Locally Advanced Pancreatic Adenocarcinoma Research Articles

Programmed cell death 1 inhibitor sintilimab plus concurrent chemoradiotherapy for locally advanced pancreatic adenocarcinoma

BACKGROUND Pancreatic adenocarcinoma, a malignancy that arises in the cells of the pancreas, is a devastating disease with unclear etiology and often poor prognosis. Locally advanced pancreatic cancer, a stage where the tumor has grown significantly but has not yet spread to distant organs, presents unique challenges in treatment. This article aims to discuss the current strategies, challenges, and future directions in the management of locally advanced pancreatic adenocarcinoma (LAPC). AIM To investigate the feasibility and efficacy of programmed cell death 1 (PD-1) inhibitor sintilimab plus concurrent chemoradiotherapy for LAPC. METHODS Eligible patients had LAPC, an Eastern cooperative oncology group performance status of 0 or 1, adequate organ and marrow functions, and no prior anticancer therapy. In the observation group, participants received intravenous sintilimab 200 mg once every 3 wk, and received concurrent chemoradiotherapy (concurrent conventional fractionated radiotherapy with doses planning target volume 50.4 Gy and gross tumor volume 60 Gy in 28 fractions and oral S-1 40 mg/m2 twice daily on days 1-14 of a 21-d cycle and intravenous gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-d cycle for eight cycles until disease progression, death, or unacceptable toxicity). In the control group, participants only received concurrent chemoradiotherapy. From April 2020 to November 2021, 64 participants were finally enrolled with 34 in the observation group and 30 in the control group. RESULTS Thirty-four patients completed the scheduled course of chemoradiotherapy, while 32 (94.1%) received sintilimab plus concurrent chemoradiotherapy with 2 patients discontinuing sintilimab in the observation group. Thirty patients completed the scheduled course of chemoradiotherapy in the control group. Based on the Response Evaluation Criteria in Solid Tumors guidelines, the analysis of the observation group revealed that a partial response was observed in 11 patients (32.4%), stable disease was evident in 19 patients (55.9%), and 4 patients (11.8%) experienced progressive disease; a partial response was observed in 6 (20.0%) patients, stable disease in 18 (60%), and progressive disease in 6 (20%) in the control group. The major toxic effects were leukopenia and nausea. The incidence of severe adverse events (AEs) (grade 3 or 4) was 26.5% (9/34) in the observation group and 23.3% (7/30) in the control group. There were no treatment-related deaths. The observation group demonstrated a significantly longer median overall survival (22.1 mo compared to 15.8 mo) (P < 0.05) and progression-free survival (12.2 mo vs 10.1 mo) (P < 0.05) in comparison to the control group. The occurrence of severe AEs did not exhibit a statistically significant difference between the observation group and the control group (P > 0.05). CONCLUSION Sintilimab plus concurrent chemoradiotherapy was effective and safe for LAPC patients, and warrants further investigation.

A phase II study of cadonilimab plus mFOLFIRINOX as induction therapy for locally advanced pancreatic adenocarcinoma (LAPC).

TPS4213 Background: Locally advanced pancreatic adenocarcinoma (LAPC) constitutes a significant proportion of pancreatic cancer, which ranks among the most lethal malignancies globally. Treatment options specifically tailored for LAPC patients (pts) are scarce, and chemotherapy alone yields limited efficacy. Various studies have provided supportive evidence for the synergistic effects of combining immunotherapy with chemotherapy in the context of pancreatic cancer. Cadonilimab, a novel recombinant humanized bispecific antibody, holds the capability to concurrently inhibit PD-1 and CTLA-4 pathways, thereby restoring T-cell immune response to the tumor. This study aims to assess the efficacy and safety of combining cadonilimab with modified FOLFIRINOX for the treatment of LAPC. Methods: This ongoing phase II trial is enrolling pts with histologically or cytologically confirmed unresectable LAPC who have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1 and have not previously received systemic anti-tumor therapy. Eligible pts will be administered cadonilimab (6mg/kg, intravenous drip, Day 1, every 2 weeks) plus mFOLFIRINOX (oxaliplatin 85mg/m2, Day 2 + leucovorin 400mg/ m2, Day 2 + irinotecan 150mg/ m2, Day 2 + 5-fluorouracil 2,400mg/ m2, continuous infusion for 46 hours) for a total of 4 cycles (8 weeks). After the completion of every 4 treatment cycles, pts will undergo imaging examinations of tumor lesions. Pts will receive treatment continuously until surgical resection, disease progression, intolerable toxic reactions, initiation of new anticancer drug treatments, withdrawal from the study, death, or loss of follow-up. Following the 12th cycle of treatment, maintenance treatment will consist of capecitabine or S-1 in combination with cadonilimab. The primary endpoint of this study was the R0/R1 resection rate. The main secondary endpoints include the objective response rate (ORR) per RECIST 1.1, progression-free survival (PFS), overall survival (OS), and safety assessments. Additionally, pts will undergo peripheral blood next-generation sequencing (NGS) panel analysis before and after treatment to investigate the correlation between circulating tumor DNA (ctDNA) changes, surgical decisions, and prognosis. Enrollment is ongoing. Clinical trial information: NCT06153368 .

PANOVA-4 (EF-39): Pilot study of tumor treating fields (TTFields) therapy with atezolizumab, gemcitabine (GEM), and nab-paclitaxel (NabP) as first-line (1L) treatment for metastatic pancreatic ductal adenocarcinoma (mPDAC).

