From 08/2019 to 09/2021 we collected blood samples from 94 PDAC pts. 56% of them were male and 53% were >65 years old. At the time of sample collection, nearly all pts were metastatic (98%). Regarding previous lines of Tx, 57% pts were Tx naïve; 10% were receiving active systemic Tx and 33% had experienced disease progression. Molecular reports were available in an average of 9.1 days. A total of 243 gene alterations were detected, having 94% of pts at least 1 genomic alteration, which was pathogenic in 69% of the cases (see Table). There were no pathogenic alterations ranked as OncoKB LE 1-2 ( MSI or NTRK). Seventy alterations (30%) were ranked as OncoKB LE 3A and 4 ( ARID1A, BRAC2, CDKN2A, KRAS). Three of these pts were treated with PARP inhibitors due to the presence of BRCA2 mutations. No ctDNA was detected in 15 pts (16%), despite being the sample collected >10 days from receiving their last Tx. Of these, 11 had low tumor burden (only peritoneal or lung metastases) and 4 had documented response to the Tx by the time the samples were collected. Conclusions: Real-time and prospective genomic profiling of pts with advanced PDAC using ctDNA is feasible and conveniently fast, which would allow its role in identifying and developing therapeutic targets for approved Tx or clinical trial treatments. [Table: see text]

A phase Ib/II study of sotorasib combined with chemotherapy for second-line treatment of KRAS p. G12C–mutated advanced pancreatic cancer.

TPS4194 Background: Kirsten rat sarcoma viral oncogene homolog( KRAS) p.G12C mutation is an oncogenic driver mutation in several solid tumors. Sotorasib is a specific, irreversible, small molecule inhibitor of KRASG12C that has demonstrated durable clinical benefit in NSCLC, with mild and manageable toxicities. Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related death in the world, although recent advances in chemotherapeutic regimens for metastatic PDAC provide better clinical outcomes. KRAS p.G12C mutations are found in 1-2% of PDAC. Modest single agent activity of Sotorasib was observed in chemo-refractory PDAC patients (pts). Combination of Sotorasib with approved PDAC chemotherapy regimens is expected to enhance antitumor efficacy. This study is designed to evaluate safety, tolerability and efficacy of Sotorasib in combination with second line chemotherapy in pts with KRASp.G12C mutated advanced PDAC who have progressed on first-line chemotherapy. Methods: This investigator initiated study run through Hoosier Cancer Research Network, is a phase Ib/II study evaluating Sotorasib in combination with either Liposomal Irinotecan/5-Fluorouracil/Leucovorin or Gemcitabine/nab-paclitaxel. Physician choice of chemotherapy based on first line chemotherapy regimen used. Histologically confirmed PDAC pts who have KRAS p.G12C mutation identified through tumor or blood based testing, progressed on first-line chemotherapy, adequate organ function and performance status are eligible. A safety lead-in will be conducted to evaluate the safety of Sotorasib at a dose of 960 mg in combination with each of the two chemotherapy regimens. A “3+3” dose de-escalation design will be used for each combination separately. All patients treated at the RP2D in the initial safety cohort will be evaluable for response and included in the first stage of Simon’s two stage design. The phase II trial conducted at the RP2D follows Simon’s two-stage “minimax” design. The trial is designed to test whether addition of Sotorasib to chemotherapy will improve the objective response rate (ORR), from 16% to 31%. In Stage 1, 22 evaluable patients will be enrolled, and the trial will be stopped if 3 or fewer of the 22 evaluable patients respond. If ≥ 4 responses are observed, an additional 28 patients will be enrolled in Stage 2, for a total of 50 evaluable patients. Up to 59 subjects will be enrolled across 15 academic cancer institutions in order to obtain the required number of 50 evaluable subjects, assuming 15% attrition rate. Primary endpoint is to determine the objective response rate (ORR) by RECIST 1.1. The secondary endpoint to evaluate safety, and further evaluate efficacy in terms of disease control rate, duration of response, progression-free survival and overall survival. Correlative endpoints will determine biomarkers based on analysis of blood and/or tumor on study. Clinical trial information: IND 159412.

