FOLFIRINOX Therapy Research Articles

Use of empegfilgrastim for primary prevention of febrile neutropenia in patients receiving myelosuppressive therapy. Experience of the Arkhangelsk Clinical Oncological Dispensary

Background. Granulocyte colony-stimulating factors (G-CSFs) are used in oncology practice for prevention of febrile neutropenia caused by cytotoxic chemotherapy. Despite the proven safety of G-CSFs use in randomized clinical trials and in real clinical practice, clinicians have questions about the tolerability of this group of drugs.Aim. To demonstrate the safety profile of a long-acting G-CSF produced in Russia which was used to prevent febrile neutropenia and maintain dose intensity of drug therapy in patients with various solid tumors undergoing chemotherapy at the Arkhangelsk Clinical Oncological Dispensary.Materials and methods. The retrospective analysis included patients with a confirmed diagnosis of malignant neoplasm who received various chemotherapy regimens that required the inclusion of G-CSF. For primary prevention of febrile neutropenia, patients were prescribed empegfilgrastim (Extimia®) at a dose of 7.5 mg subcutaneously once per course of chemotherapy.Results. Data of 151 patients were analyzed for the period from July 2021 to April 2023. The average age was 57 years (28–75). The group of elderly patients (over 65 years) consisted of 38 (25 %) patients. The majority of patients were diagnosed with breast cancer (56 (37 %) patients) and gastric cancer (37 (25 %) patients). The number of empegfilgrastim injections over the entire observation period was 773. Adverse reactions associated with the use of empegfilgrastim were registered in 13 (8.6 %) patients, the most common of which was grade 1–2 leukocytosis according to the CTCAE v.5 classification. One patient developed a serious adverse reaction: grade 4 neutropenia according to the CTCAE v.5 classification. A subgroup of patients with metastatic pancreatic cancer treated with FOLFIRINOX was analyzed separately to assess the relative dose intensity of the chemotherapy courses. Nine patients with metastatic pancreatic cancer received FOLFIRINOX therapy with a median of 8 (5–12) courses. A total of 69 chemotherapy cycles were administered to 9 patients with a median of 7.5 (2–13) cycles. The relative dose intensity of the chemotherapy courses was 83.71 ± 19.33.Conclusion. Empegfilgrastim has shown a favorable safety and tolerability profile in patients with various solid tumors in real-world clinical practice including the highly toxic FOLFIRINOX regimen.

Long-Duration Neoadjuvant Therapy with FOLFIRINOX Yields Favorable Outcomes for Patients Who Undergo Surgery for Pancreatic Cancer

BackgroundIn 2023 alone, it’s estimated that over 64,000 patients will be diagnosed with PDAC and more than 50,000 patients will die of the disease. Current guidelines recommend neoadjuvant therapy for patients with borderline resectable and locally advanced PDAC, and data is emerging on its role in resectable disease. Neoadjuvant chemotherapy may increase the number of patients able to receive complete chemotherapy regimens, increase the rate of microscopically tumor-free resection (R0) margin, and aide in identifying unfavorable tumor biology. To date, this is the largest study to examine surgical outcomes after long-duration neoadjuvant chemotherapy for PDAC.Methods Retrospective analysis of single-institution data.ResultsThe routine use of long-duration therapy in our study (median cycles: FOLFIRINOX = 10; gemcitabine-based = 7) is unique. The majority (85%) of patients received FOLFIRINOX without radiation therapy; the R0 resection rate was 76%. Median OS was 41 months and did not differ significantly among patients with resectable, borderline-resectable, or locally advanced disease.ConclusionsThis study demonstrates that in patients who undergo surgical resection after receipt of long-duration neoadjuvant FOLFIRINOX therapy alone, survival outcomes are similar regardless of pretreatment resectability status and that favorable surgical outcomes can be attained.

A randomized, multi-center, phase 2 study of ivaltinostat (Ival) plus capecitabine (Cape) versus capecitabine alone in the maintenance setting in patients with metastatic pancreatic adenocarcinoma (mPDAC).