TPS718 Background: TTFields are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. TTFields therapy is noninvasive, locoregional, and is delivered via a portable electric field generator and skin-placed arrays. TTFields therapy has low risk of systemic toxicity and is approved for glioblastoma (and grade 4 glioma in Europe), and pleural mesothelioma. In vitro, TTFields (150 kHz) application decreased pancreatic cancer cell proliferation and clonogenicity; in vivo, TTFields concomitant with chemotherapy (chemo) had greater antitumor effect than chemo alone in orthotopic pancreatic tumors. Co-application of TTFields with immune checkpoint inhibitors (ICIs) significantly decreased tumor volume, increased tumor infiltration and IFN-γ production, and did not impede ICI-induced effector memory T-cell production versus in vivo controls. The pilot (phase 2) PANOVA clinical study (NCT01971281) showed safety and feasibility with TTFields therapy plus NabP and GEM in metastatic and locally advanced pancreatic adenocarcinoma (LAPC). The randomized, pivotal (phase 3) PANOVA-3 clinical study (NCT03377491), evaluating TTFields therapy with GEM and NabP in LAPC, is ongoing. Methods: PANOVA-4 (pilot, single-arm clinical study) assesses the safety and efficacy of TTFields therapy (NovoTTF-200T device) concomitant with atezolizumab, GEM, and NabP as 1L treatment for mPDAC. Eligible patients (pts) are ≥18 years of age and have a new mPDAC diagnosis, measurable abdominal disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1, and no prior systemic PDAC therapy. Atezolizumab (1680 mg, IV infusion) is given before chemo on day 1 of each 28-d cycle, with NabP (125 mg/m2 IV) and GEM (1000 mg/m2 IV) given on days 1, 8, and 15. TTFields therapy (150 kHz) is delivered for ≥18 h/d until disease progression per RECIST v1.1 or loss of clinical benefit. Clinical follow-up occurs every 4 weeks (q4w) with CT scans q8w. Survival is assessed every 3 mo post last on-site visit. The primary endpoint is disease control rate (DCR). Secondary endpoints include overall survival (OS), progression-free survival (PFS), 1-year OS rate, objective response rate, PFS at 6 mo, duration of response, and safety. 76 pts are required to achieve 80% power (1-sided α level 0.05) to detect a 63% DCR vs historical 48% DCR in pts with mPDAC receiving 1L GEM and NabP. Clinical trial information: EUCTR2022-003157-55 .

Phase 3 PANOVA-3 study: Tumor treating fields (TTFields) therapy concomitant with gemcitabine and nab-paclitaxel (GnP) for front-line treatment of locally advanced pancreatic cancer.

TPS4199 Background: Tumor Treating Fields (TTFields) therapy is a locoregional antimitotic treatment approved for newly diagnosed and recurrent glioblastoma GBM and pleural mesothelioma. TTFields (150 kHz) therapy, with/without chemotherapy, had antiproliferative and anticlonogenic activity in pancreatic cancer cell lines, and reduced tumor volume and weight more than chemotherapy alone in in vivo models. TTFields therapy with gemcitabine and nab-paclitaxel (GnP) was well-tolerated, with promising efficacy in metastatic and locally advanced pancreatic adenocarcinoma (LAPC) in the phase 2 PANOVA study (NCT01971281). LAPC prognosis remains poor despite available therapies, which can negatively impact quality of life (QoL). As such, there remains a need for effective and tolerable treatments. Methods: PANOVA-3 (EF-27, NCT03377491) is a prospective, randomized, phase 3 study investigating the efficacy and safety of TTFields therapy with GnP in patients with LAPC, with a planned enrollment of 556 patients. Key inclusion criteria are: a diagnosis of unresectable LAPC (per NCCN guidelines), ECOG PS of 0–2, and no prior treatment. Patients will be stratified by performance status and geographical region and assigned 1:1 to treatment groups to receive TTFields therapy + GnP or GnP alone. GnP will be administered at a standard dose per standard of care. TTFields therapy (150 kHz, 18h/day) will be delivered by the NovoTTF-200T System until local disease progression per RECIST v1.1. Usage will be tracked by the device. Follow-up will be performed every 4 weeks and computed tomography scans of the chest and abdomen will be taken every 8 weeks until disease progression. Patients will be followed every month until death. The primary endpoint is overall survival and key secondary endpoints include QoL, pain-free survival, and puncture-free survival, which will be compared between treatment groups. Other secondary endpoints include progression-free survival (PFS), local PFS, objective response rate, 1-year survival rate, rate of resectability, and safety. Guidance around usage, lifestyle integration and prevention and management of skin adverse events will be provided by Device Support Specialists and field personnel. Usage information will be provided to patients and physicians to facilitate discussions to optimize outcomes by maximizing time on therapy. Together, these novel support approaches aim to optimize patient usage and outcomes. The trial is currently recruiting at 149 sites, globally. The DMC last reviewed the trial in August 2022, and suggested that the trial continue as planned. Clinical trial information: NCT03377491 .

Predictive value of computed tomography on surgical resectability in locally advanced pancreatic cancer treated with multiagent induction chemotherapy: Results from a prospective, multicentre phase 2 trial (NEOLAP-AIO-PAK-0113)

PurposeTo assess the role of current imaging-based resectability criteria and the degree of radiological downsizing in locally advanced pancreatic adenocarcinoma (LAPC) after multiagent induction chemotherapy (ICT) in multicentre, open-label, randomized phase 2 trial. MethodLAPC patients were prospectively treated with multiagent ICT followed by surgical exploration within the NEOLAP trial. All patients underwent CT scan at baseline and after ICT to assess resectability status according to national comprehensive cancer network guidelines (NCCN) criteria and response evaluation criteria in solid tumors (RECIST) at the local study center and retrospectively in a central review. Imaging results were compared in terms of local and central staging, downsizing and pathological resection status. Results83 patients were evaluable for central review of baseline and restaging imaging results. Downstaging by central review was rarely seen after multiagent ICT (7.7%), whereas tumor downsizing was documented frequently (any downsizing 90.4%, downsizing to partial response (PR) according to RECIST: 26.5%). Patients with any downsizing showed no significant different R0 resection rate (37.3%) as patients that fulfilled the criteria of PR (40.9%). The sensitivity of any downsizing for predicting R0 resection was 97% with a negative predictive value (NPV) of 0.88. ROC-analysis revealed that tumor downsizing was a predictor of R0 resection (AUC 0.647, p = 0.028) with a best cut-off value of 22.5% downsizing yielding a sensitivity of 65% and a specificity of 61%. ConclusionsImaging-based tumor downsizing and not downstaging can guide the selection of patients with a realistic chance of R0-resection in LAPC after multi-agent ICT.

