Metastatic PDAC Research Articles

Pancreatic cancer tumor organoids exhibit subtype-specific differences in metabolic profiles

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease characterized by complex metabolic rewiring that enables growth in changing nutrient availability and oxygen conditions. Transcriptome-based prognostic PDAC tumor subtypes, known as ‘basal-like’ and ‘classical’ subtypes are associated with differences in metabolic gene expression including genes involved in glycolysis. Tumor subtype-specific metabolism phenotypes may provide new targets for treatment development in PDAC, but their functional relevance has not been fully elucidated. We aimed to investigate differences in metabolic profiles and transcriptomes in tumor models derived from patients with basal-like and classical tumors.MethodsPatient-derived organoids (PDOs) were established from tumor biopsies collected from patients with metastatic PDAC, including three PDOs from basal-like and five PDOs from classical tumors. Metabolic analyses included assessment of differences in metabolic activity using Seahorse Glycolysis and Mito Stress tests and 13C-glucose metabolites tracing analysis. In order to investigate the influence of mitochondrial pyruvate transport on metabolic differences, PDOs were treated with the mitochondrial pyruvate carrier 1 (MPC1) inhibitor UK-5099. Prognostic relevance of MPC1 was determined using a tumor tissue microarray (TMA) in resectable, and proteomics profiling in metastatic PDAC datasets. Whole genome and transcriptome sequencing, differential gene expression and gene set enrichment analyses were performed in PDOs.ResultsMetastatic PDAC PDOs showed subtype-specific differences in glycolysis and oxidative phosphorylation (OXPHOS). Basal-like tumor-derived PDOs had a lower baseline extracellular acidification rate, but higher glycolytic reserves and oxygen consumption rate (OCR) than classical tumor-derived PDOs. OCR difference was eliminated following treatment with UK-5099. In the 13C-glucose metabolites tracing experiment, a basal-like tumor PDO showed lower fractions of some M + 2 metabolites but higher sensitivity to UK-5099 mediated reduction in M + 2 metabolites than a classical tumor PDO. Protein level analyses revealed lower MPC1 protein levels in basal-like PDAC cases and association of low MPC1 levels with clinicopathologic parameters of tumor aggressiveness in PDAC. PDO differential gene expression analyses identified additional subtype-specific cellular pathways and potential disease outcome biomarkers.ConclusionsOur findings point to distinct metabolic profiles in PDAC subtypes with basal-like tumor PDOs showing higher OXPHOS and sensitivity to MPC1 inhibition. Subtypes-specific metabolic vulnerabilities may be exploited for selective therapeutic targeting.

Olaparib as maintenance therapy in non resectable pancreatic adenocarcinoma associated with homologous recombination deficiency profile: A French retrospective multicentric AGEO real-world study

BackgroundPancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. The POLO trial showed that olaparib (PARP inhibitor) improved progression-free survival (PFS) but not overall survival (OS), when used as maintenance therapy after ≥ 16 weeks of disease control with first-line platinum-based chemotherapy in patients with germline (g) BRCA 1 or 2 pathogenic variants (PV) metastatic PDAC. However, real-world data on the effectiveness of olaparib are missing. MethodsPatients with unresectable PDAC associated with somatic (s) or (g)BRCA1/2 and (g)non-BRCA-HRD PV (i.e. other homologous recombination deficiency/HRD genes) who were treated with olaparib between 2020–2023 were included. The primary objective was to describe treatment patterns. Secondary exploratory objectives included OS and PFS in patients treated with olaparib according to the POLO trial or not, OS and PFS in patients with (g)HRD PV-associated PDAC versus (s)PVs, olaparib safety profile and factors associated with olaparib poor outcomes. ResultsAmong 85 patients, 45.9 % received olaparib as defined by the POLO trial. No difference in OS and PFS was observed between patients who received olaparib according to the POLO trial versus not. Patients with (g)HRD PV-associated PDAC had better OS compared to others (22.3 versus 10.5 months, p = 0.038). Factors associated with olaparib poor outcomes included a high neutrophil-to-lymphocyte ratio and the use of olaparib outside the recommendations of the POLO trial. Few grade ≥ 3 adverse events were reported (9.4 %). ConclusionPatients with (g)HRD PV-associated PDAC had longer OS than those with (s)HRD PV. Olaparib use beyond the scope of the POLO trial was associated with poor outcomes.

1516P Lung-only metastatic PDAC: Another disease?

1516P Lung-only metastatic PDAC: Another disease?

Comparative analysis of the mutational landscape and evolutionary patterns of pancreatic ductal adenocarcinoma metastases in the liver or peritoneum

BackgroundPancreatic ductal adenocarcinoma (PDAC) often presents with liver or peritoneal metastases at diagnosis. Despite similar treatment approaches, patient outcomes vary between these metastatic sites. To improve targeted therapies for metastatic PDAC, a comprehensive analysis of the genetic profiles and evolutionary patterns at these distinct metastatic locations is essential. MethodsWe performed whole exome sequencing on 44 tissue samples from 27 PDAC patients, including primary tumours and matched liver or peritoneal metastases. We analysed somatic mutation profiles, signatures, and affected pathways for each group, and examined clonal evolution using subclonal architectures and phylogenetic trees. ResultsKRAS mutations remained the predominant driver alteration, with a prevalence of 89 % across all tumours. Notably, we observed site-specific differences in mutation frequencies, with KRAS alterations detected in 77.8 % (7/9) of peritoneal metastases and 87.5 % (7/8) of liver metastases. TP53 mutations exhibited a similar pattern, occurring in 55.6 % (5/9) of peritoneal and 37.5 % (3/8) of liver metastases. Intriguingly, we identified site-specific alterations in DNA repair pathway genes, including ATM and BRCA1, with distinct mutational profiles in liver versus peritoneal metastases. Furthermore, liver metastases demonstrated a significantly higher tumor mutational burden (TMB) compared to peritoneal metastases (median [IQR]: 2.14 [1.77–2.71] vs. 1.29 [1.21–1.69] mutations/Mb; P = 0.048). ConclusionsIn conclusion, metastasis of pancreatic cancer may be influenced by variables other than KRAS mutations, such as TP53. PDAC peritoneal and liver metastases may differ in potential therapeutic biomarkers. Further inquiry is needed on the biological mechanisms underlying metastasis and the treatment of diverse metastases.

