Gemcitabine And Nab-paclitaxel Research Articles

A phase II/III randomized clinical trial of CisPlatin plUs Gemcitabine and Nabpaclitaxel (GAP) as pReoperative chemotherapy versus immediate resection in patIents with resecTable BiliarY Tract Cancers (BTC) at high risk for recurrence: PURITY study

BackgroundBiliary tract cancers (BTCs) are rare and lethal cancers, with a 5-year survival inferior to 20%(1–3). The only potential curative treatment is surgical resection. However, despite complex surgical procedures that have a remarkable risk of postoperative morbidity and mortality, the 5-year survival rate after radical surgery (R0) is 20–40% and recurrence rates are up to ~ 75%(4–6). Up to ~ 40% of patients relapse within 12 months after resection, and half of these patient will recur systemically(4–6). There is no standard of care for neoadjuvant chemotherapy (NAC) in resectable BTC, but retrospective reports suggest its potential benefit (7, 8).MethodsPURITY is a no-profit, multicentre, randomized phase II/III trial aimed at evaluating the efficacy of the combination of gemcitabine, cisplatin and nabpaclitaxel (GAP) as neoadjuvant treatment in patients with resectable BTC at high risk for recurrence. Primary objective of this study is to evaluate the efficacy of neoadjuvant GAP followed by surgery as compared to upfront surgery, in terms of 12-month progression-free survival for the phase II part and of progression free survival (PFS) for the phase III study.Key Secondary objectives are event free survival (EFS), relapse-free survival, (RFS), overall survival (OS), R0/R1/R2 resection rate, quality of life (QoL), overall response rate (ORR), resectability. Safety analyses will include toxicity rate and perioperative morbidity and mortality rate.Exploratory studies including Next-Generation Sequencing (NGS) in archival tumor tissues and longitudinal ctDNA analysis are planned to identify potential biomarkers of primary resistance and prognosis.DiscussionConsidering the poor prognosis of resected BTC experiencing early tumor recurrence and the negative prognostic impact of R1/R2 resections, PURITY study is based on the rationale that NAC may improve R0 resection rates and ultimately patients’ outcomes. Furthermore, NAC should allow early eradication of microscopic distant metastases, undetectable by imaging but already present at the time of diagnosis and avoid mortality and morbidity associated with resection for patients with rapid progression or worsening general condition during neoadjuvant therapy. The randomized PURITY study will evaluate whether patients affected by BTC at high risk from recurrence benefit from a neoadjuvant therapy with GAP regimen as compared to immediate surgery.Trial registrationPURITY is registered at ClinicalTrials.gov (NCT06037980) and EuCT(2023–503295-25–00).

Abstract 6649: Tumor treating fields (TTFields) induce an anti-tumor immune response in a pancreatic cancer mouse model

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy with few therapeutic options. Tumor Treating Fields (TTFields) are low-intensity electric fields that disrupt cellular processes critical for cancer cell division and tumor progression and are approved for the treatment of glioblastoma and pleural mesothelioma. A phase 3 clinical trial is in progress to test the efficacy and safety of TTFields concomitant with standard-of-care gemcitabine and nab-paclitaxel (GnP) as front-line treatment of locally advanced PDAC. TTFields have been shown to induce immunogenic cell death (ICD) in cancer cells and elicit a systemic anti-cancer immune response. Accordingly, the benefit of applying TTFields together with immune checkpoint inhibitors (ICI) was demonstrated in a phase 3 study in patients with non-small cell lung carcinoma. This preclinical study investigated TTFields-induced immune responses in PDAC. Methods: An orthotopic PDAC tumor model was established by inoculating 4 × 105 Panc02 pancreatic cancer cells with stable luciferase expression into the pancreas tail of immune-competent C57BL/6 mice. The mice were randomized into four groups following bioluminescence detection of tumor volume: control, TTFields (150 kHz, 10 days), GnP (50 mg/kg for each drug, i.p. injected once a week for a total of two administrations), and GnP + TTFields. At the end of treatment, tumor volume was measured using caliper, and blood was collected for spectral flow cytometry-based immunophenotyping and ELISA testing for the ICD marker HMGB-1. In vitro, Panc02 cells were treated for 72h with TTFields (150 kHz, 1.62 V/cm RMS) and examined by flow cytometry for apoptosis and ATP secretion (using quinacrine staining) and surface exposure of calreticulin. Results: TTFields markedly reduced the tumor size in Panc02 tumor-bearing mice compared to control mice. Analysis of peripheral blood effector (CD62L-CD44+) and central (CD62L+CD44+) memory T cells demonstrated the induction of circulating effector-memory cytotoxic CD8+ T cells. Additionally, serum HMGB-1 concentrations were significantly elevated in mice treated with TTFields compared to control mice, implying the involvement of ICD in the response to TTFields. In vitro, TTFields application induced apoptosis of Panc02 cells and increased ICD, as indicated by increased surface exposure of calreticulin and ATP depletion. When TTFields were used in Panc02 tumor bearing mice concomitantly with GnP, a substantial reduction in tumor size was detected, and a complete tumor regression was observed in a number of mice. Conclusions: Our results suggest that TTFields may enhance the effects of standard-of-care chemotherapy for the treatment of PDAC. Furthermore, TTFields were shown to induce ICD and activate an antitumor immune response in PDAC, supporting future studies evaluating the efficacy of TTFields together with ICI in PDAC. Citation Format: Tal Kan, Tharwat Haj Khalil, Yiftah Barsheshet, Tali Voloshin, Avital Vorontsov, Boris Brant, Lilach Koren, Roni Blatt, Shay Cahal, Efrat Zemer-Tov, Rom Paz, Anat Klein-Goldberg, Catherine Tempel Brami, Sara Jacobovitch, Alexandra Volodin, Bella Koltun, Cfir David, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti. Tumor treating fields (TTFields) induce an anti-tumor immune response in a pancreatic cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6649.