Nivolumab and a CCR2/CCR5 dual antagonist (BMS-813160) with or without GVAX for locally advanced pancreatic ductal adenocarcinomas: Results of phase I study.

730 Background: Surgical resection is the only potentially curative treatment for pancreatic adenocarcinoma (PDAC) but involvement of adjacent vital structures in locally advanced pancreatic adenocarcinoma (LAPC) precludes upfront resection. Neoadjuvant chemotherapy and/or radiation allows some LAPC patients to undergo resection but outcomes remain dismal. In this trial, we investigate the benefit of combining chemotherapy, radiation, and immunotherapy to improve outcomes in LAPC by enhancing antitumor immunity. The use of GVAX, Nivolumab, and BMS-813160 is hypothesized to promote immune responses through enhanced effector T cell infiltration and activation by GVAX and nivolumab while inhibiting immunosuppressive tumor associated macrophages via CCR2/5 inhibition with BMS-813160. Testing this combination in LAPC will facilitate assessment of the changes this combination produces in the tumor microenvironment. Methods: This open-label, single center two-arm phase I/II trial uses neoadjuvant/adjuvant nivolumab and BMS-813160 +/- GVAX following 8 to 16 doses of FOLFIRINOX and SBRT in patients with newly diagnosed LAPC. The primary endpoint of the phase I portion is safety of nivolumab, BMS-813160, and GVAX in patients with LAPC following chemotherapy and SBRT. The phase II portion randomizes patients 1:1 to nivolumab and BMS-813160 +/- GVAX with primary endpoint of immune response defined as > 80% increase in CD8+CD137+ cell infiltration. For the phase I portion a 3+3 dose escalation was used: nivolumab 480mg IV and GVAX 5x108 cells intradermal were administered at a fixed dose every 4 weeks. BMS-813160 was administered at a dose of 150mg and 300mg PO BID in levels 1 and 2 respectively. DLTs were evaluated during the 1st cycle of treatment and study-related adverse events (AE) were graded according to NCI CTCAE v5.0. Results: In the phase I portion of this trial, 13 patients were enrolled. The patient characteristics of the enrolled patients were: median age (range), 67 (44, 78), Female/Male, (4/9), Race, (Asian: 2, Black: 3, White: 8), histological grade (moderately/poor/moderately poor), (10/2/1). Nine of the 13 patients proceeded to immunotherapy after neoadjuvant chemotherapy and radiation. Three patients received treatment at dose level 1 and 6 patients at dose level 2. No DLTs were observed with the only grade 3 or higher AE being maculo-papular rash (n = 1). The RP2D for BMS-813160 was determined to be 300mg PO BID. Conclusions: We determined that nivolumab 480mg IV q4 weeks, GVAX 5x108 cells intradermal q4 weeks, and BMS-813160 300mg PO BID were the RP2D for the phase 2 portion of this investigation which is ongoing. This combination appears safe and neoadjuvant use does not lead to delay in surgery. Clinical trial information: NCT03767582 .

Tumor treating fields (TTFields) concomitant with gemcitabine and nab-paclitaxel (GnP) for front-line treatment of locally advanced pancreatic cancer: The phase 3 PANOVA-3 study.

TPS770 Background: Tumor Treating Fields (TTFields) therapy is a loco-regional antimitotic treatment approved for glioblastoma and malignant mesothelioma. TTFields (150 kHz), with/without chemotherapy, induced antiproliferative and anticlonogenic activity in pancreatic cancer cell lines in vitro. The phase (ph) 2 PANOVA study (NCT01971281) demonstrated that TTFields therapy with gemcitabine and nab-paclitaxel (GnP; TTFields/GnP) is well-tolerated, with promising efficacy in metastatic and locally advanced pancreatic adenocarcinoma (LAPC). Despite advances in the treatment of LAPC, prognosis is poor and available therapies negatively impact quality of life (QoL); there is an unmet need for effective and tolerable treatments. Methods: PANOVA-3 (NCT03377491) is a prospective, randomized, ph 3 trial investigating the efficacy and safety of TTFields/GnP in patients (pts) with LAPC, with a planned enrollment of 556 pts. Pts with unresectable LAPC (per NCCN guidelines), ECOG PS of 0–2, and no prior treatment are eligible. Pts will be stratified by performance status and geographical region, and assigned 1:1 to TTFields/GnP or GnP alone. Standard doses of GnP will be administered on days 1, 8, and 15 of a 28-day cycle. TTFields (150 kHz) generated by the NovoTTF-200T System, will be delivered ≥ 18 h/day until local disease progression per RECIST v1.1. Pt usage is tracked by the device. Follow-up will be performed Q4W; CT scans of the chest and abdomen will be taken Q8W. After local disease progression, pts will be followed every month until death. The primary endpoint is overall survival. QoL, pain-free survival, and puncture-free survival will be compared between TTFields/GnP and GnP alone. Other secondary endpoints include progression-free survival (PFS), local PFS, objective response rate, 1-year survival rate, rate of resectability, and safety. Device Support Specialists (DSS) will provide technical and lifestyle integration training for pts and caregivers throughout TTFields therapy. The device manufacturer will also provide guidance on preventing and managing skin adverse events in line with published guidance, by means of DSS, field personnel, and various information resources. Usage information from the NovoTTF-200T System is provided to pts and physicians to facilitate discussions to optimize outcomes by maximizing time on therapy. Together, these novel support approaches help pts to confidently operate the NovoTTF-200T System with the knowledge that a multi-faceted support structure is available, ensuring TTFields therapy is seamlessly integrated into everyday life, increasing likelihood of high usage and ultimately optimizing pt outcomes. The trial is currently recruiting at 148 sites, globally. The DMC last reviewed the trial in September 2022, and suggested that the trial continue as planned. Clinical trial information: NCT01971281 .