Alliance A022106: A phase II/III trial of NABPLAGEM vs nab-paclitaxel/gemcitabine as second-line treatment for BRCA1/2 or PALB2 mutant metastatic pancreatic ductal adenocarcinoma (PLATINUM).

TPS4205 Background: Multiple lines of evidence support the use of platinum-based chemotherapy for patients with homologous recombination deficiency-associated pancreatic adenocarcinoma (HRD PDAC; 15-20%). However, the impact of the specific platinum agent used remains uncertain. Mechanistically, oxaliplatin and cisplatin act distinctly on cancer cells, reflected in disparate toxicity profiles and target disease indications; furthermore, preclinical studies have shown that BRCA2-deficient cell lines and mice demonstrate significantly greater sensitivity to cisplatin compared to oxaliplatin. While oxaliplatin, part of the FOLFIRINOX regimen, represents the most commonly used platinum analogue for PDAC, clinical data shows that cisplatin (in combination with gemcitabine) can produce robust response rates (~70%) specifically in patients with germline BRCA/PALB2-mutated metastatic PDAC. We therefore designed a randomized clinical trial (PLATINUM) through the Alliance for Clinical Trials in Oncology cooperative group to assess the optimal chemotherapy regimen in patients with HRD-associated metastatic PDAC following front-line FOLFIRINOX and to test the hypothesis that a platinum switch strategy will be beneficial. Methods: The study consists of a seamless phase II/III design, with the primary endpoint of the phase III component being overall survival. Eligible patients will have metastatic PDAC, a confirmed pathogenic BRCA1/2 or PALB2 mutation (somatic or germline), and demonstrated disease progression on front-line FOLFIRINOX, with or without subsequent PARP inhibitor maintenance. Patients will be randomized 1:1 to receive (1) the de facto standard of gemcitabine plus nab-paclitaxel; or (2) the experimental 3-drug combination of gemcitabine, nab-paclitaxel, and cisplatin (NABPLAGEM), which has been previously studied in non-biomarker-selected patients with advanced biliary tract cancer (SWOG1815) and metastatic PDAC. Both treatment arms will use a once every other week dosing schedule. A total of 100 patients will be enrolled, which provides 90% power to detect an effect size of hazard ratio 0.5 (median OS of 18 vs 9 months) at a one-sided alpha of 0.05. Reports containing efficacy, adverse events, and administrative information will be provided to the Alliance DSMB every 6 months. Planned correlatives include ctDNA analysis for BRCA reversion mutations in all patients, as well as whole genome and transcriptome sequencing in an optional biopsy cohort. This study was activated in December 2023. Clinical trial information: NCT06115499 .

Impact on chemotherapy induced peripheral neuropathy of nadunolimab, a first-in-class monoclonal antibody against IL1RAP, in patients with pancreatic cancer, with supportive mouse model data.

4148 Background: Chemotherapy induced peripheral neuropathy (CIPN) is one of the major nonhematological adverse events arising from chemotherapies. CIPN is a neuroinflammatory condition that can be driven by immune cell activation and interleukin-1 (IL-1) release. Nadunolimab is a fully humanized monoclonal IgG1 antibody targeting IL1 receptor accessory protein (IL1RAP). Through binding IL1RAP, nadunolimab can induce ADCC of IL1RAP-expressing tumor cells and inhibits tumor-promoting signals mediated by both IL-1α and IL-1β in the tumor microenvironment. The phase I/IIa CANFOUR trial of nadunolimab in combination with nab-paclitaxel and gemcitabine (GN) in previously untreated, unresectable, locally advanced or metastatic PDAC, showed promising efficacy with median OS: 13.2 months; median iPFS: 7.2 months; 1-year survival: 58% and iORR: 33%, with a good safety profile. Notably, only 1 of 73 patients reported a grade ≥ 3 peripheral neuropathy suggesting that targeting IL1RAP may also alleviate the neuroinflammation leading to CIPN. Methods: To assess the potential neuroprotective activity of nadunolimab, we investigated the impact of nadunolimab on CIPN in the CANFOUR trial where 73 PDAC patients received nadunolimab at 1 mg/kg (n=20), 2.5 mg/kg (n=20), 5 mg/kg (n=25) or 7.5 mg/kg (n=8) in combination with GN. Adverse events were monitored at weekly to biweekly intervals. Relations between study drugs dosing and occurrence, severity and timing of adverse events indicative of CIPN were investigated using exploratory statistical analyses. In mice, CIPN was induced by i.p. administration of vincristine at 0.5 mg/kg, or nab-paclitaxel at 4 mg/kg. The effects of an anti-mouse IL1RAP surrogate antibody (i.p. at 10 mg/kg) on CIPN were evaluated using electronic von Frey apparatus, Parallel Rod Floor apparatus and grip strength meter. Results: Among the 73 PDAC patients in CANFOUR, patients in the individual 2.5 mg/kg, 5 mg/kg and 7.5 mg/kg dose groups all had trends towards lower incidence of onset and longer time to onset of CIPN compared to the 1 mg/kg group. When pooled, patients in the 2.5-7.5 mg/kg dose groups compared to the 1 mg/kg dose group had a lower incidence of any-grade CIPN; 36% vs 60% (Chi-square test p=0.06) and a significantly longer time to onset; median not estimable vs 112 days (hazard ratio=0.48, log-rank p=0.04). In mice, vincristine and nab-paclitaxel caused long-lasting (2 weeks) CIPN. This was abrogated by co-administration of the anti-mouse IL1RAP surrogate antibody, without a negative impact on motor performance, blood values or animal body weight. Conclusions: Data from PDAC patients receiving nadunolimab + GN and experiments in preclinical models suggest that targeting IL1RAP by nadunolimab may combine antitumor activity with potent reduction of CIPN. Clinical trial information: NCT03267316 .