Abstract PR05: CheMo4METPANC: Combination Chemotherapy (gemcitabine and nab-paclitaxel), chemokine (C-X-C) Motif receptor 4 inhibitor (motixafortide), and immune checkpoint blockade (cemiplimab) in METastatic treatment-naïve PANCreatic adenocarcinoma

Abstract Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) is a uniformly fatal disease. Immune checkpoint inhibitors have thus far failed to improve outcomes due to an immunosuppressive tumor microenvironment (TME). In preclinical mouse models, signaling through the C-X-C motif chemokine receptor 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12) axis results in exclusion of anti-tumor immune cells. Using the KPC mouse PDAC model, we have demonstrated that treatment with the combination of a CXCR4 inhibitor (CXCR4i), αPD-1, and gemcitabine improves survival when compared to mice treated with either gemcitabine alone or the combination of CXCR4i and αPD-1 therapy. The goal of this first-in-human study was to test preliminary safety and radiologic response rate of motixafortide (CXCR4i), cemiplimab (αPD1), gemcitabine, and nab-paclitaxel (MCGN) in treatment-naïve mPDAC. Methods: This was an open label, multicenter, investigator-initiated, single arm pilot study evaluating MCGN in mPDAC. This signal seeking study incorporated a six-patient safety run-in cohort with enrollment of four additional patients (N=10). The primary aim of this trial was to study the safety of MCGN. If ≥3 of the initial 10 patients within the pilot stage experienced a partial response (PR) by RECIST criteria within 16 weeks, the combination would be considered promising and an expansion cohort of an additional 30 patients would be enrolled. Clinical trial information: NCT04543071. Results: A total of 11 patients (1 over-enrolled) with mPDAC participated in the study at Columbia University and Brown University (11/9/2020-3/3/2023). The median age was 58y. Two (18%) patients were female and 3 (27%) were black. As of 05/05/23, 6 (55%) patients experienced a partial response (PR) of which 4 (36%) were confirmed PRs with 1 patient experiencing resolution of the hepatic metastatic lesion. Three (27%) patients experienced stable disease. At a median follow-up of 9.5m, 5 remain on study (duration on treatment [DOT]: 11.6, 6.7, 3.7, 2.7, and 2 months), 4 are off treatment due to disease progression (DOT: 13.4, 9.7, 3.7, and 1.5 months), 1 withdrew consent, and 1 was removed per physician discretion. Five patients have died. As of 03/31/23, 9 patients experienced grade 3-4 treatment-related adverse events, including urticaria (18%), and allergic reaction, bone pain, hypertension, hypotension, pain, rash (each 9%). Analyses interrogating the TME, including single-cell profiling, will be presented on paired tumor biopsies obtained on all patients. Conclusions: Preliminary results from this pilot study of MCGN in mPDAC were promising, with a durable PR rate of 55% and disease control rate (DCR) of 82%, compared to historic PRs and DCRs of 23% and 48% reported with gemcitabine and nab-paclitaxel (GN), respectively. Based on these results, the study was amended to transition to a randomized phase 2 trial testing MCGN compared to GN (N=112). The primary endpoint is progression free survival (PFS). Citation Format: Gulam A. Manji, Michael May, Morteza Hajkarim Chalabi, Ilenia Pellicciotta, Sarah I. Sta Ana, Naomi Sender, Samuel S. Pan, Isabelle V. Ross, Kenneth P. Olive, Shikun Wang, Benjamin Izar, Ruth A. White, Susan E. Bates, Alexander G. Raufi. CheMo4METPANC: Combination Chemotherapy (gemcitabine and nab-paclitaxel), chemokine (C-X-C) Motif receptor 4 inhibitor (motixafortide), and immune checkpoint blockade (cemiplimab) in METastatic treatment-naïve PANCreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr PR05.

NALIRIFOX, FOLFIRINOX, and Gemcitabine With Nab-Paclitaxel as First-Line Chemotherapy for Metastatic Pancreatic Cancer

The NAPOLI 3 trial showed the superiority of fluorouracil, leucovorin, liposomal irinotecan, and oxaliplatin (NALIRIFOX) over the combination of gemcitabine and nab-paclitaxel (GEM-NABP) as first-line treatment of metastatic pancreatic ductal adenocarcinoma (PDAC). Analyses comparing NALIRIFOX and GEM-NABP with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) have not yet been reported. To derive survival, response, and toxic effects data from phase 3 clinical trials and compare NALIRIFOX, FOLFIRINOX, and GEM-NABP. After a systematic search of PubMed, Scopus, Embase, and American Society of Clinical Oncology and European Society for Medical Oncology meetings' libraries, Kaplan-Meier curves were extracted from phase 3 clinical trials conducted from January 1, 2011, until September 12, 2023. Phase 3 clinical trials that tested NALIRIFOX, FOLFIRINOX, or GEM-NABP as first-line treatment of metastatic PDAC and reported overall survival (OS) and progression-free survival (PFS) curves were selected. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses of Individual Participant Data reporting guidelines. Individual patient OS and PFS data were extracted from Kaplan-Meier plots of original trials via a graphic reconstructive algorithm. Overall response rates (ORRs) and grade 3 or higher toxic effects rates were also collected. A pooled analysis was conducted, and results were validated via a network meta-analysis. The primary end point was OS. Secondary outcomes included PFS, ORR, and toxic effects rates. A total of 7 trials with data on 2581 patients were analyzed, including 383 patients treated with NALIRIFOX, 433 patients treated with FOLFIRINOX, and 1756 patients treated with GEM-NABP. Median PFS was longer in patients treated with NALIRIFOX (7.4 [95% CI, 6.1-7.7] months) or FOLFIRINOX (7.3 [95% CI, 6.5-7.9] months; [HR], 1.21 [95% CI, 0.86-1.70]; P = .28) compared with patients treated with GEM-NABP (5.7 [95% CI, 5.6-6.1] months; HR vs NALIRIFOX, 1.45 [95% CI, 1.22-1.73]; P < .001). Similarly, GEM-NABP was associated with poorer OS (10.4 [95% CI, 9.8-10.8]; months) compared with NALIRIFOX (HR, 1.18 [95% CI, 1.00-1.39]; P = .05], while no difference was observed between FOLFIRINOX (11.7 [95% CI, 10.4-13.0] months) and NALIRIFOX (11.1 [95% CI, 10.1-12.3] months; HR, 1.06 [95% CI, 0.81-1.39]; P = .65). There were no statistically significant differences in ORR among NALIRIFOX (41.8%), FOLFIRINOX (31.6%), and GEM-NABP (35.0%). NALIRIFOX was associated with lower incidence of grade 3 or higher hematological toxic effects (eg, platelet count decreased 1.6% vs 11.8% with FOLFIRINOX and 10.8% with GEM-NABP), but higher rates of severe diarrhea compared with GEM-NABP (20.3% vs 15.7%). In this systematic review and meta-analysis, NALIRIFOX and FOLFIRINOX were associated with similar PFS and OS as first-line treatment of advanced PDAC, although NALIRIFOX was associated with a different toxicity profile. Careful patient selection, financial toxic effects consideration, and direct comparison between FOLFIRINOX and NALIRIFOX are warranted.