Reconstructing the tumor microenvironment to unlock therapeutic options in pancreatic cancer.

589 Background: Spatiotemporal heterogeneity, paucity of actionable targets, and complexity of the tumor microenvironment (TME) are major barriers to therapeutic advances in pancreatic ductal adenocarcinoma (PDAC). We reconstructed the transcriptomic data from a heterogeneous cohort of PDAC patients (pts) to examine the TME and identify putative therapeutic strategies. Methods: Transcriptomic profiling and targeted gene sequencing data (Tempus) on primary or metastatic specimens from PDAC pts treated at the Medical College of Wisconsin (MCW) between 2015-2020 were analyzed. Mutation calling, expression analysis, cell type deconvolution from the transcriptome, and TME reconstruction were performed using BostonGene’s automated pipelines. Mann-Whitney U test and Fisher's exact test were used to assess statistical significance. Results: The cohort (N = 79) comprised of resectable (19%), borderline resectable (37%), locally advanced (24%) and metastatic (20%) PDAC pts. The most frequently used tumor sites for transcriptomic profiling were pancreas primary (59%), liver (16%), lung (10%) and peritoneum (10%). Four distinct subtypes were identified based on the BostonGene classification of the transcriptomic TME– Immune Enriched (IE; 14%), Fibrotic (F; 28%), Immune Enriched & Fibrotic (IEF; 36%), and Immune Depleted (ID; 22%). Analyses of the cellular composition of the TME subtypes with RNA-seq-based deconvolution showed that T-cell fractions (CD4, CD8) were higher in the IE/IEF subtypes compared to the F/ID subtypes (CD8 means: 6.4% vs 2.9%, p < 0.001; CD4 means: 15.1% vs. 7.6%, p < 0.001), while fibroblast content was higher in the F/IEF subtypes compared to the IE/ID subtypes (37.4% vs 18.4%; p < 0.001). KRAS wild-type (WT) tumors were enriched in the IEF subtype (58%), while KRAS mutated tumors comprised all four transcriptomic subtypes. Primary PDACs that underwent radiotherapy were significantly more enriched in fibroblasts compared to samples from the TCGA cohort that did not undergo radiotherapy (means: 30%(MCW) vs. 20% (TCGA), p < 0.001). Primary PDACs were enriched in the IEF subtype (46%), while liver and lung metastases were enriched in the ID (74%) and IE subtypes (70%), respectively. When pts were dichotomized to short (< 400 days) versus long (> 800 days) survivors, tumors from pts with longer survival demonstrated a trend towards enrichment in CD4/CD8 T cells and IE subtype that did not meet statistical significance. Conclusions: Lung metastases and KRAS WT PDACs harbor an immunogenic TME while liver metastases harbor an immune-cold TME, highlighting the biologic heterogeneity of PDAC. The efficacy of immunotherapeutic strategies in PDAC pts who demonstrate an IE/IEF transcriptomic subtype merits prospective evaluation. The four distinct subtypes identified by TME transcriptomic classification highlight the possibility of personalized immunotherapeutic strategies in PDAC.

Targeted therapy (TT) in patients with KRAS wildtype (WT) pancreatic ductal adenocarcinoma (PDAC) produces durable response.