Effect of age on delivering chemotherapy to older adults with advanced pancreatic adenocarcinoma.

e13767 Background: Age is one of the most important risk factors for developing pancreatic adenocarcinoma (PDAC), 65% of the newly diagnosed cancer cases occur in individuals above 65 years of age (yo). The only potential cure for PDAC includes surgical resection, however, the majority of patients (70%) present with locally advanced/unresectable or metastatic PDAC (APDAC). Many oncologists remain hesitant to administer treatment to older adults for fear of perceived increased chemotoxicity risk and the thought of treatment intolerability. Methods: This retrospective cohort study included patients who were diagnosed and treated for APDAC within the Veterans Integrated Services Network (VISN) 8 which includes Veterans Affairs medical facilities in Florida, southern Georgia, Puerto Rico, and the U.S. Virgin Islands. Demographic data such as age, sex, race, ethnicity and treatment data such as chemotherapy and palliative care use were pulled from the VA Cancer Registry, available from Corporate Data Warehouse Data. We conducted a detailed chart review in the VA electronic health record to confirm stage and the eastern cooperative oncology group (ECOG) status at the time of diagnosis. Statistical analyses were conducted using GraphPad Prism 10.1.2 software. Analyses consisted of t-test for normally distributed continuous variables, chi-squared test for categorical variables and the Mann Whitney U test for the ECOG score of both groups. Results: Ninety-nine patients with APDAC above the of age 65 were identified from the period of June 1, 2017 till July 31, 2021. 46 received chemotherapy (C group) and 53 patients did not receive chemotherapy (NC group), characteristics (Table). The mean age for those in the C group were 72 years old (yo) vs 76 yo from the NC group with a P value of 0.0017 which was statistically significant. Looking at the age subgroups, the majority of the patients that received C, were of the 65-74 age subgroup (71%). The median ECOG for the NC group was 2 and that for C was 1 group. 39% of the C group received palliative care as opposed to 32% of the NC group with a P value of 0.532. Conclusions: Despite an acceptable ECOG range between 1 and 2, Age played an important factor in determining who received chemotherapy in APDAC. Studies other than ECOG are needed to help oncologists determine the fitness of APDAC patients and minimize hesitancy to deliver treatment. The involvement of palliative care in patients with APDAC was suboptimal and a push for more involvement of palliative care is needed. [Table: see text]

Altering the gut microbiome and TME in advanced liver cancers: A phase II study of nivolumab, tadalafil, and oral vancomycin in refractory HCC or liver-dominant metastatic CRC or PDAC.

e14642 Background: The gut-liver axis shapes the environment that promotes liver disease. In murine models of liver cancer, our group showed that altering gut microbiome with oral vancomycin can induce an antitumor effect by modifying bile acids (BA) that then recruit natural killer T cells (NKTC). However, these NKTC were met by an immunosuppressive counter-regulatory response where myeloid-derived suppressor cells (MDSC) accumulated, impairing their cytotoxicity. Tadalafil, a PDE5 inhibitor, can suppress these MDSC in the TME. The aim of this study was to examine if the immunomodulatory effects of oral vancomycin and tadalafil can enhance nivolumab activity in advanced primary liver cancer or liver metastases. Methods: This is a phase II study of adult patients (pts) with refractory hepatocellular carcinoma (HCC) or liver-dominant metastatic colorectal (mCRC) or pancreatic (mPDAC) cancers. Pts received IV nivolumab 480mg on D1, oral vancomycin 125mg every 6 hours on D1-21, and tadalafil 10mg once daily in 28d cycles until disease progression or unacceptable toxicity. Primary endpoint was best overall response (BOR) according to RECIST v1.1. Secondary endpoints included safety/tolerability and mOS. Correlative studies were performed on paired stool, blood, and tumor biopsies. Results: From 6/2019 - 7/2021, 22 heavily pretreated pts were enrolled: 6 HCC, 9 PDAC, 7 CRC. Median age was 63y (41-82), and 27% were female. Molecular testing showed MSS, TMB low to intermediate (1.57-13.35), and frequent mutations in KRAS and TP53. The BOR was SD (3pts, 18.75%), followed by PD (13pts, 81.25%); there were no PR or CR (ORR = 0%). Six pts had symptomatic deterioration prior to restaging scans. At a median follow-up of 4m (0.9-23.0m), all 22 pts had died of progressive disease with mOS of 4m. When stratified by site of origin, mOS was 9.5m (95%CI: 1.3-21.9m) in HCC and 3.6m (95%CI: 1.9-6.6m) in liver metastases (log-rank test, p=0.27). The most common grade 3-4 trAEs were electrolyte disturbances and anemia. The stool microbiome composition of Bacteroides species did not change with treatment as detected by shotgun sequencing. Plasma secondary BA, measured by the mixed meal test, decreased with treatment (p<0.05, n=18, two-way ANOVA). The classical to non-classical monocytes ratio increased with treatment in flow cytometry analysis of PBMC immune cells (p<0.05, n=14, one-way ANOVA). Transcriptomic analysis of treated liver tumor biopsies showed an increase in BA metabolism. Conclusions: Although well tolerated, the combination of oral vancomycin and tadalafil with nivolumab did not produce any meaningful clinical responses. Correlative studies suggested enhanced activation of BA metabolization, but TME immune profiling did not reveal substantial changes in regulatory suppressor cells or NKTC activity. Clinical trial information: NCT03785210 .