TPS4206 Background: Front-line chemotherapy for patients (pts) with advanced or mPDAC typically consists of mFOLFIRINOX or gemcitabine/nab-paclitaxel given until disease progression or intolerable toxicity. For pts with durable disease control on front-line treatment, maintenance therapy that can effectively delay disease progression while preserving quality of life with minimal cumulative toxicity is highly desirable. Ivaltinostat (ival) is a pan-histone deacetylase inhibitor that increases histone acetylation, suppresses PDAC cell proliferation, and promotes apoptosis in PDAC cell lines. Preclinical data demonstrated synergy with 5-FU/cape in mouse models. RP2D of the Phase 1b combination study of ival and cape in advanced pancreatic cancer was ival 250mg/m2 IV on days 1 and 8 with cape 1000mg/m2 po days 1-14 of a 21-day cycle. Both ival and cape treatment-related AEs >15% were fatigue, nausea, diarrhea, and decreased appetite. Palmar-plantar erythrodysaesthesia syndrome was also commonly observed; all events were attributed to cape. PK and PD demonstrated dose proportionality. Overall and progression-free survival (PFS) were immature, but 70% of pts who enrolled with measurable disease had stable disease as best response. Several pts remained on study with the longest duration of response about 10 months, as of the data cut off for ASCO GI 2024. Based on this data, a randomized phase 2 study is being conducted comparing the combination of ival and cape versus cape alone in the maintenance setting for pts with mPDAC after first line FOLFIRINOX, mFOLFIRINOX or NALFIRINOX therapy. Methods: Key eligibility criteria for the randomized Phase 2 study include: mPDAC; no evidence of disease progression following at least 16 weeks of front-line FOLFIRINOX or NALIRIFOX at full or modified doses; ECOG PS 0-1; and no known germline BRCA1/2 mutation. A total of 52 pts will be randomized 1:1 to receive cape with or without ival until disease progression, with tumor assessments occurring at 6-week intervals. The primary endpoint is investigator-adjudicated PFS, and the primary analysis will compare PFS distributions in the ival/cape and cape alone arms using a one-sided log rank test with an alpha=0.10. The assumed 6-mo PFS rates are 35% (cape), based on historic data, and 60% (ival/cape), corresponding to an HR of 0.487. Enrollment in the phase 2 study began in January 2024 across multiple sites in the US. Accrual is anticipated to complete 4Q2024. Clinical trial information: NCT05249101 .

Development of transcriptomic tools for predicting the response to individual drug of the mFOLFIRINOX regimen in patients with metastatic pancreatic cancer.

The utilization of modified FOLFIRINOX (mFFX) therapy has shown notable advancements in patient outcomes in both localized and metastatic PDAC. Nevertheless, the effectiveness of mFFX treatment comes at the cost of elevated toxicity, leading to its restriction to patients with adequate performance status. Consequently, the administration of mFFX is contingent upon patient performance rather than rational criteria. The ideal scenario would involve the ability to assess the sensitivity of each drug within the mFFX regimen, minimizing unnecessary toxicity without compromising clinical benefits. We developed transcriptomic signatures for each drug of the mFFX regimen (5FU, oxaliplatin and irinotecan) by integrating transcriptomic data from PDC, PDO and PDX with their corresponding chemo-response profiles to capture the biological components responsible for the response to each drug. We further validated the signatures in a cohort of 167 patients with advanced and metastatic PDAC. All three signatures captured high responder patients for OS and PFS in the mFFX arm exclusively. We then studied the response of patients to 0, 1, 2 and 3 drugs and we identified a positive correlation between the number of drugs predicted as sensitive and the OS and PFS, and the with objective response rate. We developed three novel transcriptome-based signatures which define sensitivity for each mFFX components that can be used to rationalize the administration of the mFFX regimen in patients with metastatic pancreatic cancer and could help to avoid unnecessary toxic effects.