Translational PK-PD/TD modeling of antitumor effects and peripheral neuropathy in gemcitabine and nab-paclitaxel chemotherapy from xenograft mice to patients for optimal dose and schedule.

Gemcitabine and nab-paclitaxel (GnP) treatment, the standard first-line chemotherapy for unresectable pancreatic cancer, often causes peripheral neuropathy (PN). To develop alternative dosing strategies to avoid severe PN, understanding the relationship between pharmacokinetics (PK) and pharmacodynamics/toxicodynamics (PD/TD) is necessary. We established a PK-PD/TD model of GnP treatment to develop an optimal dose schedule. A mouse xenograft model of human pancreatic cancer was generated to measure drug concentrations in the plasma and tumor, antitumor effects, and PN after GnP treatment. The Simeoni tumor growth inhibition model with tumor concentrations and empirical indirect response models were used for the PD and TD models, respectively. Clinical outcomes were predicted with reported population estimates of PK parameters in cancer patients. The PK-PD/TD model simultaneously described the observed tumor volume and paw withdrawal frequency in the von Frey test. For the standard GnP regimen, the model predicted clinical overall response (75.1%), which was overestimated compared to that in a recent phase II study (42.1%) but lower than the observed disease control rate (96.5%). Model simulation showed that dose reduction to less than 40% GnP dose was not effective; a change of dose schedule from every week for 3weeks to every 2weeks was a more favorable approach than dose reduction to 60% every week. The PK-PD/TD model-based translational approach provides a guide for optimal dose determination to avoid severe PN while maintaining antitumor effects during GnP chemotherapy. Further research is needed to enhance its applicability and potential for combination chemotherapy regimens.

Mobilization of Circulating Tumor Cells after Short- and Long-Term FOLFIRINOX and GEM/nab-PTX Chemotherapy in Xenograft Mouse Models of Human Pancreatic Cancer.

Mobilization of CTCs after various types of therapy, such as radiation therapy, has been reported, but systematic study of CTCs after chemotherapy remained quite limited. In this study, we sequentially examined CTC numbers after single-dose and repetitive-dose chemotherapy, including FORFIRINOX (FFX) and Gemcitabine and nab-Paclitaxel (GnP) using two pancreatic cancer xenograft models. CTC was detected by the immunocytology-based microfluidic platform. We further examined the dynamic change in the histology of primary tumor tissues during chemotherapy. We confirmed a transient increase in CTCs 1-2 weeks after single-dose and repetitive-dose of FFX/GnP chemotherapy. Histological examination of the primary tumors revealed that the peak period of CTC at 1-2 weeks after chemotherapy corresponded to the maximal destructive phase consisting of cell cycle arrest, apoptosis of tumor cells, and blood vessel destruction without secondary reparative tissue reactions and regeneration of tumor cells. These findings indicate that mobilization of CTCs early after chemotherapy is mediated by the shedding of degenerated tumor cells into the disrupted blood vessels driven by the pure destructive histological changes in primary tumor tissues. These results suggest that sequential CTC monitoring during chemotherapy can be a useful liquid biopsy diagnostic tool to predict tumor chemosensitivity and resistance in preclinical and clinical settings.

Semaphorin 3 C enhances putative cancer stemness and accelerates peritoneal dissemination in pancreatic cancer

PurposeSemaphorins, axon guidance cues in neuronal network formation, have been implicated in cancer progression. We previously identified semaphorin 3 C (SEMA3C) as a secreted protein overexpressed in pancreatic ductal adenocarcinoma (PDAC). We, therefore, hypothesized that SEMA3C supports PDAC progression. In this study, we aimed to investigate the clinical features of SEMA3C, especially its association with chemo-resistance and peritoneal dissemination.MethodsIn resected PDAC tissues, we assessed the relationship between SEMA3C expression and clinicopathological features by immunohistochemistry. In vitro studies, we have shown invasion assay, pancreatosphere formation assay, colony formation assay, cytotoxicity assay, and activation of SEMA3C downstream targets (c-Met, Akt, mTOR). In vivo, we performed a preclinical trial to confirm the efficacy of SEMA3C shRNA knockdown and Gemcitabine and nab-Paclitaxel (GnP) in an orthotopic transplantation mouse model and in peritoneal dissemination mouse model.ResultsIn resected PDAC tissues, SEMA3C expression correlated with invasion and peritoneal dissemination after surgery. SEMA3C promoted cell invasion, self-renewal, and colony formation in vitro. We further demonstrated that SEMA3C knockdown increased Gem-induced cytotoxicity by suppressing the activation of the Akt/mTOR pathway via the c-Met receptor. Combination therapy with SEMA3C knockdown and GnP reduced tumor growth and peritoneal dissemination.ConclusionsSEMA3C enhances peritoneal dissemination by regulating putative cancer stemness and Gem resistance and activates phosphorylation of the Akt/mTOR pathway via c-Met. Our findings provide a new avenue for therapeutic strategies in regulating peritoneal dissemination during PDAC progression.