386P Exploratory biomarker analysis based on the PREDICT trial (AIO-PAK-0216) for response prediction to second-line nal-IRI/5-FU/FA chemotherapy (CTX) in metastatic PDAC patients (mPDAC Pts)

386P Exploratory biomarker analysis based on the PREDICT trial (AIO-PAK-0216) for response prediction to second-line nal-IRI/5-FU/FA chemotherapy (CTX) in metastatic PDAC patients (mPDAC Pts)

Abstract CT136: Phase Ib study of siltuximab and spartalizumab in advanced pancreatic cancer

Abstract Background: Pancreatic adenocarcinoma (PDAC) is an aggressive malignancy with dismal prognosis. Most patients present with advanced stages. Heightened levels of serum interleukin-6 (IL-6) are associated with carcinogenesis, immune suppression, and poor prognosis in PDAC. Preclinical data of dual inhibition of IL-6 and programmed death ligand-1 (PD-L1) facilitates CD8+ T-cell migration into pancreatic tumors and was effective in controlling tumor growth in syngeneic and genetically engineered PDAC mouse models. Siltuximab (Sil) is a chimeric monoclonal antibody which targets the IL-6 molecule specifically. Spartalizumab (Sparta) is a high-affinity ligand-blocking humanized IgG4 antibody against the PD-1 receptor. We developed a phase Ib/II trial to evaluate the safety, immunogenicity and preliminary antitumor activity of Sil and Sparta in metastatic PDAC (mPDAC). Methods: Patients (pts) with mPDAC who have progressed on at least one line of systemic chemotherapy were eligible for the trial. Other selected inclusion criteria were ≥18 years of age, ECOG PS 0-1 and measurable disease per RECIST v1.1. The phase Ib trial design is standard 3+3, with a primary endpoint of recommended phase II dose (RP2D). An additional 24 patients were planned for an expansion cohort. Sil was administered at escalating dose levels of 6 mg/kg (DL1) and 11 mg/kg (DL2), in combination with Sparta at 300 mg IV on day 1 of each 21-day cycle. Key secondary endpoints included overall response rate (ORR = CR + PR), progression-free survival (PFS) and overall survival (OS). Results: We enrolled 4 patients on DL1 and escalated to DL2/RP2D in the absence of a dose limiting toxicity (DLT). A total of 31 patients were subsequently treated at the RP2D (escalation + expansion). The median age was 68 years, 42% were male. Majority were White (63%) and 20% were Black. About 43% had head of pancreas primary tumors and 86% had liver involvement. The median number of lines of prior therapy was 3 (range 1-4). There was no objective response among the 4 patients on DL1; 1 had stable disease (SD) for 11 weeks as best response. 17 of 31 patients on RP2D had only a baseline assessment and came off study for progression of disease, prior to follow-up imaging assessment for response evaluation. Of the 14 RP2D patients with a follow-up assessment, ORR was 0% (3 were SD and 11 had progression of disease (PD) as best response), mPFS - 2.2 mos (95% CI: 1.9, 2.6), mOS - 5.5mos (95% CI: 2.8, 6.5). Treatment related adverse events (TRAEs) of any grade included fatigue (23%), anemia (18%), and increased liver enzymes (9.5%). There were no grade 4-5 TRAEs. Conclusions: The combination Sil/Sparta had an acceptable safety profile but did not elicit responses in advanced PDAC pts. Correlative studies using paired biopsies and blood are ongoing to determine how dual IL-6/PD-1 blockade impacts stromal and immune biomarkers in relationship to the clinical outcome measures. Funding and medications for the study were provided by Novartis and Recordati Rare Diseases Inc (NCT04191421) and NIH/NCI (R21CA266088). Citation Format: Olatunji B. Alese, Olumide Gbolahan, Kathleen M. Coleman, Yichun Cao, Sujata Kane, Sarah Craven, Emily Greene, Natalie Horvat, Andrew McDonald, Walid L. Shaib, Christina S. Wu, Mehmet Akce, Maria Diab, Jeffrey M. Switchenko, Gregory B. Lesinski, Bassel F. El-Rayes. Phase Ib study of siltuximab and spartalizumab in advanced pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT136.