Dose-escalated pancreas radiotherapy for unresected pancreatic adenocarcinoma: Patterns of care and survival in the United States.

676 Background: Randomized trials have not shown an overall survival (OS) benefit to adding radiotherapy (RT) to chemotherapy for patients with locally advanced pancreatic adenocarcinoma (LAPC). However, trials such as LAP07 did not incorporate escalated-dose RT (EDR), which may confer longer survival. The adoption of EDR across the United States and associated outcomes are unknown. Methods: We queried the National Cancer Data Base for non-surgically managed patients with LAPC diagnosed between 2004 and 2019. RT with biologically effective doses (BED10) > 70 and ≤ 200 Gy were labeled EDR and conventional-dose RT (CDR) for 39-70 Gy doses. Associations with receipt of EDR and with OS were identified using multivariate analysis (MVA) logistic and Cox regressions, respectively. Bonferroni corrections were applied. Cochran-Armitage and Mann-Kendall trend tests were performed to assess trends in use of RT. Results: Of 64,303 patients, the most common treatments were chemotherapy alone (CT) (71%), chemoradiation (CRT) (27%), and pancreas RT alone (2%). 18,970 patients received pancreas RT, of which 91% was CDR (median dose 50.4 Gy; median 28 fractions) and 9% was EDR (50 Gy; 5 fractions). Use of pancreas RT increased from 14% in 2004 to a peak of 18% in 2010, decreased to a nadir of 13% in 2016, and subsequently increased to 15% by 2019 ( Ptrend < 0.001). EDR use increased from 7% in 2004 to 22% in 2019 ( Ptrend < 0.0001). Median BED10 increased from 53 to 59 Gy ( Ptrend< 0.001). Of patients receiving pancreas RT, use of intensity-modulated RT (IMRT) and stereotactic body RT (SBRT) respectively increased from 25% and 2% in 2004 to 60% and 27% in 2019, while use of 3-D conformal RT (3D-CRT) decreased from 64% to 9% ( Ptrend < 0.02 for all comparisons). On MVA logistic regression, primary tumor location in the body/tail vs. head (aOR 1.22, 95% CI 1.07-1.40; P = 0.003) associated with greater EDR receipt, whereas T3-4 vs. T2 disease (aOR 0.81, CI 0.71-0.92; P = 0.002) associated with lesser receipt. At a median follow up of 59.1 months (CI 57.5-61.0), median OS estimates for CDR and EDR were 10.2 months (CI 10.1-10.3) and 13.3 months (CI 13.2-13.5; P < 0.0001), respectively. On MVA Cox regression, N1 vs. N0 disease (HR 1.08, CI 1.06-1.10; P < 0.001) correlated with higher risk of death, whereas CRT vs. CT (HR 0.83, CI 0.81-0.85; P < 0.001) correlated with lower risk of death. Subset MVA of 14,634 CRT patients correlated higher RT dose—as both a categorical variable (EDR vs. CDR; HR 0.84, CI 0.79-0.90; P < 0.001) and continuous variable (BED10; HR 0.994, CI 0.992-0.995; P < 0.001)—with lower risk of death. Conclusions: Fewer than 1 in 6 patients with unresected LAPC received pancreas RT, despite a nominal increase in utilization in recent years. Although retrospective, these NCDB data suggest longer OS with the addition of RT for unresected LAPC, suggesting continued unmet need. EDR is associated with longer survival vs. CDR.

Abstract A021: Tumor Treating Fields (TTFields) therapy concomitant with gemcitabine and nab-paclitaxel (GnP) for front-line treatment of locally advanced pancreatic cancer: the phase 3 PANOVA-3 study

Abstract Background: Tumor Treating Fields (TTFields) therapy is a loco-regional antimitotic treatment approved for glioblastoma and malignant pleural mesothelioma. TTFields (150 kHz), with/without chemotherapy, induced antiproliferative and anticlonogenic activity in pancreatic cancer cell lines in vitro. The phase (ph) 2 PANOVA study (NCT01971281) demonstrated that TTFields therapy with gemcitabine and nab-paclitaxel (GnP) is well-tolerated, with promising efficacy in metastatic and locally advanced pancreatic adenocarcinoma (LAPC). Despite advances in the treatment of LAPC, prognosis is poor and available therapies negatively impact quality of life (QoL). As such, there is an unmet need for effective and tolerable treatments. Trial design: PANOVA-3 (NCT03377491) is a prospective, randomized, ph 3 trial investigating the efficacy and safety of TTFields therapy with GnP in patients (pts) with LAPC, with a planned enrollment of 556 pts. Pts with unresectable LAPC (per NCCN guidelines), ECOG PS of 0–2, and no prior treatment are eligible. Pts will be stratified by performance status and geographical region, and assigned 1:1 to TTFields therapy + GnP or GnP alone. Standard doses of GnP will be administered on days 1, 8, and 15 of a 28-day cycle. TTFields (150 kHz) generated by the NovoTTF-200T System, will be delivered ≥ 18 h/day until local disease progression per RECIST v1.1. Pt usage is tracked by the device. Follow-up will be performed every 4 wks; CT scans of the chest and abdomen will be taken every 8 wks. After local disease progression, pts will be followed every month until death. The primary endpoint is overall survival. QoL, pain-free survival, and puncture-free survival will be compared between TTFields therapy + GnP and GnP alone. Other secondary endpoints include progression-free survival (PFS), local PFS, objective response rate, 1-year survival rate, rate of resectability, and safety. Device Support Specialists (DSS) will provide technical and lifestyle integration training for pts and caregivers throughout TTFields therapy. The device manufacturer will also provide guidance on preventing and managing skin adverse events in line with published guidance, by means of DSS, field personnel, and various information resources. Furthermore, usage information from the NovoTTF-200T System is provided to both pts and physicians to facilitate discussions to optimize outcomes by maximizing time on therapy. Together, these novel support approaches help pts to confidently operate the NovoTTF-200T System with the knowledge that a multi-faceted support structure is available, ensuring TTFields therapy is seamlessly integrated into everyday life, increasing likelihood of high usage and ultimately optimizing pt outcomes. The trial is currently recruiting at 120 sites, globally. The DMC last reviewed the trial in August 2021, and suggested that the trial continue as planned. Citation Format: Vincent J. Picozzi, Teresa Macarulla, Philip Agop Philip, Carlos Roberto Becerra, Tomislav Dragovich. Tumor Treating Fields (TTFields) therapy concomitant with gemcitabine and nab-paclitaxel (GnP) for front-line treatment of locally advanced pancreatic cancer: the phase 3 PANOVA-3 study [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A021.