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 .

KRAS G12C-mutated pancreatic cancer: Clinical outcomes based on chemotherapeutic regimen.

4150 Background: Frontline treatment for advanced pancreatic ductal adenocarcinoma (PDAC) has been either 5-fluorouracil, oxaliplatin and irinotecan (FOLFIRINOX) or gemcitabine and nab-paclitaxel (GP) for the past decade. While the NAPOLI-3 trial, utilizing liposomal irinotecan, highlighted the superiority of a triplet regimen over GP, the question remains whether certain subgroups may derive particular benefit from GP. Pre-clinical data in lung cancer suggest that KRAS G12C may facilitate enhanced DNA adduct removal after platinum chemotherapy and confer resistance to this drug class. While multiple KRAS G12C inhibitors have shown early promise in PDAC, multi-agent chemotherapy remains the frontline standard and will likely remain an important therapeutic tool. This study aimed to investigate clinical outcomes after platinum and non-platinum-based chemotherapy in patients with advanced KRAS G12C-mutated PDAC. Methods: PDAC samples were tested using whole transcriptome sequencing (WTS; Illumina NovaSeq) and NextGen DNA sequencing (NextSeq, 592 Genes and NovaSEQ, WES) at Caris Life Sciences (Phoenix, AZ). Significance was determined by X2 and Fisher-Exact and p adjusted for multiple comparisons (q). Real-world overall survival (rwOS) was obtained from insurance claims data and calculated from first of treatment to last contact with comparison done by Kaplan-Meier test. Results: A total of 5,555 PDAC patients harboring KRAS pathogenic variants were identified, including 109 with a G12C mutation. For KRAS G12C mutants, median overall survival was 470 days for those who received GP (n=22) compared to 240 days for patients who received FOLFIRINOX (n=9) with a median difference of 230 days (HR 0.32, CI 0.12-0.82, p=0.013). In contrast, median overall survival was higher for patients harboring G12D (392 vs 297 days, p=0.003), G12V (500 vs 356 days, p=0.012) or G12R (469 vs 391 days, p=0.095) mutations who received FOLFIRINOX compared to GP. KRAS G12C mutated PDAC showed the highest rate of PDL1+ staining (27%) compared to other variants (G12R 13% and G12D 19%, q&lt;0.01). TMB-H and MSI-H prevalence were highest in G12C compared to other variants (no statistical significance observed). Conclusions: In patients with advanced PDAC and a G12C mutation, median overall survival appears significantly longer in those treated with GP compared to FOLFIRINOX. The opposite trend was seen in patients with other KRAS variants including G12D, G12V, and G12R, consistent with the recently presented NAPOLI-3 trial. PDL1 staining was also highest in the KRAS G12C cohort. While this is the largest reported analysis of outcomes to frontline chemotherapy in KRAS G12C-mutated PDAC, the sample size is small and needs validation in additional datasets. Next steps include evaluating DNA mutational status and RNA expression of genes involved in DNA repair in G12C vs other KRAS variants to better understand the outcome data presented here.

Safety and clinical activity of oleclumab (O) ± durvalumab (D) + chemotherapy (CT) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC): A phase 1b/2 randomized study.

4136 Background: In a phase 1 study, the anti-CD73 monoclonal antibody (mAb) O plus the anti-PD-L1 mAb D showed antitumor activity and manageable safety in previously treated pts with advanced PDAC (Overman et al, J Clin Oncol 2018;36[suppl 15]:abs 4123). Here we report a multicenter, open-label study of O ± D + CT in pts with mPDAC. Methods: Pts were ≥18 years old with ECOG PS 0–1. Part 1 was a dose escalation phase: in Cohort A, previously untreated (1L) pts received O 1500 or 3000 mg IV Q2W for 4 doses then Q4W + D 1500 mg IV Q4W, with Q4W gemcitabine and nab-paclitaxel (GnP). In Cohort B, pts with previous G-based CT (2L) received O 1500 or 3000 mg Q2W for 4 doses then Q4W + D 1500 mg Q4W, with Q4W mFOLFOX. The primary objective for Part 1 was safety and tolerability; secondary objectives included antitumor activity and pharmacokinetics (PK). Part 2 was an expansion phase in which pts were stratified by high/low tumoral CD73 expression by IHC. In Cohort A, 1L pts were randomized 1:1:1 to GnP alone (Arm A1), O + GnP (Arm A2) or O + D + GnP (Arm A3). O was given at the recommended phase 2 dose, 3000 mg. Cohort B did not proceed to dose expansion due to emerging therapies in 2L PDAC pts. The primary endpoint for Part 2 was investigator-assessed objective response rate (ORR) by RECIST v1.1; secondary included PFS, OS, safety, PK and antidrug antibody data. Results: As of November 11, 2022, 25 pts were treated in Part 1 (Cohort A, n=14; Cohort B, n=11), and 170 pts were treated in Part 2 (Arm A1, n=62; Arm A2, n=38; Arm A3, n=70). In Part 1, dose-limiting toxicities occurred in 1 pt (Cohort B, O 3000 mg: Gr 3 nausea and Gr 3 localized edema). Safety was generally similar in Parts 1 and 2. In Part 2, Gr ≥3 treatment-emergent adverse events (TEAEs) occurred in 85.5%, 89.5% and 90.0% of pts in Arms A1, A2 and A3 respectively, most commonly neutropenia (22.6%, 34.2% and 17.1%). In Part 2, TEAEs led to discontinuation in 11.3%, 23.7% and 24.3% of pts respectively. In Part 2, ORR was similar across Arms with a trend toward longer PFS and OS in Arm 3 vs Arm 1. There was a trend toward greater clinical benefit in pts with high CD73 expression when comparing Arm A3 vs Arm A1. Conclusions: O + D + GnP had similar safety and a trend toward improved outcomes compared to GnP. Clinical trial information: NCT03611556 . [Table: see text]

A phase I/II study of durvalumab and stereotactic ablative body radiotherapy (SABR) in locally advanced (LA) and borderline resectable (BR) pancreatic cancer.