596 Background: Genomic alterations (GA) that drive cancer development and predict therapeutic response remain elusive in patients (pts) with KRAS WT PDAC. We interrogated our institutional database to identify actionable GAs in pts with metastatic, KRAS WT PDAC and analyzed the therapeutic impact of matched TT. Methods: We reviewed electronic medical records of KRAS WT PDAC pts (n=24) who underwent comprehensive genomic profiling (CGP) utilizing Foundation One CDx (25.0%) or Tempus (75.0%) between 2015-2021. Duration of response (DOR) was calculated from date of treatment (Tx) initiation to Tx discontinuation. Overall survival (OS) was measured from the date of the diagnosis (Dx) of advanced disease (AD) to death or last follow-up. OS was estimated using the Kaplan-Meier method, with at-risk periods left-truncated at the time of CGP. The effect of covariates on survival was evaluated using Cox proportional hazards regression. Results: Of the 24 KRAS WT pts, 14 (58%) had AD: 8 (57%) pts had metastatic disease at or shortly after Dx, 6 (43%) pts developed metachronous recurrence. Median age at Dx for pts with AD was 65, and 57% were female. Seven of 14 pts with AD (50%) had highly actionable GA (HAGA), (Table). Pts with HAGA demonstrated durable responses to TT (Table) with manageable toxicities. Pts with HAGA had a median OS of 28 mo compared to 5.9 mo for those without (Hazard Ratio = 0.47, p = 0.33). Conclusions: The sustained therapeutic benefit noted with TT matched to HAGA in pts with KRAS WT PDAC underscores the need for systematic interrogation of the somatic genome in PDAC pts. Optimal sequencing of cytotoxic therapy with TT and its impact on modulating clonal selection pressure in pts with KRAS WT PDAC merits prospective evaluation.[Table: see text]

Abstract PO-052: A pilot study of miRNA expression profile in surgically resected pancreatic ductal adenocarcinoma: Initial report from a bi-institutional cohort

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies: novel therapeutic approaches beyond conventional chemotherapy are still lacking and prognosis remains poor, even for resectable patients (pts). Furthermore, there is an almost complete absence of validated predictive factors. Consequently, robust biomarkers for the early diagnosis and the prognostic stratification are urgently needed in clinical practice, especially in the context of neoadjuvant and adjuvant settings. In the last years, evidence revealed the crucial role of miRNAs in cancer initiation and progression, as well as in the chemo-resistance mechanisms, suggesting their use as clinical biomarkers. Material and methods: In this pilot study, we performed a microarray analysis to characterize global miRNA expression profile from surgical tissue samples collected from 20 resected PDAC pts pooled into 4 groups according to different clinico-pathological features: nodal metastases (N+/N-) and tumor grading (G2/G3). Results: According to expression patterns, we identified, among 384 miRNAs, a significant different modulation for 11 miRNAs associated to G2 vs G3 and for 7 miRNAs in N+ vs N- disease, suggesting a possible specific signature reflecting histological grade and nodal metastasis occurrence, respectively. We focused on 2 up-regulated (miR-138-5p and miR-518-3p) and 3 down-regulated (miR-215-5p, miR-519a-3p and miR-576-5p) miRNAs in N+ pts, and on 3 up-regulated (miR-1-3p, miR-31-5p and miR-205-5p) in G3 pts, in order to verify their possible implication in the molecular changes behind tumor differentiation and spread, as well as their potential use for prognostic and therapeutic purpose. A bio-informatic analysis was also performed, using different in silico tools, to study both high affinity miRNA targets and cross-regulated pathways among the upand down-regulated miRNAs. The results identified several associated targets involved in multiple signaling pathways commonly dysregulated in cancer. Finally, BRCA1/2 and RB1 miRNAs-mediated-modulation is actually ongoing, considering the pivotal role of these genes in some PDAC pts. Conclusion: These preliminary data provide a strong rationale to further investigate miRNAs expression in larger cohorts of PDAC pts, possibly integrating validated tissue miRNAs data with circulating miRNAs, in order to identify strong (and easily accessible) potential biomarker(s) with prognostic and/or predictive significance. Citation Format: Luca Pompella, Michela Falco, Carlo Caputo, Anna Grimaldi, Giuseppe Tirino, Severo Campione, Francesca Sparano, Maria Lucia Iacovino, Chiara Carmen Miceli, Carlo Molino, Marco Montella, Renato Franco, Gennaro Galizia, Giovanni Conzo, Vincenzo Napolitano, Annamaria Auricchio, Francesca Cardella, Fortunato Ciardiello, Michele Caraglia, Angela Lombardi, Gabriella Misso, Ferdinando De Vita. A pilot study of miRNA expression profile in surgically resected pancreatic ductal adenocarcinoma: Initial report from a bi-institutional cohort [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-052.