Circulating tumor DNA: a help to guide therapeutic strategy in patients with borderline and locally advanced pancreatic adenocarcinoma?

prognostic biomarkers could be useful to better select patients with borderline resectable (BR) or locally advanced (LA) pancreatic adenocarcinoma (PA) for chemoradiotherapy (CRT) and/or secondary resection. The main objective of this work was to study characteristics, received treatments and prognostic of patients with BR or LA PA according to their baseline circulating tumor DNA status and, for secondary objective, neutrophil-to-lymphocyte Ratio (NLR). ctDNA status at baseline was determined using Next Generation Sequencing in a consecutive monocentric cohort of patients with a BR or LA PA. 69 patients were included, 31 with BR PA and 38 with LA PA. 14 (20.3%) patients had baseline positive ctDNA. Five (7.8%) patients had NLR> 5. Patients with positive ctDNA had 3.7 months shorter progression free survival (p=0.006). Patients with positive ctDNA had earlier progression after the beginning of CRT (4.4vs 7.1 months; p=0.068) and shorter relapse free survival after secondary resection (9.2vs 22.9 months; p=0.016). positive ctDNA at baseline was associated with a worse prognosis in patients with BR or LA PA. These data are exploratory and must be confirmed in further prospective trials.

Low Pre-ChemoradiotherapyPan-Immune-Inflammation Value (PIV) Measures Predict Better Survival Outcomes in Locally Advanced Pancreatic Adenocarcinomas.

ObjectiveThis study sought to determine whether pretreatment pan-immune-inflammation value (PIV) could be used to predict prognosis in patients with locally advanced pancreatic adenocarcinoma (LA-PAC) following definitive concurrent chemoradiotherapy (C-CRT).MethodsThe outcomes of 178 LA-PAC patients who received definitive C-CRT were analyzed retrospectively. For all patients, the PIV was calculated using the peripheral blood platelet (P), monocyte (M), neutrophil (N), and lymphocyte (L) counts obtained on the first day of C-CRT: PIV=P×M×N÷L. The optimum cutoff values for PIV connected to progression-free (PFS) and overall survival (OS) results were sought using receiver operating characteristic (ROC) curve analysis. The OS and PFS differences between the PIV groups constituted the primary and secondary endpoints, respectively.ResultsROC curve analysis indicated that the ideal PIV cutoff was 464 (AUC: 75.9%, sensitivity: 74.1%, specificity: 71.9%), which categorized patients into two groups based on PFS and OS results: low PIV (L-PIV; N = 69) and high PIV (H-PIV; N = 109). According to comparative survival analyses, patients in the L-PIV group had significantly longer median PFS (14.3 vs 7.3 months; HR: 3.04; P<0.001) and OS (25.9 vs 13.3 months; HR: 2.86; P<0.001) than those in the H-PIV group. Although none of the H-PIV patients could survive beyond 5 years, the estimated 5-year OS rate was 29.7% in the L-PIV cohort. In multivariate analyses, besides the L-PIV, N0 nodal stage, and CA 19–9 ≤ 90 U/mL appeared to be the independent predictors of better PFS (P < 0.05 for each) and OS (P < 0.05 for each) results.ConclusionThe present results indicated that pre-C-CRT L-PIV measures were associated with favorable median and long-term PFS and OS results in LA-PAC patients, suggesting that the PIV is a potent and independent novel prognostic biomarker.

1308P Comparison of tumour size on outcomes for patients with unresectable locally advanced pancreatic adenocarcinoma (LAPC) receiving P-32 microparticles with standard-of-care chemotherapy (SoC CT)

Unresectable LAPC (uLAPC) has a poor prognosis. SoC is CT or chemoradiotherapy. Brachytherapy enables beta radiation emitting Phosphorus-32 (P-32) microparticles to be implanted into pancreatic tumours via endoscopic ultrasound (EUS) guidance. We report a post hoc analysis of tumour size in PanCO, a single-arm, multicentre study of P-32 microparticles with SoC CT in uLAPC.