4164 Background: Pancreatic cancer (PC) is largely refractory to immune checkpoint blockade (ICB) in genomically unselected patients (pts). Synergistic effects of combined ICB and radiotherapy have been suggested in varied solid tumors. Few studies have evaluated this approach in pts with PC. We sought to evaluate the safety and efficacy of PD-L1 inhibitor durvalumab (D) and SABR after induction chemotherapy, in LA and BR PC. Herein, we present phase II data from two cohorts. Methods: A multi-institutional, non-randomized phase 1/2 trial of SABR and D was conducted at Cedars-Sinai Medical Center (CS) and Memorial Sloan Kettering (MSK). Key eligibility: ECOG 0-1; unresectable PC, with stable/responding disease following 2-3 cycles gemcitabine and nab-paclitaxel (GnP) or 4-6 months (m) FOLFIRINOX (FFX). CS enrolled pts with BR and LA PC; MSK enrolled pts with LA PC only. All pts received SABR between dose 1 and 2 of D, with slight variation in ablative radiation techniques (CS: 33Gy/5#; MSK: MRI adaptive ablative radiation, 50Gy/5#). D dosed on day 1: 750mg x 4 doses Q14 days, and subsequently Q2 or Q4 weeks x 1 year total, or until resection, progression of disease (POD), or limiting toxicity. Primary endpoint: 6-month progression free survival (6 m PFS). Secondary endpoints: rate of downstaging to resectability, objective response by RECIST v1.1, duration of response, PFS, Overall Survival (OS). PFS and OS estimated from consent date using Kaplan-Meier method. Association between surgery and outcomes was analyzed as a time dependent covariate in univariate Cox regression models for OS and PFS. To assess immunogenomic biomarkers of response, pre- and on-treatment tissue, blood and microbiome samples were gathered. Results: Between 08/2017 and 05/2022, N= 36 enrolled. Median age 67.5 years (range 48-79), 39% (14/36) female. Performance Status: N=12 (33%) ECOG 0; N= 24 (67%) ECOG 1. Median duration chemotherapy: 3.5 m (range 1.4, 5.8). Staging: N=31 (86%) LA; N=5 (14%) BR. N = 9 (25%) underwent resection; all R0. Conversion to resection was not associated with PFS (HR 0.45; 95% CI 0.17, 1.17, p=0.1) or OS (HR 0.69; 95% CI 0.26, 1.84, p=0.5). Survival and response data summarized in table. Toxicities of special interest: Grade 3 treatment-related: in N= 7; diarrhea N= 2; elevated AST/ALT N= 2; lipase/amylase elevation, N=1; nausea N=1. Grade 4: amylase elevation N=1. Conclusions: D and SABR after induction chemotherapy in LA and BR PC is safe, had an encouraging 6-m PFS of 69% and favorable R0 resection rate, warranting further evaluation. Immuno-genomic biospecimen analyses underway. Clinical trial information: NCT03245541 . [Table: see text]

Safety, tolerability, and effectiveness of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin in combination with standard chemotherapy for patients with advanced, inoperable pancreatic adenocarcinoma: a phase 1b observational study

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Thus, there is an urgent need for safe and effective novel therapies. PDAC’s excessive reliance on glucose metabolism for its metabolic needs provides a target for metabolic therapy. Preclinical PDAC models have demonstrated that targeting the sodium-glucose co-transporter-2 (SGLT2) with dapagliflozin may be a novel strategy. Whether dapagliflozin is safe and efficacious in humans with PDAC is unclear.MethodsWe performed a phase 1b observational study (ClinicalTrials.gov ID NCT04542291; registered 09/09/2020) to test the safety and tolerability of dapagliflozin (5 mg p.o./day × 2 weeks escalated to 10 mg p.o./day × 6 weeks) added to standard Gemcitabine and nab-Paclitaxel (GnP) chemotherapy in patients with locally advanced and/or metastatic PDAC. Markers of efficacy including Response Evaluation Criteria in Solid Tumors (RECIST 1.1) response, CT-based volumetric body composition measurements, and plasma chemistries for measuring metabolism and tumor burden were also analyzed.ResultsOf 23 patients who were screened, 15 enrolled. One expired (due to complications from underlying disease), 2 dropped out (did not tolerate GnP chemotherapy) during the first 4 weeks, and 12 completed. There were no unexpected or serious adverse events with dapagliflozin. One patient was told to discontinue dapagliflozin after 6 weeks due to elevated ketones, although there were no clinical signs of ketoacidosis. Dapagliflozin compliance was 99.4%. Plasma glucagon increased significantly. Although abdominal muscle and fat volumes decreased; increased muscle-to-fat ratio correlated with better therapeutic response. After 8 weeks of treatment in the study, partial response (PR) to therapy was seen in 2 patients, stable disease (SD) in 9 patients, and progressive disease (PD) in 1 patient. After dapagliflozin discontinuation (and chemotherapy continuation), an additional 7 patients developed the progressive disease in the subsequent scans measured by increased lesion size as well as the development of new lesions. Quantitative imaging assessment was supported by plasma CA19-9 tumor marker measurements.ConclusionsDapagliflozin is well-tolerated and was associated with high compliance in patients with advanced, inoperable PDAC. Overall favorable changes in tumor response and plasma biomarkers suggest it may have efficacy against PDAC, warranting further investigation.