1487TiP A randomized non-comparative phase II study of maintenance therapy with FOLFIRI alone or in combination with Tedopi vaccine after induction therapy with FOLFIRINOX in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (TEDOPAM – D17-01 PRODIGE 63 STUDY)

Tedopi (OSE2101) is a multiple neoepitope vaccine restricted to HLA-A2 positive patients (Pts) targeting 5 tumor-associated antigens (ACE, HER2, MAGE2, MAGE3, TP53) frequently expressed in pancreatic ductal adenocarcinoma (PDAC). The TEDOPaM - PRODIGE 63 aims to assess the efficacy and safety of Tedopi in advanced PDAC Pts after FOLFIRINOX induction chemotherapy (CT). It was initially a randomized, non-comparative phase II study with 3 arms: FOLFIRI, Tedopi, Tedopi + nivolumab. Following the IDMC meeting in July 2020 (N=29 Pts), suggesting that early CT discontinuation may be deleterious, Sponsor decided to stop the evaluation of Tedopi without CT and maintain a CT backbone with FOLFIRI.

Fecal microbiome composition in pancreatic cancer cachexia and response to nutrition support.

4129 Background: Pancreatic ductal adenocarcinoma (PDAC) carries a poor prognosis with a 5-year survival rate of 10.0%. Previous studies in stool microbiome indicate that microbiome composition has been associated with therapy response and pathogenesis across multiple cancers, and PDAC patients (pts) with higher bacterial diversity have demonstrated greater long-term survival. The fecal microbiome has not previously been characterized for PDAC pts with cancer cachexia or associated interventions. The study addressed the changes in microbiome over the course of treatment and the association between baseline bacterial composition and outcome in PDAC pts with cachexia. Methods: Stool specimens were collected from the PNCX1 trial (NCT02400398), where all pts were given a semi-elemental diet—enzymatically hydrolyzed protein—with enteral tube feeding. Stool samples (n = 29) were collected at time points aligned with enteral feeding and chemotherapy cycles separated by 6 weeks (C1D1, C2D1, and C3D1) and analyzed using 16S v4 sequencing of the microbiome. Microbiome changes from C1D1 to C3D1, weight stability, and overall survival (OS) were measured alongside microbiome characterization. Results: Pts with a complete set of stool samples were analyzed (n = 6) for differences in microbiome composition across treatment cycles. C3D1 samples were significantly associated with both an increased population of Veillonella and Actinomyces and decreased Bacteroides and Butyricicoccus compared to C1D1. Baseline stool microbiome composition was also evaluated to predict weight stability throughout treatment. In patient stool samples (n = 8) at C1D1, greater abundance of Veillonella (p = 0.0006) and reduced Bifidobacterium (p = 2.62E-5) were linked to greater weight stability. Microbiome alpha-diversity was also characterized using Shannon and Chao1 indices, where stable weight was related to reduced species richness (Chao1, p = 0.0194) but not evenness (Shannon, p = 0.1716). C1D1 patient stool samples were then analyzed and compared to OS (n = 16). Although no significant differences in global microbiome composition were noted between OS < 180 days and OS > 180 days, Parasutterella, Tyzzerella, Phascolarctobacterium, and Lachnoclostridium were identified as more prevalent in OS > 180 days despite their relatively low abundance. Conclusions: We are among the first evaluate stool bacteria changes over treatment course in PDAC pts. While Veillonella was associated with weight stability in a cohort of advanced PDAC pts all receiving enteral feeding, several genera were found in abundance in pts with prolonged OS, though this needs further validation. The potential impact of the gut microbiome and enteral feeding on weight stability is provocative given that cachexia is a hallmark of PDAC and an effective strategy to mitigate this process would be transformative.

Safety and efficacy of the anti-CD73 monoclonal antibody (mAb) oleclumab ± durvalumab in patients (pts) with advanced colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), or EGFR-mutant non-small cell lung cancer (EGFRm NSCLC).