Pancreatic ductal adenocarcinoma (intestinal-type differentiation) presenting as ovarian metastases: A case report

Introduction: Metastasis of pancreatic adenocarcinoma to the ovaries is uncommon and can clinically present similarly to primary ovarian disease, presenting challenges for diagnosis. Immunohistochemical staining is typically useful in distinguishing ovarian primaries from ovarian metastasis. A newer and rarer variant of pancreatic adenocarcinoma, that with intestinal-type differentiation, has not previously been reported as metastasizing to the ovary. Its diagnosis is particularly difficult due to the overlap in staining patterns with primary ovarian neoplasms. Case Report: This case report presents the case of a 60-year-old female who presented with non-specific abdominal symptoms and was found to have a large adnexal mass. Imaging showed additional lesions in the peritoneum, pancreas, and liver. She underwent biopsy with morphology and immunohistochemical staining consistent with pancreatic ductal adenocarcinoma with intestinal-type differentiation. She was started on FOLFIRINOX therapy but ultimately opted to pursue comfort care due to disease progression. Conclusion: Although rare, with this being the first report of this disease course to our knowledge, clinicians should be aware of this possibility, as it impacts choice of treatment.

Management of Metastatic Pancreatic Cancer-Comparison of Global Guidelines over the Last 5 Years.

Pancreatic cancer (PC) is usually diagnosed at an advanced stage of its development, which results in lower overall survival (OS). Prognosis is also poor even with curative-intent surgery. Approximately 80% of patients with localized PDAC have micrometastases at the time of diagnosis, which leads to a worse prognosis than in other cancers. The objective of this study is to present the progress in the treatment of metastatic pancreatic cancer based on the recommendations of oncological scientific societies, such as ESMO, NCCN, ASCO, NICE and SEOM, over the last 5 years. Combined FOLFIRINOX therapy is mostly a recommended therapy among patients with good performance statuses, while gemcitabine is recommended for more fragile patients as a first-line treatment. The newest guidelines suggest that molecular profiling of the tumor should be the first step in determining the course of treatment. The use of modern molecular therapies in patients with specific gene mutations should extend the survival of patients with this disease.

Predicting conversion surgery in patients with locally advanced pancreatic cancer after modified FOLFIRINOX treatment.

/Objective: FOLFIRINOX therapy (FFX) for locally advanced pancreatic cancer (LAPC) is increasingly recognized as a potent neoadjuvant therapy that enables transition to conversion surgery (CS). However, predictors of CS achievement after chemotherapy are controversial. This study aimed to demonstrate the efficacy of CS after modified FFX (mFFX) in patients with LAPC and to identify and score predictors of CS. From January 2014 to December 2018, patients with LAPC who received mFFX as a first-line treatment were screened. Patients' overall survival was compared with and without CS. Moreover, the predictors for CS were analyzed to create scores for the CS factors. Forty-three patients received mFFX, including 20 patients who underwent CS (CS group, 46.5%). R0 resection was achieved in 16 patients (80%). The median survival time was 39.2 months (95% confidence interval [CI] 17.3-53.8) for the CS group and 16 months (95% CI 10.5-22.6) for the non-CS group (P<0.001; hazard ratio 0.25, 95% CI 0.12-0.54). Since an average relative dose intensity of ≥90%, tumor reduction of ≥35%, and carbohydrate antigen 19-9 reduction of ≥70% or normalization were associated with successful transition to CS in the multivariate analysis, these factors were scored (CS score, range 0-3). All of the patients in the CS group fell into the 2-3 category, compared with 2 of 23 patients in the non-CS group (P<0.001). CS after FFX contributes to the long-term survival of patients with LAPC. The CS score could be an indicator for transition to CS.