Abstract 2172: Tumor IL1RAP levels and reduction in serum biomarkers correlate with response in PDAC patients treated with nadunolimab, an anti-IL1RAP monoclonal antibody, in combination with gemcitabine and nab-paclitaxel

Abstract Background: Interleukin-1 Receptor Accessory Protein (IL1RAP) is expressed on cancer and stromal cells in pancreatic ductal adenocarcinoma (PDAC), and high tumor IL1RAP RNA expression is a negative prognostic marker1. Dimerization between IL1RAP and the IL-1 receptor is required for IL-1 signaling, and the IL-1 axis has been implicated in the tumor microenvironment and immune response to PDAC. Nadunolimab (CAN04), a fully humanized ADCC-enhanced IgG1 anti-IL1RAP antibody, blocks IL-1α and IL-1β signaling. Preliminary efficacy from the clinical phase 1/2a trial CANFOUR, where PDAC patients (n=73) received nadunolimab with gemcitabine and nab-paclitaxel (GN), show median iPFS of 7.2 months (iRECIST; 95% CI 5.2-8.5), median OS of 12.7 months (10.0-19.1) with 59% of patients alive, and 1-year survival of 57%2. Methods: Patients with previously untreated, locally advanced or metastatic PDAC received nadunolimab at doses from 1 to 7.5 mg/kg, in combination with GN. The exploratory objective was to measure serum and tumor biomarkers related to treatment outcome. Pre-treatment tumor biopsies were assessed for IL1RAP expression by immunohistochemistry. Serum from all patients was analyzed for biomarkers by Meso Scale Discovery (MSD) and Olink. Results: IL1RAP was expressed on tumor and stromal cells in all biopsies analysed and IL1RAP-positive infiltrating immune cells were detected in biopsies from 94% of patients (n=38). The level of IL1RAP on tumor cells was associated with response (PR vs SD and PD; p=0.082). Patients with PR had a median IL1RAP H-score of 200, while patients with SD or PD as best response had a median H-score of 110. The data suggest a relationship between high IL1RAP expression and increased iPFS and OS. Reductions in serum biomarkers downstream of IL-1, detected by MSD, were also associated with response. Patients with the largest treatment-related decreases in IL-6 displayed a prolonged iPFS (p&amp;lt;0.023), while patients with a decrease in IL-8 showed prolonged iPFS (p&amp;lt;0.025) and OS (p&amp;lt;0.041). Patients with the most decreased CRP levels following treatment also showed extended iPFS (p&amp;lt;0.009) and OS (p&amp;lt;0.008). A reduction in other IL-1-related biomarkers, such as CXCL5, VEGFA, EGF, Angiopoietin 1 and TWEAK, was also detected by Olink post-treatment. Conclusions: Nadunolimab combined with GN shows promising iPFS and OS in 73 PDAC patients. In these patients, high tumor cell expression of IL1RAP, the molecular target for nadunolimab, correlated with response. Reduction of the downstream biomarkers IL-6 and IL-8, as well as CRP, were most pronounced in responding patients and correlated with efficacy. These data strongly suggest that nadunolimab interaction with IL1RAP is important for the treatment effects observed in the CANFOUR study. 1TCGA Database2Van Cutsem et al; ASCO 2022 Citation Format: Eric Van Cutsem, Joelle Collignon, Rikke Eefsen, Sebastian Ochsenreither, Zanete Zvirbule, Audrius Ivanauskas, Camilla Rydberg Millrud, Petter Skoog, Nedjad Losic, Susanne Magnusson, Annika Sanfridson, David Liberg. Tumor IL1RAP levels and reduction in serum biomarkers correlate with response in PDAC patients treated with nadunolimab, an anti-IL1RAP monoclonal antibody, in combination with gemcitabine and nab-paclitaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2172.

Early skeletal muscle mass decline is a prognostic factor in patients receiving gemcitabine plus nab-paclitaxel for unresectable pancreatic cancer: a retrospective observational study

PurposePatients with pancreatic cancer often have cancer cachexia at diagnosis. Recent studies suggested that loss of skeletal muscle mass was related to cancer cachexia, which hindered continuance of chemotherapy and could be one of prognostic factors in pancreatic cancer, however the association remains unclear in patients receiving gemcitabine and nab-paclitaxel (GnP).MethodsWe retrospectively studied 138 patients with unresectable pancreatic cancer receiving first-line GnP at the University of Tokyo from January 2015 to September 2020. We calculated body composition in CT images before chemotherapy and at initial evaluation, and evaluated the association of both body composition before chemotherapy and its changes at initial evaluation.ResultsCompared by skeletal muscle mass index (SMI) change rate between pre-chemotherapy and initial evaluation, there were statistically significantly differences in the median OS: 16.3 months (95%CI 12.3–22.7) and 10.3 months (95%CI 8.3–18.1) between SMI change rate ≥ -3.5% and < -3.5% groups (P = 0.01). By multivariate analysis for OS, CA19-9 (HR 3.34, 95%CI 2.00–5.57, P < 0.01), PLR (HR 1.68, 95%CI 1.01–2.78, P = 0.04), mGPS (HR 2.32, 95%CI 1.47–3.65, P < 0.01) and relative dose intensity (HR 2.21, 95%CI 1.42–3.46, P < 0.01) were significantly poor prognostic factors. SMI change rate (HR 1.47, 95%CI 0.95–2.28, P = 0.08) showed a trend to poor prognosis. Sarcopenia before chemotherapy was not significantly associated with PFS or OS.ConclusionEarly skeletal muscle mass decline was associated with poor OS. Further investigation is warranted whether the maintenance of skeletal muscle mass by nutritional support would improve prognosis.

Zolbetuximab plus gemcitabine and nab-paclitaxel (GN) in first-line treatment of claudin 18.2–positive metastatic pancreatic cancer (mPC): Phase 2, open-label, randomized study.