9047 Background: Upregulation of CD73 in multiple cancers increases adenosine production, leading to local immunosuppression. Oleclumab, a human IgG1λ mAb, inhibits CD73 function and may increase antitumor immunity. Initial data from a Phase I, first-in-human, dose-escalation and expansion study showed that oleclumab ± durvalumab had manageable safety and encouraging clinical activity in pts with advanced CRC or PDAC. We report updated safety and activity in these cohorts and the first results in an expansion cohort of pts with advanced EGFRm NSCLC. Methods: Previously treated pts with histologically or cytologically confirmed microsatellite stable CRC, PDAC, or EGFRm NSCLC received oleclumab 5–40 mg/kg (escalation) and 40 mg/kg (expansion) IV Q2W, alone (escalation only) or with durvalumab 10 mg/kg IV Q2W. The primary objective was safety; secondary efficacy objectives included objective response (OR) per RECIST v1.1 and duration of response (DoR). Results: 66 pts were enrolled in the escalation phase (35 CRC, 31 PDAC) and 126 in the expansion phase (42 CRC, 42 PDAC, 42 EGFRm NSCLC). At data cutoff (DCO; June 9, 2020), the median number of oleclumab doses was 4 in pts on monotherapy (range 1–26) and 4 in pts on combination therapy across both phases (range 1–76). In the escalation phase, there were no DLTs in pts on monotherapy or combination therapy; treatment-related adverse events (TRAEs) occurred in 54.8% of pts on monotherapy (Grade 3–4 in 7.1%) and 54.2% of pts on combination therapy (Grade 3–4 in 20.8%); fatigue was the most common TRAE with both regimens. No TRAEs resulted in death. In previous interim analyses before this DCO, no ORs were reported in the escalation phase. In the expansion phase, 5 pts were treated for ≥12 mos; 6 pts were ongoing at DCO. TRAEs occurred in 54.0% (Grade 3–5 in 15.1%); the most common TRAEs were fatigue (15.1%), diarrhea (9.5%), and rash (7.1%). One pt had a TRAE resulting in death (systemic inflammatory response syndrome). ORs were seen in 1 CRC pt (DoR 35.9+ mos [+ = ongoing response]), 2 PDAC pts (DoR 22.1+ and 28.6+ mos), and 4 EGFRm NSCLC pts (DoR range 5.6 to 15.7+ mos, median not reached; only 1 of the 4 pts had ≥25% programmed cell death ligand-1 [PD-L1]+ tumor cells). Nine CRC pts, 8 PDAC pts, and 9 EGFRm NSCLC pts had SD. Of 6 pts with matched biopsies who received combination therapy, 5 had increases in CD8+ T cells, PD-L1, and granzyme B. Baseline tumor CD73 expression and association with clinical response will be presented. Conclusions: Oleclumab ± durvalumab had a tolerable safety profile and combination therapy showed promising antitumor activity in EGFRm NSCLC. ORs and SD were durable, even in tumor types that are generally immunotherapy-resistant. Clinical trial information: NCT02503774.

Efficacy of olaparib therapy in metastatic pancreatic ductal adenocarcinoma (PDAC) with homologous recombination deficiency (HRD).