Pancreaticoduodenal resection for primary unresectable pancreatic head cancer after neoadjuvant chemotherapy

The paper describes a clinical case of successful combined modality treatment of a patient with pancreatic ductal adenocarcinoma with extension to the superior mesenteric artery and vein. The examination revealed an unresectable tumor. Twelve courses of FOLFIRINOX therapy showed good results, upon which the treatment plan was changed and a typical pancreaticoduodenal resection was performed. Pathological examination revealed ductal adenocarcinoma urT1N0M0R0, TRG 2. The postoperative period was uneventful. The efficacy of drug treatment for ductal adenocarcinoma has increased markedly in recent years. Neoadjuvant chemotherapy can be considered the most effective for locally advanced tumors.

FOLFIRINOX-loaded immunoliposome-like particles for localized pancreatic cancer treatment

FOLFIRINOX therapy, a combination of oxaliplatin, 5-fluorouracil, irinotecan, and leucovorin, is one of the most applied treatment schemes for pancreatic adenocarcinoma. However, because this form of treatment causes significant side effects, it has become important to reduce the dose of the drug administered to the patients and target the drug to the tumor tissue. This study presents the liposomal type of this therapy scheme to demonstrate its applicability to localized chemotherapy strategies. Briefly, lipid-based liposome-like particles have been synthesized and physically, chemically, and thermally characterized. Following the decoration of the liposome-like particles with anti-Mucin-4, a malignancy marker for pancreatic adenocarcinoma, the encapsulation efficiency of the FOLFIRINOX components and release profile of the FOLFIRINOX-loaded liposome-like particles have been analyzed using the high-pressure liquid chromatography. Cytotoxicity analyses and cellular encapsulation studies of Mucin-4-targeted liposome-like particles were performed in HPAF-II (ascites-derived cell, Mucin-4(+)) and PANC-I (tumor-derived cell, Mucin-4(−)) cells. The results have shown that Mucin-4-targeted liposome-like particles enter HPAF-II cells more selectively than PANC-I cells. Besides, after the FOLFIRINOX application, a significant difference was observed between the viability of HPAF-II and PANC-I cells at 100-fold dilution. In genotoxicity and apoptosis analysis, it was found that drug-loaded liposome-like particles caused DNA damage in cancer cells with the increase in concentration. The study suggests that Mucin-4-targeted liposome-like particles can provide superior patient welfare and a promising treatment model for pancreatic adenocarcinoma and can be used in localized chemotherapy applications due to their long-term stability, nanoscale size, and target-driven nature.

Abstract 979: Development of a methylation-based classifier to identify pancreatic adenocarcinoma subtype

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) demonstrates variable prognosis and response to first-line FOLFIRINOX therapy depending on molecular subtype; patients with classical tumors showed a greater response compared to basal-like tumors. Identifying molecular subtype may inform treatment approaches, but current subtyping schemas rely on tumor biopsies which are invasive and can be technically challenging. Blood based epigenetic assays are commercially available, and identification of subtype-associated epigenetic modifications may provide a path toward blood-based PDAC molecular subtyping. We analyzed methylation levels and developed a subtype classifier using methylation data on PDAC tumors. Using this classifier, we then developed a methylation-specific qPCR assay to subtype PDAC tumors by analyzing methylation at particular sites in tumor DNA which may now be further adapted to more facile liquid biopsy approaches. Methods: Using methylation data (n=150) from TCGA PAAD, we applied a random forest (RF) model followed by a k-Top Scoring Pairs (k-TSP) algorithm to develop a methylation site-based classifier that allows prediction of subtype by comparing methylation levels between paired sites. The classifier was validated on two independent datasets, including ICGC (n=82) and patient-derived xenografts (PDXs) (n=21). We designed methylation-specific qPCR primers for these sites and validated their specificity with fully methylated or fully unmethylated DNA. Using genomic DNA extracted from 10 PDAC PDXs of known molecular subtype, we obtained methylation levels at sites identified by the classifier via a SYBR Green-based qPCR assay. We then used our classifier to predict subtype of the PDX tumors. Results: We validated our RF-kTSP methylation subtype classifier on two independent cohorts and predicted subtype using 20 methylation sites. In ICGC, we found balanced accuracy=0.94, AUROC=0.98, AU-PR=0.89. In PDX PDAC tumors, we found balanced accuracy=1, AUROC=1, AU-PR=1. We designed 14/20 primers for qPCR and confirmed specificity for methylated DNA. Using 14/20 methylation sites, we achieved 80% correct subtype prediction of 10 PDX tumors (5/5 basal-like, 3/5 classical). Conclusion: We have developed a methylation-based classifier that accurately and replicably predicts PDAC subtype. We continue to develop a qPCR assay for PDAC subtype that so far has 80% accuracy using 14/20 probes. We are completing validation of the remaining 6 primers and correlating methylation levels at each site with those obtained from EPIC array methylation analysis. The long-term goal is to apply our complete set of primers in a digital droplet PCR assay that will be amenable for subtyping using circulating tumor DNA (ctDNA). Citation Format: Zachary Schrank, Des Weighill, Hannah Thel, Hannah Trembath, Ashley Morrison, Jen Jen Yeh. Development of a methylation-based classifier to identify pancreatic adenocarcinoma subtype [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 979.