TPS782 Background: GN is a first-line treatment option for patients (pts) with mPC. Poor prognosis and low 5-year survival rate ( &lt; 5%) with mPC highlight the need for new therapeutics. Claudin 18.2 (CLDN18.2), a tight junction protein expressed exclusively on normal gastric epithelial cells, is maintained during malignant transformation in gastric cancers and is frequently expressed in some carcinomas from organs that do not normally express it, such as pancreatic cancer. Zolbetuximab, a chimeric IgG1 monoclonal antibody, binds to CLDN18.2 and mediates tumor cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. This phase 2 study (NCT03816163) will assess safety and efficacy of GN alone or with zolbetuximab in CLDN18.2-positive mPC. Methods: The study was expanded to enroll approximately 369 pts with histologically confirmed mPC and high CLDN18.2 expression (moderate-to-strong IHC staining intensity in ≥75% of tumor cells). The study included a safety lead-in that enrolled 3-12 pts to assess safety/tolerability of zolbetuximab (n = 3 at 1,000 mg/m2 on Cycle 1 Day 1 then 600 mg/m2 Q2W, then expand/de-escalate using a 3+3 design) plus GN. Dose-limiting toxicities (DLTs, defined as a specified zolbetuximab-related toxicity that occurs during DLT assessment period) will be assessed after Cycle 1 (28 days). Based on the recommended phase 2 dose (RP2D), confirmed during the safety lead-in, approximately 357 pts will be randomized 2:1 to zolbetuximab Q2W on Days 1 and 15 plus GN on Days 1, 8, and 15 of each cycle (Arm 1), or GN alone on Days 1, 8, and 15 of each cycle (Arm 2). Randomization will be stratified by ECOG performance status (0 or 1) and liver metastasis (yes or no). At sites in Japan, DLTs (assessed from Cycle 1 Day 1 to Cycle 2 Day 1) will be evaluated in ≤6 pts randomized to the RP2D in Arm 1. Pts will undergo imaging (CT/MRI) at baseline and Q8W until investigator-assessed disease progression (RECIST v1.1) or the start of another systemic anticancer treatment, whichever comes earlier. In addition to confirming the RP2D during the safety lead-in, primary objectives are to assess whether treatment with zolbetuximab plus GN, versus GN alone, improves overall survival (randomization phase) and to establish the safety/tolerability profile of zolbetuximab plus GN (across the study). Secondary endpoints include progression-free survival, objective response rate, disease control rate, duration of response, pharmacokinetics, and health-related quality of life (per protocol amendment). Descriptive statistics will be used for continuous endpoints and frequency and percentage for categorical endpoints. Original protocol enrollment completion was in October 2021. Under the expanded protocol amendment, 95 of ~140 sites in North America, Latin America, Europe, and Asia Pacific were activated. Clinical trial information: NCT03816163 .

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 .

Effects of Gemcitabine/Nab-Paclitaxel and DMAPT in PDAC Cachexia in vivo and in vitro

Cachexia is the involuntary wasting of skeletal muscle and adipose tissue, affecting over 80% of patients with pancreatic ductal adenocarcinoma (PDAC). Gemcitabine and nab-paclitaxel (GemNP) combination are commonly given as first-line treatments for PDAC. Data from our lab showed GemNP reduced tumor growth and prevented muscle and fat wasting. Dimethylaminoparthenolide (DMAPT), a small molecule inhibitor, prevented muscle wasting and prolonged survival in a genetic murine model of breast cancer. It has yet to determine if GemNP in combination with DMAPT can improve indices of cachexia and overall survival. Therefore, I hypothesize that GemNP in combination with DMAPT will improve indices of cachexia and overall survival in a murine model of pancreatic cancer. Male 10-week-old C57BL/6J mice underwent orthotopic injection of 5x104 KPC cells or SHAM surgery. Mice were randomly assigned to 1 of 4 groups (N=10/group): SHAM+Vehicle, KPC+Vehicle, KPC+GemNP, KPC+GemNP+DMAPT. Gemcitabine (120mg/kg) and Nab-paclitaxel (10mg/kg) were injected intraperitoneally starting on day 4 and continued every 6 days. DMAPT (100mg/kg) was administered by gavage Monday-Friday. To determine the role of GemNP and DMAPT in vitro, KPC cells were treated with GemNP and/or DMAPT and cell viability evaluated. Additionally, we treated myotubes with GemNP with/without DMAPT to assess myotube diameter in an established KPC conditioned media. In KPC mice, GemNP (24.4days) increased survival compared to Vehicle (16.8days, p=.0007). However, the combination GemNP+DMAPT did not extend survival over GemNP alone (25.4days, p=.693). Tumor mass was similar between all groups (p=0.411). Interestingly, at the time of sacrifice, all KPC treated mice independent of treatment had similar reduction in adipose tissue and muscle mass compared to SHAM. In conclusion, the addition of DMAPT to GemNP did not extend survival over GemNP alone in an aggressive pancreatic tumor cell line. Future studies should determine if less aggressive tumor cell lines might benefit from GemNP and DMAPT.

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.