Abstract NG08: Dissecting and quantifying pancreatic cancer plasticity using single-cell multiomics, lineage tracing and functional genomics reveals novel mediators of therapy resistance

Abstract NG08: Dissecting and quantifying pancreatic cancer plasticity using single-cell multiomics, lineage tracing and functional genomics reveals novel mediators of therapy resistance

Abstract CT082: Phase I study of autologous CD8+ and CD4+ transgenic T cells expressing high-affinity KRAS G12V mutation-specific T cell receptors (FH-A11KRASG12V-TCR) in patients with metastatic pancreatic, colorectal and non-small cell lung cancers with KRAS G12V mutations

Abstract Background: KRAS, the most common driver oncogene in human malignancies, has predictable mutations. 85% of RAS mutations occur at the Glycine (G) 12 position with G12V being amongst the most common. Cancers driven by mutant KRAS include pancreatic (PDAC), colorectal (CRC), and non-small cell lung (NSCLC) malignancies. The prognosis of patients with activating KRAS mutations remains poor. Preliminary anti-tumor activity has been observed in the clinic with T cell receptor (TCR) T cell therapies targeting KRAS mutations, but durable clinical benefit is lacking. Rationale: FH-A11KRASG12V-TCR is an autologous CD8+ and CD4+ transgenic T cell product expressing (1) an HLA-A11-restricted, high affinity KRASG12V mutation-specific T cell receptor (TCR) and (2) the wildtype CD8α/β coreceptor enabling CD4+ T cell recognition of KRAS G12V presented on an MHC class I allele mediating helper T cell activity and cytotoxicity. The TCR sequence is derived from the peripheral blood of a healthy HLA-A11+ adult based on a strong pre-clinical dataset. Methods: This is an ongoing, investigator-initiated, Phase 1, first-in-human, single-center, open-label dose escalation study of FH-A11KRASG12V-TCR. The aims are to evaluate the safety, tolerability, maximum tolerated dose (MTD), and preliminary anti-tumor activity of FH-A11KRASG12V-TCR in patients with advanced PDAC, CRC, and NSCLC who express the HLA-A11-restricted KRAS G12V mutation. Dose modification will be guided by the Bayesian Optimal Interval design (BOIN). Patients will initially be treated in cohorts of 3 at each dose level (DL). BOIN will be used to identify the recommended dose for subsequent patients. The planned target doses are 5 x 109 transgenic TCR T cells in DL 1 with dose escalation up to 15 x 109 transgenic TCR T cells in DL 3. This study enrolls patients who are 18 years or older, HLA-A*11:01-positive, with KRAS G12V mutated metastatic PDAC, CRC, or NSCLC. Patients must have progressed on or be intolerant of at least two lines of prior therapies including any targeted therapies indicated for their current malignancy. Patients undergo leukapheresis prior to treatment and receive lymphodepleting chemotherapy with either cyclophosphamide intravenously (IV) and fludarabine IV on days -6, -5, -4, and -3 or bendamustine IV on days -4 and -3. FHA11KRASG12V-TCR is administered IV on day 0. The dose-limiting toxicity observation period is 28 days. Patients may receive an additional FHA11KRASG12V-TCR IV infusion at the same or lower dose as soon as 28 days or up to 1 year after the first infusion. One patient enrolled to date and the study is actively recruiting (NCT06043713). Citation Format: Elena Gabriela Chiorean, Andrew Coveler, Rachael Safyan, Stacey Cohen, Sylvia Lee, Cecilia Yeung, Mary Redman, Thomas Schmitt, Aude Chapuis, Philip D. Greenberg. Phase I study of autologous CD8+ and CD4+ transgenic T cells expressing high-affinity KRAS G12V mutation-specific T cell receptors (FH-A11KRASG12V-TCR) in patients with metastatic pancreatic, colorectal and non-small cell lung cancers with KRAS G12V mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT082.

Results of a Randomized, Double-Blind, Placebo-Controlled, Phase 1b/2 Trial of Nabpaclitaxel + Gemcitabine ± Olaratumab in Treatment-Naïve Participants with Metastatic Pancreatic Cancer.

The efficacy and safety of olaratumab plus nabpaclitaxel and gemcitabine in treatment-naïve participants with metastatic pancreatic ductal adenocarcinoma was evaluated. An initial phase 1b dose-escalation trial was conducted to determine the olaratumab dose for the phase 2 trial, a randomized, double-blind, placebo-controlled trial to compare overall survival (OS) in the olaratumab arm vs. placebo arms. In phase 1b, 22 participants received olaratumab at doses of 15 and 20 mg/kg with a fixed dose of nabpaclitaxel and gemcitabine. In phase 2, 159 participants were randomized to receive olaratumab 20 mg/kg in cycle 1 followed by 15 mg/kg in the subsequent cycles (n = 81) or the placebo (n = 78) on days 1, 8, and 15 of a 28-day cycle, plus nabpaclitaxel and gemcitabine. The primary objective of the trial was not met, with a median OS of 9.1 vs. 10.8 months (hazard ratio [HR] = 1.05; 95% confidence interval [CI]: 0.728, 1.527; p = 0.79) and the median progression-free survival (PFS) was 5.5 vs. 6.4 months (HR = 1.19; 95% CI: 0.806, 1.764; p = 0.38), in the olaratumab vs. placebo arms, respectively. The most common treatment-emergent adverse event of any grade across both arms was fatigue. Olaratumab plus chemotherapy failed to improve the OS or PFS in participants with metastatic PDAC. There were no new safety signals.