Feasibility, safety, and efficacy of stereotactic body radiotherapy combined with intradermal heat-killed mycobacterium obuense (IMM-101) vaccination for non-progressive locally advanced pancreatic cancer, after induction chemotherapy with (modified)FOLFIRINOX – The LAPC-2 trial

Background and purposeIn this phase I/II trial, non-progressive locally advanced pancreatic cancer (LAPC) patients after (modified)FOLFIRINOX therapy were treated with stereotactic body radiotherapy (SBRT) combined with heat-killed mycobacterium (IMM-101) vaccinations. We aimed to assess safety, feasibility, and efficacy of this treatment approach. Materials and methodsOn five consecutive days, patients received a total of 40 Gray (Gy) of SBRT with a dose of 8 Gy per fraction. Starting two weeks prior to SBRT, they in addition received six bi-weekly intradermal vaccinations with one milligram of IMM-101. The primary outcomes were the number of grade 4 or higher adverse events and the one-year progression free-survival (PFS) rate. ResultsThirty-eight patients were included and started study treatment. Median follow-up was 28.4 months (95 %CI 24.3 – 32.6). We observed one grade 5, no grade 4 and thirteen grade 3 adverse events, none related to IMM-101. The one-year PFS rate was 47 %, the median PFS was 11.7 months (95 %CI 11.0 – 12.5) and the median overall survival was 19.0 months (95 %CI 16.2 – 21.9). Eight (21 %) tumors were resected, of which 6 (75 %) were R0 resections. Outcomes were comparable with the outcomes of the patients from the previous LAPC-1 trial, in which LAPC patients were treated with SBRT, without IMM-101. ConclusionCombination treatment with IMM-101 and SBRT was safe and feasible for non-progressive locally advanced pancreatic cancer patients after (modified)FOLFIRINOX. No improvement in the progression-free survival could be demonstrated by adding IMM-101 to SBRT.

Pre-treatment inflamed tumor immune microenvironment is associated with FOLFIRINOX response in pancreatic cancer.