e16266 Background: Pancreatic cancer is one of the deadliest malignancies, with a 5 year OS of around 3%. Up to 3% of unselected patients (pts) with (PDAC) have the BRCA 1/2 mutation, while up to 15% possess HRD (ARID1A, ATM, BAP1, BARD1, BRIP1, CHEK1/2, FANCA, PALB2, RAD50, RAD51). PARP inhibitors, like olaparib, demonstrate clinical benefit in metastatic PDAC with BRCA mutations (mBRCA) and may have a role in those with HRD. The objective of this study is to determine the role of PARP inhibition in PDAC with HRD. Methods: This was a retrospective chart review of metastatic PDAC pts with germline (g) or somatic (s) mBRCA or HRD who received olaparib. An analysis of PFS and OS was performed for PDAC pts with mBRCA vs. HRD. Results: Forty-six pts with metastatic pancreatic cancer were identified to have mBRCA (n = 13) or HRD (n = 23) and received olaparib in our database. Median age was 73 years for mBRCA and 66 years for HRD. Five pts received olaparib as maintenance therapy after disease control with platinum: 2 mBRCA and 3 HRD pts. Six pts with mBRCA and 7 pts with HRD were platinum naïve prior to olaparib. Zero pts with mBRCA and 3 pts with HRD received olaparib after disease progression on platinum. The median (med)PFS for mBRCA vs. HRD was 6.1 months vs. 2.8 months (HR 0.5, 95% CI: 0.2-1.1, p = 0.07). The medOS for mBRCA vs. HRD was 7.7 vs. 5.3 months (HR 0.7, 95% CI: 0.2-1.9, p = 0.4). Of those with mBRCA who received olaparib, prior cisplatin exposure (n = 8) vs. cisplatin naïve (n = 5) led to medPFS of 6.1 vs. 7.8 months (HR 1.8, 95% CI 0.5-6.7, p = 0.3) and medOS of 6.8 months vs. 9.5 months (HR 1.5, 95% 0.3-6.4, p = 0.6). Six pts with HRD including gCHEK2 c.407T > C, gCHEK2 c.1461+1 G > A, gPALB2 gain (exon 11), sFANCI p.N1252S, sATM p.V2716A, sARID1A Q944fs*14 were noted to have disease control of at least 3 months on olaparib. Only one of these pts received olaparib as maintenance therapy after platinum. The medPFS was 6.1 months and medOS was not reached. One pt with HRD (sFANCI N1252S) had progressive disease on platinum prior to olaparib, but had stable disease > 5 months with olaparib. Conclusions: Our study suggests olaparib may have anticancer activity in PDAC with certain HRD. In addition, olaparib may have a role outside maintenance therapy in PDAC with mBRCA. Prospective studies are needed to confirm these findings.

KG 4/2015: A randomized, controlled, multicenter, open-label phase III clinical trial of GV1001 with gemcitabine/capecitabine in previous untreated, eotaxin-high patients with advanced pancreatic ductal adenocarcinoma.

4020 Background: In the TeloVac study, GV1001 with Gemcitabine/capecitabine (G/C) did not show increased overall survival (OS) than G/C in patients (pts) with advanced pancreatic ductal adenocarcinoma (PDA). But cytokine examination suggested high serum eotaxin level may predict improved survivals in pts received GV1001 with G/C. This phase III trial was designed to assess the efficacy of GV1001 with G/C for previous untreated eotaxin-high Korean pts with advanced PDA. Methods: Eligible pts with histologically proven locally advanced and metastatic PDA (except peritoneal carcinomatosis), age > 18 years, and ECOG PS 0–2 were recruited. Pts were randomly assigned (1:1) to receive either G/C or G/C with GV1001 (G/C/GV). All pts receiving G/C/GV were with high serum eotaxin level (≥81.02 ng/mL), and the pts receiving G/C were randomly assigned again (1:1) to eotaxin-high and eotaxin-low pts. Study was designed according to Korean MFDS guidance for approval of clinical trial. G/C treatment included G (1000 mg/m2, 30 min IVF, D 1, 8, & 15) and C (830 mg/m2 BID for 21 days per month (m). G/C/GV treatment included an intradermal injection of GM-CSF (75 μg) and GV1001 (0.56 mg; D 1, 3, & 5, once on week 2–4, & 6, then monthly thereafter) from the start of G/C. The primary endpoint was OS. The secondary endpoints included time to progression (TTP), objective response rate, and safety. Survival data was analyzed using the copula graphic estimate method under dependent censoring. The response was independently assessed per RECIST v1.1. Under the one-sided significance level of 2.5% and to achieve the power of 80% of the statistical significance with the median OS difference from 7.9 to 14.9 m (HR = 0.53), 85 events and 118 registrations needed. Considering 20% drop-outs, 148 registrations were required. Results: Between Nov 2015 and Apr 2020, of 511 pts screened in 16 centers, eotaxin-high pts were identified as 34.7% (174 / 502 pts). 148 pts randomly assigned to G/C/GV (n = 75; all eotaxine-high) and G/C (n = 73; 37 eotaxine-high, 36 eotaxine-low). Median OS was significantly improved in the G/C/GV group with 11.3m [95% CI 8.6-14.0] than G/C group with 7.5 m [95% CI 5.1-10.0] (p = 0.021). Also, median TTP was significantly improved in the G/C/GV group (7.3 m [95% CI 5.0-9.7]) than in the G/C group (4.5 m [95% CI 3.2-5.8], p = 0.021). In other secondary endpoints, no statistical significance was confirmed between the two groups. Grade 3-4 treatment-emergent adverse events were reported in 49 pts (73.13%) vs. 58 pts (77.33%) in the G/C and G/C/GV group, without significant differences (p = 0.562). Conclusions: G/C/GV treatments significantly extend OS and TTP in advanced PDA than G/C, and specific safety-related issues had not been found. GV1001 should be considered as one of the options in PDA pts with high serum eotaxin levels. Clinical trial information: NCT02854072.