Abstract A002: Purity Independent Subtyping of Tumor (PurIST): Real-world data validation of a pancreatic ductal adenocarcinoma (PDAC) gene expression classifier and its prognostic implications

Abstract Background: PDAC is a highly morbid disease with no validated biomarkers for first-line (1L) treatment selection. The PurIST single-sample molecular subtyping gene signature, initially described by Rashid et al. (Clin. Cancer Res., 2020), classifies PDAC tumors as basal or classical. Prior work showed that these subtypes are associated with prognosis and that basal subtype patients have significantly lower objective response rate to FOLFIRINOX (FFX) compared to classical subtype patients. This suggests potential implications for treatment with FFX versus gemcitabine and nab-paclitaxel (GnP). Here, we retrospectively demonstrate the clinical validity of PurIST implemented as a laboratory developed test (LDT) on the Tempus Labs sequencing platform using a real-world dataset of advanced PDAC patients. Methods: De-identified PDAC patients were selected from the Tempus Oncology Data Ecosystem under an IRB-approved protocol according to the following inclusion criteria: no systemic treatment, surgically unresectable/metastatic, available RNA-sequencing data from primary or metastatic tissue, and FFX or GnP as 1L systemic therapy with available outcomes. Sequencing was performed by the CAP/CLIA validated Tempus xT assay. The PurIST model was applied to normalized RNA-sequence abundance files to compute a basal or classical subtype label. Predefined statistical analysis parameters included 12-month survival rate and median overall survival (OS) in FFX treated patients. OS was compared using Kaplan-Meier estimates, hazard ratios, and log-rank statistical tests. Results: 258 PDAC patients (64.9 +/- 9.9 yrs, 42% female), were identified for analysis with median OS of 11.7 months (95% CI: 10.6-13.7) and 12-month censorship rate of 12.8%. 151 patients were treated with FFX and 107 with GnP. 42 patients (28%) receiving FFX and 31 patients (29%) receiving GnP were classified as basal. Among FFX treated patients, median OS was 14.4 months (95% CI: 12.5-16.9) in classical patients vs. 9.4 months (95% CI: 8.3-14.5) in basal patients (HR = 1.72, 95% CI = 1.2-2.6, p=0.006). The 12-month survival rate was significantly lower in basal patients receiving FFX vs. classical patients (33.3% vs. 59.4%, p=0.011). In basal patients, no difference in OS was observed between FFX and GnP groups (p=0.6). Classical patients receiving FFX had a 14.4 months median OS vs. 10.8 months for patients receiving GnP (p=0.046). Conclusions: In this real-world cohort, we validate the association between PurIST subtypes and PDAC patient survival when administered FFX or GnP. Among FFX-treated patients, classical patients had significantly better outcomes compared to basal patients. Moreover, classical patients appeared to have improved outcomes with FFX vs. GnP. These findings represent underlying biological PDAC differences and demonstrate the clinical validity of PurIST as a prognostic marker in PDAC patients when performed as an LDT on the Tempus xT platform. Ongoing evaluation of PurIST performance will be continuously monitored through the Tempus Oncology Data ecosystem. Citation Format: Stephane Wenric, James M. Davison, Yun E. Wang, Gregory M. Mayhew, Kirk Beebe, Hyunseok P. Kang, Michael V. Milburn, Vincent Chung, Tanios Bekaii-Saab, Charles M. Perou. Purity Independent Subtyping of Tumor (PurIST): Real-world data validation of a pancreatic ductal adenocarcinoma (PDAC) gene expression classifier and its prognostic implications [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 A002.

Pathologic and clinical outcomes after neoadjuvant modified FOLFIRINOX and gemcitabine and NAB-paclitaxel for pancreatic cancer.

e16236 Background: Surgical resection is the only potentially curative option for pancreatic cancer (PC). Unfortunately, just 15-20% of patients (pts) have resectable disease at the time of diagnosis. Recently, for a variety of reasons, neoadjuvant chemotherapy (NAC) has been widely adopted in both borderline resectable and resectable tumors. Most guidelines recommend either modified FOLFIRINOX (mFOLFIRINOX) or gemcitabine and NAB-paclitaxel (GnP) in this setting. This is largely based on phase II trials and extrapolations from trials in the metastatic setting. Here we investigate the difference in tumor regression score (TRS) and clinical outcomes between these regimens. Methods: We retrospectively collected data from pts who underwent resection of PC after NAC at Ochsner Health between July 2012 and July 2021. Primary objective was TRS on operative pathology as assessed by the reading pathologist. Secondary objectives were progression free survival (PFS) from the date of surgery and overall survival (OS) from the date of diagnosis. TRSs were dichotomized as complete (0)/moderate (1) responses versus (vs) minimal (2)/poor (3) responses. The dichotomized score was assessed using log-binomial regression. Kaplan-Meier survival analysis was utilized to estimate PFS and OS. Survival curves were compared by the log-rank test. Results: We identified 96 pts with PC who had NAC followed by surgical resection. Mean age at diagnosis was 65.7. 55% had borderline resectable and 45% had clearly resectable disease at diagnosis. 74 pts received mFOLFIRINOX and 22 pts received GnP. Pts receiving GnP were more likely to be older (71 vs 64, P = 0.001) and have a worse Eastern Cooperative Oncology Group performance status (PS) (P = 0.019). TRSs were similar between the 2 groups with 58.1% and 59.1% in each group achieving a TRS of 2. 7 pts in the mFOLFIRINOX group had TRS of 0 (CR) while 0 pts in the GnP group had a TRS of 0. When controlling for age and PS, risk ratio for a lower TRS (0/1 vs 2/3) with mFOLFIRINOX vs GnP was 1.22 (0.27 - 5.47). 40% and 36.4% had disease recurrence after mFOLFIRINOX and GnP, respectively. Median PFS and OS were 15.6 and 23.4 months (m) in the mFOLFIRINOX group and 18.9 and 27.6 m in the GnP group (P = 0.996, P = 0.933, respectively). On multivariate analysis, controlling for age and PS, hazard ratios for OS and PFS with mFOLFIRINOX vs GnP were 0.86 (95% CI 0.38–2.18) and 1.17 (95% CI 0.53–2.84), respectively. Conclusions: Our study showed no difference in TRS between mFOLFIRINOX or GnP as NAC, although the small number of pts who received GnP precluded statistical inference. Differences in survival outcomes between the two NAC regimens were not significantly different, and outcomes were comparable to those reported in the phase II SWOG S1505 trial. Large prospective trials comparing these two regimens in terms of efficacy and toxicity will be required to better answer these questions.