Abstract CT234: PANOVA-3: A phase 3 study of tumor treating fields with gemcitabine and nab-paclitaxel for front-line treatment of locally advanced pancreatic adenocarcinoma

Abstract Background: Tumor Treating Fields (TTFields) are a novel, locoregional antimitotic treatment modality approved for glioblastoma and malignant pleural mesothelioma. Continuous, non-invasive low intensity, intermediate frequency (150-200 kHz) alternating electric fields are delivered to the tumor via skin-placed arrays. In vitro, TTFields (150 kHz), with or without chemotherapy, induced antiproliferative and anticlonogenic activity on pancreatic cancer cell lines. The phase 2 PANOVA study (NCT01971281) demonstrated that the combination of TTFields with nab-paclitaxel and gemcitabine (GnP) is well-tolerated, with promising efficacy in both metastatic and locally advanced pancreatic adenocarcinoma (LAPC). These data indicate that TTFields with GnP warrant phase 3 evaluation. Methods: PANOVA-3 (NCT03377491) is a prospective, randomized, phase 3 trial designed to investigate the efficacy and safety of TTFields concomitant with GnP in patients with LAPC. The planned enrollment is 556 patients. Eligibility criteria include unresectable LAPC (per National Comprehensive Cancer Network guidelines), Eastern Cooperative Oncology Group performance status of 0-2, and no prior progression or treatment. Patients will be stratified by performance status and geographical region, and randomly assigned 1:1 to TTFields plus GnP or GnP alone. Based on a recent protocol amendment, a smaller and lighter-weight (reduced from 6 to 2.7 lbs) TTFields device will be used. Standard doses of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) will be administered on days 1, 8, and 15 of a 28-day cycle. TTFields (150 kHz) will be delivered ≥ 18 h/day until local disease progression per Response Evaluation Criteria in Solid Tumors V1.1. Follow-up will be performed every 4 weeks and a computed tomography scan of the chest and abdomen every 8 weeks. After local disease progression, patients will be followed every month until death. The primary endpoint is overall survival (OS). Secondary endpoints include progression-free survival (PFS), local PFS, objective response rate, 1-year survival rate, pain- and puncture-free survival rate, rate of resectability, quality of life, and toxicity. The sample size was estimated per log-rank test comparing time to event in patients treated with TTFields plus GnP with published clinical trial data on patients treated with GnP alone. PANOVA-3 is designed to detect a hazard ratio of 0.75 in OS. Type I error is set to 0.05 (2-sided) and power to 80%. The trial is currently recruiting at 104 sites in Austria, Belgium, Canada, China, Croatia, Czech Republic, France, Germany, Hong Kong, Hungary, Israel, Italy, Poland, Spain, Switzerland, and USA. Citation Format: Vincent J. Picozzi, Judith Finlay, Teresa Macarulla, Philip A. Philip, Carlos R. Becerra, Tomislav Dragovich. PANOVA-3: A phase 3 study of tumor treating fields with gemcitabine and nab-paclitaxel for front-line treatment of locally advanced pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT234.

PANOVA-3: A phase 3 study of tumor-treating fields with gemcitabine and nab-paclitaxel for frontline treatment of locally advanced pancreatic adenocarcinoma.

TPS4187 Background: Tumor Treating Fields (TTFields) are a novel, locoregional antimitotic treatment modality approved for glioblastoma and malignant pleural mesothelioma. Continuous, non-invasive low intensity, intermediate frequency (150–200 kHz) alternating electric fields are delivered to the tumor via skin-placed arrays. In vitro, TTFields (150 kHz), with or without chemotherapy, induced antiproliferative and anticlonogenic activity on pancreatic cancer cell lines (Giladi M, et al. Pancreatology 2014;14:54–63). The phase 2 PANOVA study (NCT01971281) demonstrated that the combination of TTFields with nab-paclitaxel and gemcitabine (GnP) is well-tolerated, with promising efficacy in metastatic and locally advanced pancreatic adenocarcinoma (LAPC) (Rivera F, et al. Pancreatology 2019;19:64–72). These data indicate that TTFields with GnP warrant phase 3 evaluation. Methods: PANOVA-3 (NCT03377491) is a prospective, randomized, phase 3 trial designed to investigate the efficacy and safety of TTFields concomitant with GnP in patients with LAPC. Planned enrollment is 556 patients. Eligibility criteria include unresectable LAPC (per National Comprehensive Cancer Network guidelines), Eastern Cooperative Oncology Group performance status of 0–2, and no prior treatment. Patients will be stratified by performance status and geographical region, and randomly assigned 1:1 to TTFields plus GnP or GnP alone. Based on a recent protocol amendment, a smaller and lighter-weight (reduced from 6 to 2.7 lbs) TTFields device will be used. Standard doses of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) will be administered on days 1, 8, and 15 of a 28-day cycle. TTFields (150 kHz) will be delivered ≥ 18 h/day until local disease progression per Response Evaluation Criteria in Solid Tumors V1.1. Follow-up will be performed every 4 weeks and a computed tomography scan of the chest and abdomen every 8 weeks. After local disease progression, patients will be followed every month until death. The primary endpoint is overall survival (OS). Secondary endpoints include progression-free survival (PFS), local PFS, objective response rate, 1-year survival rate, pain- and puncture-free survival rate, rate of resectability, quality of life, and toxicity. The sample size was estimated per log-rank test comparing time to event in patients treated with TTFields plus GnP with published clinical trial data on patients treated with GnP alone. PANOVA-3 is designed to detect a hazard ratio of 0.75 in OS. Type I error is set to 0.05 (2-sided) and power to 80%. The trial is currently recruiting at 106 sites in Austria, Belgium, Canada, China, Croatia, Czech Republic, France, Germany, Hong Kong, Hungary, Israel, Italy, Poland, Spain, Switzerland, and USA. The DMC last reviewed the trial in August 2021, and suggested that the trial continue as planned. Clinical trial information: NCT03377491.