Abstract 5901: A targetable secreted protein drives pancreatic cancer metastatic colonization and HIF1a nuclear retention

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an increasingly diagnosed cancer that kills 90% of afflicted patients. Thus, effective systemic therapy to PDAC remains a significant unmet medical need. NPTX1 is over-expressed in in vivoselected highly metastatic pancreatic cancer cells and promotes liver metastasis: Ex vivo mRNAseq of highly metastatic human and murine PDAC liver metastatic tumors identified neuronal pentraxin 1 (NPTX1) as a cancer secreted protein that becomes over-expressed during PDAC metastatic progression. CRISPRi-based silencing of NPTX1 reduced liver metastatic tumor burden by 15-fold in the highly metastatic clones. NPTX1 is over-expressed in PDAC liver metastases and predicts survival of PDAC patients: To assess NPTX1 protein expression in situ, two independent board-certified pathologists developed an immunohistochemical (IHC) scoring system and blindly scored NPTX1 expression in a large cohort of 125 primary and 47 liver metastatic PDAC tumors obtained through the rapid-autopsy program at MSKCC. Liver metastatic samples exhibited significantly higher IHC scores than primary PDAC samples (>2-fold increase). NPTX1 upregulation promotes cell growth under hypoxia: NPTX1 depletion suppressed growth of PDAC cells under hypoxia but not normoxia. Extracellular supplementation of recombinant NPTX1 was sufficient to rescue cell growth of NPTX1 depleted cells supporting the critical role of secreted NPTX1 in promoting cell growth under hypoxia. AMIGO2 is a cell surface NPTX1 receptor and mediates HIF1a nuclear retention via specific HIF1a residues: We next sought to identify the cell surface receptor for NPTX1. We reasoned that a receptor for NPTX1 may become upregulated as a feedback response to depletion of its ligand. mRNA sequencing of ex vivo NPTX1-depleted tumors identified AMIGO2. AMIGO2 promoted nuclear retention of HIF1a and conversely, its depletion drove the degradation of HIF1a. HIF1a/hypoxia reporter assay revealed that AMIGO2 depletion led to 300-fold reduction of HIF1a activity. Overexpression of a phosphomimetic construct at HIF1a serine 641 and 643, not a full length HIF1a ORF rescued AMIGO2 mediated HIF1a reporter signal reduction. Therapeutic targeting of NPTX1-AMIGO2 axis in primary and metastatic PDAC: Through phage display and mouse immunization campaigns, we identified 6 human IgG1 and 1 murine IgG1 antibodies that exhibited high affinity binding to human NPTX1. We identified anti- NPTX1 murine IgG1 antibody 31B01(31B01) as a lead antibody that substantially and significantly suppressed liver metastatic colonization by >80% outperforming gemcitabine. We also tested the impact of 31B01 on the pancreas orthotopic tumor growth. 31B01 suppressed orthotopic patient derived organoid (PDO) growth (>70% reduction), caused a regression response and dramatically extended the overall survival of treated mice harboring PDAC PDO. Citation Format: Norihiro Yamaguchi, Gloria Wu, Ethan Ravetch, Mai Takahashi, Abdul G. Khan, Akimasa Hayashi, Wenbin Mei, Dennis Hsu, Elisa de Stanchina, Ivo C. Lorenz, Christine Iacobuzio-Donahue, Sohail F. Tavazoie. A targetable secreted protein drives pancreatic cancer metastatic colonization and HIF1a nuclear retention [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 5901.

Abstract 4134: The abscopal effect of combination IRE with αPD-1 treatment against PDACs

Abstract Pancreatic ductal adenocarcinoma (PDAC) is associated with a high capacity of metastatic dissemination, which results in a dismal 5-year relative survival rate. Irreversible electroporation (IRE) represents an innovative intervention utilizing short high-voltage electric pulses to induce cell death through either permanent membrane lysis or disruption of cellular homeostasis. Previous studies from our lab have demonstrated that the combination of IRE and immune checkpoint blockade using anti-PD-1 antibody (αPD-1) enhances the infiltration of CD8+ cytotoxic T cells, significantly prolonging survival in an orthotopic murine PDAC model. However, the impact of IRE/αPD-1 on metastatic PDAC tumors, known as the abscopal effect, remains unclear. In this investigation, we bilaterally implanted C57BL/6J mice with subcutaneous KRAS* PDAC tumors, treating the right flank tumors with or without IRE, in conjunction with or without αPD-1 administered intraperitoneally. Tumor growth in both the treated (with or without IRE) and untreated (abscopal) left flank tumors was closely monitored until humane euthanasia or long-term survival. In a separate study, mice serum and tumor tissues were collection on the 5th day post-IRE/αPD-1 treatment. Luminex cytokine assays were conducted on the collected serum, and immunostaining was performed on tumor tissue. Results demonstrated significantly enhanced antitumor activity in both IRE-treated and untreated tumors on mice treated with combined IRE and αPD-1, leading to a marked extension of overall survival. Luminex cytokine assays revealed a substantial increase in crucial cytokines, including IL-2, IFN-gamma, IL-18, IL-19, and IL-3, known for their pivotal roles in fostering cytotoxic T lymphocyte development, promoting T cell differentiation into effector T cells, and facilitating the recruitment of effector CD8+ T cells to the tumor microenvironment. Moreover, immunofluorescence staining of tumor tissue illustrated a notable accumulation of CD169+ macrophages in IRE-treated tumors compared to untreated tumors. Tumors from the combined IRE with αPD-1 group exhibited increased CD8+ T cell accumulation compared to other groups. These data suggest IRE combined with PD-1 blockade promotes robust antitumor immune, leading to systemic antitumor activity and robust abscopal effect. Citation Format: Qizhen Cao, Nicholas A. Egan, Weiyi Peng, Chun Li. The abscopal effect of combination IRE with αPD-1 treatment against PDACs [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 4134.