Correlation between comprehensive genomic profiling (CGP) utilizing tissue-based testing (T-CGP) and cell-free DNA (cfDNA) in patients (pts) with pancreatic ductal adenocarcinoma (PDAC).

422 Background: Early systemic dissemination is a salient feature of PDAC and the ability to reliably detect as well as monitor cfDNA based alterations may have predictive and/or prognostic value. However, a clear correlation between the clonality of the primary tumor and micro-metastatic disease has not been established in PDAC. We examined the correlation between T-CGP and cfDNA based CGP in pts with PDAC. Methods: We performed a retrospective analysis of PDAC pts who had both T-CGP (October 2010 – March 2020) and cfDNA based CGP (May 2016 – March 2020), with an average of 645 days between tests (Range: 21 – 2101 days) For T-CGP, exonic regions and select intronic regions of cancer related genes were sequenced to a high uniform depth (>500X median coverage) using FoundationOne Heme (Exons: 315 genes; Select Introns: 28 genes) and FoundationOne CDx (Exons: 310 genes; Select Introns: 34 genes). cfDNA based CGP, was performed using either FoundationOne Liquid (Exons: 70 genes; Select Introns: 7 genes) or Foundation-ACT (Exons: 59 genes; Select Introns: 6 genes) platform. Results: Eighty-one pts were identified with both T-CGP and cfDNA based CGP - median age was 61 years, 59.3% (48/81) were male and 66.2% (49/74) had reported metastatic disease. The median tumor DNA content available for T-CGP analysis was 112.3 ng. The median cfDNA concentration was 1.7 ng/µL, and the number of reported ct-DNA based somatic alterations correlated significantly with the concentration of ct-DNA (Spearman’s R = 0.19, p < 10-8). 75/81 (92.6%) and 41/81 (50.6%) of pts had at least one pathogenic somatic alteration detected by T-CGP and cfDNA based CGP, respectively. KRAS, TP53 and CDKN2A were the most frequently altered genes in both T-CGP and cfDNA based CGP (Table1). Homologous Recombination DNA Damage Repair (HR-DDR) gene alterations [ BRCA2, ATM, and CHEK2 alterations] were detected in 7.4% (6/81) of T-CGP and 7.4% (6/81) cfDNA based CGP, respectively. Two BRAF fusions were detected from samples tested with T-CGP, however these were not detected with the cfDNA assay. Conversely, an ALK-EML4 fusion was detected using both platforms. Conclusions: The concordance between T-CGP and cfDNA based CGP in HR-DDR gene alterations may be indicative of the germline status of some of these alterations; nevertheless, it suggests the predictive utility of cfDNA based CGP in PDAC. The differential prevalence of other gene alterations between the two modalities is likely reflective of the cfDNA yield available for CGP and to a lesser extent, clonal evolution. cfDNA based CGP holds promise as a complimentary predictive tool to T-CGP. [Table: see text]