P-120 Front-line treatment of locally advanced pancreatic adenocarcinoma with tumour treating fields concomitant with gemcitabine and nab-paclitaxel: The phase 3 PANOVA-3 study

Tumour Treating Fields (TTFields) are a novel, locoregional antimitotic treatment modality approved for glioblastoma and malignant pleural mesothelioma. Continuous, non-invasive low intensity, intermediate frequency (150–200 kHz) alternating electric fields are delivered to the tumour via arrays placed on the skin. TTFields (150 kHz), with or without chemotherapy, induced antiproliferative and anticlonogenic activity on pancreatic cancer cell lines in vitro. The phase 2 PANOVA study (NCT01971281) demonstrated that the combination of TTFields with nab-paclitaxel and gemcitabine (GnP) is well-tolerated, with promising efficacy in both metastatic and locally advanced pancreatic adenocarcinoma (LAPC). These data indicated that TTFields with GnP warrant phase 3 evaluation. PANOVA-3 (NCT03377491) is a prospective, randomised, phase 3 trial designed to investigate the efficacy and safety of TTFields concomitant with GnP in patients with LAPC. The planned enrolment is 556 patients. Eligibility criteria include unresectable LAPC (per National Comprehensive Cancer Network guidelines), Eastern Cooperative Oncology Group performance status of 0–2, and no prior progression or treatment. Patients will be stratified by performance status and geographical region, and randomly assigned 1:1 to TTFields plus GnP or GnP alone. Based on a recent protocol amendment, a smaller and lighter-weight (reduced from 6 to 2.7 lbs) TTFields device will be used. Standard doses of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) will be administered on days 1, 8, and 15 of a 28-day cycle. TTFields (150 kHz) will be delivered ≥ 18 h/day until local disease progression per Response Evaluation Criteria in Solid Tumours v1.1. Follow-up will be performed every 4 weeks and a computed tomography scan of the chest and abdomen every 8 weeks. After local disease progression, patients will be followed every month until death. The primary endpoint is overall survival (OS). Secondary endpoints include progression-free survival (PFS), local PFS, objective response rate, 1-year survival rate, pain- and puncture-free survival rate, rate of resectability, quality of life, and toxicity. The sample size was estimated per log-rank test comparing time to event in patients treated with TTFields plus GnP with published clinical trial data on patients treated with GnP alone. PANOVA-3 is designed to detect a hazard ratio of 0.75 in OS. Type I error is set to 0.05 (2-sided) and power to 80%. The trial is currently recruiting at 110 sites in Australia, Austria, Belgium, Canada, China, Croatia, Czech Republic, France, Germany, Hong Kong, Hungary, Israel, Italy, Poland, Spain, Switzerland, and USA. The DMC last reviewed the trial in August 2021 and suggested that the trial continue as planned. NCT03377491. Novocure Ltd.

PANOVA-3: A phase 3 study of tumor treating fields (TTFields) with gemcitabine and nab-paclitaxel (GnP) for front-line treatment of locally advanced pancreatic adenocarcinoma.

TPS629 Background: Tumor Treating Fields (TTFields) are a non-invasive, loco-regional antimitotic therapy approved for the treatment of glioblastoma and malignant pleural mesothelioma. TTFields (150–200 kHz) are delivered via arrays placed on the skin surrounding the tumor site. In vitro, TTFields (150 kHz), with or without chemotherapy, had antiproliferative and anticlonogenic effects on pancreatic cancer cells. The Phase 2 PANOVA study (NCT01971281) demonstrated the safety and preliminary efficacy of TTFields combined with nab-paclitaxel and gemcitabine (GnP) in both metastatic and locally advanced pancreatic adenocarcinoma (LAPC). Methods: The Phase 3 PANOVA-3 trial (NCT03377491) will evaluate the efficacy and safety of adding TTFields to GnP in a larger group of patients with LAPC. This prospective, randomized trial is currently enrolling 556 patients with unresectable LAPC (per National Comprehensive Cancer Network guidelines), Eastern Cooperative Oncology Group performance status of 0-2, and no prior progression or treatment. Patients will be randomized 1:1 to receive TTFields plus GnP or to GnP alone, stratified by performance status and geographical region. A recent protocol amendment included the use of a smaller, more light-weight (reduced from 6 to 2.7 lbs.) TTFields device. Standard doses of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) will be administered on days 1, 8, and 15 of a 28-day cycle. TTFields (150 kHz) will be delivered ≥ 18 h/day until local disease progression per Response Evaluation Criteria In Solid Tumors Criteria V1.1. Follow-up visits will be conducted every 4 weeks; a computed tomography scan of the chest and abdomen will be performed every 8 weeks. After local disease progression, patients will be followed for survival on a monthly basis. The primary endpoint is overall survival (OS). Secondary endpoints include progression free survival (PFS), local PFS, objective response rate, 1 year survival rate, pain- and puncture-free survival rate, rate of resectability, quality of life, and toxicity. The sample size calculation used a log-rank test comparing time to event in patients treated with TTFields plus GnP with control patients on gemcitabine alone. PANOVA-3 is designed to detect a hazard ratio of 0.75 in OS. Type I error is set to 0.05 (2-sided) and power to 80%. Study locations in Austria, Belgium, Canada, Croatia, Czech Republic, France, Germany, Hong Kong, Hungary, Israel, Italy, Poland, Spain, Switzerland, and the US are currently recruiting. Clinical trial information: NCT03377491.

Postchemoradiotherapy Neutrophil-to-Lymphocyte Ratio Predicts Distant Metastasis and Survival Results in Locally Advanced Pancreatic Cancers.

Materials and Methods Our retrospective research included a sum of 126 LAPAC patients who received CCRT. The NLR was calculated for each patient based on the complete blood count test results obtained on the last day of the CCRT. The availability of optimal cutoff(s) that might dichotomize the whole cohort into two groups with significantly different clinical outcomes was searched using receiver operating characteristic (ROC) curve analysis. Primary and secondary endpoints were the potential association between the post-CCRT NLR measures and distant metastasis-free survival (DMFS) and overall survival (OS) outcomes. Results The median follow-up duration was 14.7 months (range: 2.4–94.5). The median and 3-year OS and DMFS rates for the whole group were 15.3 months (95% confidence interval: 12.4–18.2) and 14.5%, and 8.7 months (95% CI: 6.7–10.7) and 6.3% separately. The ROC curve analysis findings separated the patients into two groups on a rounded NLR cutoff of 3.1 (area under the curve (AUC): 75.4%; sensitivity: 74.2%; specificity: 73.9%) for OS and DMFS: NLR <3.1 (N = 62) and NLR ≥3.1 (N = 64), respectively. Comparisons between the NLR groups displayed that the median OS (11.4 vs. 21.4 months; P < 0.001) and DMFS (6.0 vs. 16.0 months; P < 0.001) lengths were significantly shorter in the NLR ≥3.1 group than its NLR <3.1 counterparts, as well as the 3-year actuarial DM rate (79.7% vs. 50.0%; P=0.003). The N1-2 nodal stage, CA 19–9>90 U/mL, and NLR >3.1 were found to be independent predictors of poor prognosis in the multivariate analysis. Conclusion The present study found that the posttreatment NLR ≥3.1 was independently linked with a higher risk of DM and subsequent degraded survival outcomes in unresectable LAPAC patients managed with exclusive CCRT.