Abstract 1194: Understanding radiation and immunotherapy induced cell state shifts in the pancreatic tumor microenvironment

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with few effective treatment options. It is characterized by a highly desmoplastic tumor microenvironment and a paucity of dendritic cells, leading to low immune cell infiltration and poor outcomes with immunotherapy treatments that are highly effective in other cancers. In a recent pilot study, metastatic PDAC patients who had progressed on chemotherapy were treated with a combination of dual immune checkpoint blockade (ICB) therapy and radiation which resulted in an 18% overall response rate (ORR) and 29% disease control rate (DCR). This led to a phase 2 study in order to further test this combination with the goal of deep correlative analysis to understand the determinants of immunotherapy response and resistance. In this follow up there was a 3.6% ORR, 10.7% DCR, progression free survival (PFS) of 2.3 months, and a single patient with complete response. We collected 36 samples from 23 patients including primary pancreas tumor tissue and liver metastases, and 13 pairs of pre and on treatment biopsies. We performed single-nucleus and paired single-cell RNA and TCR sequencing on these samples to provide comprehensive insight into the cell types and biology present in this unique tumor microenvironment. Using supervised non-negative matrix factorization we have identified both previously established and novel gene programs that co-vary between cell types. Within the various tissue sites we have identified differing proportions of basal to classical tumor cell types and a distinct shift towards the classical state post-radiation. Of particular interest is a group of interferon related gene programs present within epithelial cell subtypes, C1QC+ and MHCII+ macrophages, and CD14+/CD16+ monocytes that indicate cell type specific responses to treatment. Focusing on the T cells, we found a distinct shift towards exhausted or proliferating states on treatment and using TCR sequencing data we have identified novel and expanding clones on treatment, largely consisting of those same cell subtypes. We also collected spatial transcriptomics data on a subset of patient samples, and analysis is ongoing to further confirm the cell type relationships identified in single-cell resolution data, along with spatial localization of basal to classical tumor states. This vast multimodal dataset allows us novel insight into the radiation and dual ICB induced cellular state shifts in the tumor microenvironment. Citation Format: Milan Parikh, Ryan Park, Aparna R. Parikh, Julie L. Koenig, Leon Pappas, Moshe Sade-Feldman, Lynn Bi, Nicole Carzo, Tarin M. Grillo, Islam Baiev, Olanike Asupoto, Irena Gushterova, Tom LaSalle, Anna Gonye, Emily Blaum, David P. Ryan, David T. Ting, Theodore S. Hong, Dana Pe'er, Nir Hacohen, Arnav Mehta. Understanding radiation and immunotherapy induced cell state shifts in the pancreatic tumor microenvironment [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 1194.

Molecular Classification and Pathogenesis of Pancreatic Adenocarcinoma and Targeted Therapies: A Review.

Pancreatic adenocarcinoma (PDAC) is disease with a 5-year survival of only 12%. Many patients with PDAC present with late-stage disease and even early-stage disease can often be characterized by an aggressive tumor biology. Standard therapy for metastatic PDAC consists mainly of chemotherapy regimens like FOLFIRINOX, FOLFOX, or gemcitabine and nab-paclitaxel. Research has focused on sequencing PDAC tumors to understand better the mutational landscape and transcriptomics of PDAC with the goal to develop targeted therapies. Targeted therapies may potentially minimize the toxic risks of chemotherapy and provide a long-term survival benefit. We herein review the underlying molecular pathogenesis of PDAC, as well as the classification schema created from current sequencing data, and recent updates related to targeted therapy for PDAC.

A multicenter, randomized phase 2 study to establish combinations of CBP501, cisplatin and nivolumab for ≥3rd-line treatment of patients with advanced pancreatic adenocarcinoma

BackgroundThere is no standard of care for ≥ 3rd-line treatment of metastatic pancreatic adenocarcinoma (PDAC). CBP501 is a novel calmodulin-binding peptide that has been shown to enhance the influx of platinum agents into tumor cells and tumor immunogenicity. This study aimed to (1) confirm efficacy of CBP501/cisplatin/nivolumab for metastatic PDAC observed in a previous phase 1 study, (2) identify combinations that yield 35% 3-month progression-free survival rate (3MPFS) and (3) define the contribution of CBP501 to the effects of combination therapy. MethodsCBP501 16 or 25 mg/m2 (CBP(16) or CBP(25)) was combined with 60 mg/m2 cisplatin (CDDP) and 240 mg nivolumab (nivo), administered at 3-week intervals. Patients were randomized 1:1:1:1 to (1) CBP(25)/CDDP/nivo, (2) CBP(16)/CDDP/nivo, (3) CBP(25)/CDDP and (4) CDDP/nivo, with randomization stratified by ECOG PS and liver metastases. A Fleming two-stage design was used, yielding a one-sided type I error rate of 2.5% and 80% power when the true 3MPFS is 35%. ResultsAmong 36 patients, 3MPFS was 44.4% in arms 1 and 2, 11.1% in arm 3% and 33.3% in arm 4. Two patients achieved a partial response in arm 1 (ORR 22.2%; none in other arms). Median PFS and OS were 2.4, 2.1, 1.5 and 1.5 months and 6.3, 5.3, 3.7 and 4.9 months, respectively. Overall, all treatment combinations were well tolerated. Most treatment-related adverse events were grade 1–2. ConclusionsThe combination CBP(25)/(16)/CDDP/nivo demonstrated promising signs of efficacy and a manageable safety profile for the treatment of advanced PDAC. Clinical trial registrationNCT04953962

BNT321, a novel monoclonal antibody targeting sialyl Lewis A: Phase 1 monotherapy and combination with mFOLFIRINOX in patients with advanced CA19-9 expressing cancers.

654 Background: BNT321 is a high affinity human monoclonal antibody targeting the sialyl Lewis A epitope of CA19-9. This Phase 1/1b dose escalation/expansion study investigated BNT321 as monotherapy and in combination with mFOLFIRINOX (mFFX) in patients (pts) with advanced CA19-9 expressing cancers. Methods: Eligible pts: progressive CA19-9 expressing solid tumors, liver transaminases ≤ 2 x ULN, bilirubin WNL, ECOG PS 0-1. BNT321 given on Qwk, Q2wk, and Q4wk schedules. Lead in dose (1 mg/kg given 1 wk prior to assigned dose) evaluated on Q2wk + Q4wk schedules. BNT321 + mFFX given Q2wk as 1L or 2L metastatic therapy (1L+2L met). Dexamethasone given as premedication. Endpoints: safety, MTD, RP2D, efficacy, PK, changes in serum CA19-9. Results: 82 pts received BNT321 monotherapy and 15 received BNT321 + mFFX. BNT321 monotherapy MTD was 2 mg/kg Q2wk and MTD with mFFX was 1 mg/kg. Schedule and lead in dose did not significantly alter MTD. Dose limiting toxicities (DLTs) for BNT321 monotherapy and with mFFX were elevations in hepatic AST and ALT with or without bilirubin elevations. These events generally occurred early (cycle 1), resolved with drug hold, and did not preclude subsequent reduced dose BNT321. Frequent related AEs (total %/ > grade 3 %) for BNT321 include increased ALT (39%/19%), AST (35%/12%), T bilirubin (27%/9%), fatigue (21%/0%), infusion related reaction (IRR) (17%/1%) and for BNT321 + mFFX fatigue (67%/0%), increased AST (40%/27%), ALT (33%/20%), diarrhea (33%/0%), nausea (20%/0%). At combination MTD (n=7): fatigue (71%/0%), diarrhea (29%/0%), IRR (29%/0%), nausea (28%/0%), increased AST (14%/14%), ALT (14%/14%). BNT321 demonstrated a T1/2 of 11.75 days + dose proportional Cmax and AUC with intra-patient variability. Enhanced clearance observed among pts with higher baseline (BL) serum CA19-9. For BNT321 monotherapy stable disease (RECIST 1.1) was best response, with time on study > 90 days and > 180 days in > 20% and 10% of pts, respectively. Correlation between time on study and post BL normalization of CA19-9 was observed. For BNT321 + mFFX (1L+2L met), PRs were observed in 3/11 (27%) response evaluable pts who had time on study 10.0-15.8 months. Conclusions: BNT321 and BNT321 + mFFX MTDs were 2 mg/kg and 1 kg/kg, respectively. DLTs were hepatic AST, ALT and T bilirubin elevations which were generally cycle 1 and did not preclude subsequent BNT321 at reduced dose. BNT321 monotherapy resulted in disease stabilization and prolonged time on study (> 90 days for > 20%) in pts with advanced line, metastatic PDAC and other CA19-9+ cancers. BNT321 significantly decreased CA19-9 in the majority of pts and PK was similar to other human monoclonal antibodies. BNT321 + mFFX (1L+2L met) demonstrated multicycle tolerability and a 27% PR rate with 10+ months duration on study. BNT321 + mFFX is being evaluated in resected PDAC in the adjuvant setting. Clinical trial information: NCT02672917 .

A phase I/II study of antroquinonol in combination with nab-paclitaxel and gemcitabine for patients with metastatic pancreatic cancer.

648 Background: The survival of metastatic pancreatic cancer (mPC) is still disappointing though advancement in recent regimens. Antroquinonol, a new chemical entity, has been proposed for the treatment of neoplasms. In this phase I/II trial, we investigated the dose and efficacy of antroquinonol combined with gemcitabine and nab-paclitaxel (Gem/Nab-P) on mPC patients. Methods: Patients with chemo-naive, metastatic PDAC were enrolled. In the phase I, run-in drug-drug interaction (DDI) and dose escalation in a 3 + 3 designed to determine the maximal tolerated dose (MTD) of antroquinonol for phase II study. Gem/Nab-P (gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on days 1, 8, and 15 every 4 weeks) was given from cycle 0 in phase I. The dose of antroquinonol was escalated from 200mg orally three times a day since the first cycle of Gem/Nab-P. The primary end points were median PFS and 6-month PFS rate. This trial is registered at ClinicalTrials.gov: NCT03310632. Results: In the phase I study of 15 patients, the MTD of antroquinonol was 300mg tid. In the phase II study of 40 patients, the median PFS was 5.3 (95% CI: 3.7–7.5) months and 6-month PFS rate was 40% (95% CI: 21%–57%), whereas median OS was 12.6 (95% CI: 8.8–15.8) months and12-month OS rate was 59.9% (95% CI: 37.8%–76.4%), respectively. The adverse events including hematological and non-hematological classes were decreased in the antroquinonol plus Gem/Nab-P, the GI discomforts were increased but manageable. Conclusions: In this phase I/II trial, antroquinonol plus Gem/Nab-P showed good efficacy in survival and less adverse events than a first-line strategy of Gem/Nab-P for mPC patients. Clinical trial information: NCT03310632 . [Table: see text]