PANOVA-3: A Phase 3 Study of Tumor Treating Fields with Gemcitabine and Nab-Paclitaxel (GnP) for Front-Line Treatment of Locally Advanced Pancreatic Adenocarcinoma

TTFields are an antimitotic therapy delivering low-intensity, intermediate-frequency, alternating electric fields non-invasively to the tumor region via arrays placed on the skin. The phase 2 PANOVA study demonstrated the safety and preliminary efficacy of TTFields when combined with GnP in metastatic and locally advanced pancreatic adenocarcinoma (LAPC). The phase 3 PANOVA-3 trial (NCT03377491) will evaluate the efficacy and safety of adding TTFields to GnP in LAPC. This prospective, randomized trial is enrolling untreated patients (N = 556) with unresectable LAPC and an eastern cooperative oncology group performance status (ECOG PS) score of 0–2.

Multivisceral Resection for Pancreatic Ductal Adenocarcinoma of the Body and Tail: Is it Worth? A Multicentre Retrospective Analysis from Western European Countries

Background: Ductal left-sided pancreatic adenocarcinoma is often associated with poor prognosis due to the delayed diagnosis, with a lower resectability rate compared to pancreatic head tumours. Multivisceral resections (MVR) associated with distal pancreatectomy could be proposed for patients presenting with locally advanced disease. Methods: We retrospectively analyzed a multicentric cohort of patients operated for ductal left-sided locally-advanced pancreatic adenocarcinoma over 11 years (from 2009 to 2020). Thirteen European high-volume HPB Units participated to this study. We analyzed patients who underwent distal pancreatectomy (DP) associated with MVR and compared them to standard DP. Results: Among 258 patients treated curatively for locally advanced pancreatic adenocarcinoma of the body and tail, 28 patients successfully underwent MVR. A longer operative time was observed in MVR group (295 min +/- 74 vs. 250min +/- 96, p= 0,248). Post-operative complication rate was comparable between the two groups (46,4 % in MVR group vs. 62,2% in control group, p= 0,108). The incidence of positive margin (R1) was similar between the two groups (8/28, 28,6% vs. 61/230, 26,6%; p=0,827). After a median of follow-up of 25 (9-111) months, overall survival was comparable between the two groups (14/28, 50% vs. 116/230, 50%; p= 0,519). Conclusions: Multivisceral resection in locally-advanced left-sided pancreatic adenocarcinoma is safe and feasible and should be considered in selected cases as it seems provide acceptable surgical and oncological outcomes.

Abstract PO-051: PANOVA-3: A phase III study of tumor treating fields with nab-paclitaxel and gemcitabine for front-line treatment of locally advanced pancreatic adenocarcinoma

Abstract Tumor Treating Fields (TTFields) are a non-invasive, loco-regional antimitotic treatment modality, approved for the treatment of glioblastoma and malignant pleural mesothelioma. TTFields at a specific frequency (150-200 kHz) are delivered via arrays placed on the skin surrounding the tumor site. TTFields predominantly act by disrupting the formation of the mitotic spindle during metaphase. TTFields were effective in multiple preclinical models of pancreatic cancer. The Phase 2 PANOVA study, the first trial testing TTFields in pancreatic cancer patients, demonstrated the safety and preliminary efficacy of TTFields when combined with nab-paclitaxel and gemcitabine in both metastatic and locally advanced pancreatic adenocarcinoma (LAPC). The Phase 3 PANOVA-3 trial (NCT03377491) is designed to test the efficacy and safety of adding TTFields to nab-paclitaxel and gemcitabine combination in LAPC. Patients (N = 556) with unresectable, LAPC (per NCCN guidelines) will be enrolled in this prospective, randomized trial. Patients should have an ECOG score of 0-2 and no prior progression or treatment. Patients will be stratified based on their performance status and geographical region, and will be randomized 1:1 to TTFields plus nab-paclitaxel and gemcitabine or to nab-paclitaxel and gemcitabine alone. Chemotherapy will be administered at standard dose of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) on day 1, 8, and 15 of a 28 day cycle. The protocol has recently been amended to incorporate the use of a smaller, lighter (weight reduced from 6 to 2.7 lbs.) TTFields device. TTFields (150 kHz) will be delivered at least 18 hours/day until local disease progression per RECIST Criteria V1.1. Follow up will be performed q4w, including a CT scan of the chest and abdomen q8w. Following local disease progression, patients will be followed monthly for survival. Overall survival will be the primary endpoint. Progression-free survival, objective response rate, rate of resectability, quality of life, and toxicity will all be secondary endpoints. Sample size was calculated using a log-rank test comparing time to event in patients treated with TTFields plus chemotherapy with control patients on chemotherapy alone. PANOVA-3 is designed to detect a hazard ratio 0.75 in overall survival. Type I error is set to 0.05 (two-sided) and power to 80%. Citation Format: Vincent J. Picozzi, Teresa Macarulla, Philip A. Philip, Carlos R. Becerra, Tomislav Dragovich. PANOVA-3: A phase III study of tumor treating fields with nab-paclitaxel and gemcitabine for front-line treatment of locally advanced pancreatic adenocarcinoma [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-051.