Pancreatic adenocarcinoma (PDAC) is an aggressive tumor with limited response to both chemotherapy and immunotherapy. Pre-treatment tumor features within the tumor immune microenvironment (TiME) may influence treatment response. We hypothesized that the pre-treatment TiME composition differs between metastatic and primary lesions and would be associated with response to modified FOLFIRINOX (mFFX) or gemcitabine-based (Gem-based) therapy. Using RNAseq data from a cohort of treatment-naïve, advanced PDAC patients in the COMPASS trial, differential gene expression analysis of key immunomodulatory genes in were analyzed based on multiple parameters including tumor site, response to mFFX, and response to Gem-based treatment. The relative proportions of immune cell infiltration were defined using CIBERSORTx and Dirichlet regression. 145 samples were included in the analysis; 83 received mFFX, 62 received Gem-based therapy. Metastatic liver samples had both increased macrophage (1.2 times more, p < 0.05) and increased eosinophil infiltration (1.4 times more, p < 0.05) compared to primary lesion samples. Further analysis of the specific macrophage phenotypes revealed an increased M2 macrophage fraction in the liver samples. The pre-treatment CD8 T-cell, dendritic cell, and neutrophil infiltration of metastatic samples were associated with therapy response to mFFX (p < 0.05), while mast cell infiltration was associated with response to Gem-based therapy (p < 0.05). Multiple immunoinhibitory genes such as ADORA2A, CSF1R, KDR/VEGFR2, LAG3, PDCD1LG2, and TGFB1 and immunostimulatory genes including C10orf54, CXCL12, and TNFSF14/LIGHT were significantly associated with worse survival in patients who received mFFX (p = 0.01). There were no immunomodulatory genes associated with survival in the Gem-based cohort. Our evidence implies that essential differences in the PDAC TiME exist between primary and metastatic tumors and an inflamed pretreatment TiME is associated with mFFX response. Defining components of the PDAC TiME that influence therapy response will provide opportunities for targeted therapeutic strategies that may need to be accounted for in designing personalized therapy to improve outcomes.

Incidence of and risk factors for severe neutropenia during treatment with the modified FOLFIRINOX therapy in patients with advanced pancreatic cancer

Although FOLFIRINOX (l-Leucovorin/5-FU/Irinotecan/Oxaliplatin) is established as one of the standard therapies for patients with metastatic pancreatic cancer, the modified FOLFIRINOX (mFOLFIRINOX) is often used in clinical practice to reduce the incidence of toxicities. Febrile neutropenia (FN) and severe neutropenia during FOLFIRINOX are especially frequently observed in Japanese patients. In this study, we evaluated the incidence of FN and severe neutropenia, and explored the risk factors for severe neutropenia in patients receiving treatment with mFOLFIRINOX. The data of patients who had received mFOLFIRINOX between December 2013 and December 2014 at the National Cancer Center Hospital East were reviewed retrospectively. We graded the neutropenia severity and defined ≥ Grade 3 neutropenia as severe neutropenia. Univariate and multivariate analysis were undertaken to evaluate the associations with risk of development of severe neutropenia. A total of 122 patients were enrolled in this study. Sixty two patients (51%) and 10 patients (8%) developed severe neutropenia and FN, respectively. Multivariate analysis identified a low baseline white blood cell count (odds ratio [OR], 14.50; 95% confidence interval (CI), 3.27–111.14; p = 0.002) and presence of heterozygosity for UGT1A1*28 or UGT1A1*6 polymorphism (OR, 2.84; 95% CI, 1.18–7.17; p = 0.023) as independent risk factors for severe neutropenia. The incidences of severe neutropenia and FN in patients receiving mFOLFIRINOX in our clinical practice were comparable to previous reports. The risk factors for severe neutropenia in patients receiving mFOLFIRINOX were a low baseline white blood cell count and presence of heterozygosity for UGT1A1*28 or UGT1A1*6 polymorphism.

FOLFIRINOX as First-line Chemotherapy in Japanese Patients Suffering from Metastatic Pancreatic Cancer (KOBE FOLFIRINOX Study)

Background/Aim: FOLFIRINOX (oxaliplatin, irinotecan, 5-fluorouracil, and leucovorin) combination chemotherapy is the gold-standard therapy for advanced pancreatic cancer. In this study, FOLFIRINOX dosages for Japanese patients were established enabling FOLFIRINOX therapy optimization for efficient use. Patients and Methods: Patients with advanced pancreatic cancer were treated with varying doses of FOLFIRINOX to determine the optimum dosage for highest remission outcomes with the least post-chemotherapy toxicities. Results: Patients given 180 mg of irinotecan and a 400 mg bolus of 5-fluorouracil (5-FU) showed a marked difference in outcome when compared to irinotecan 180 mg given without the 5-FU bolus, with the overall response rate being 28%, a survival time of 6.4 months and progression-free survival time of 4.5 months. Conclusion: The optimum dose of FOLFIRINOX was a dosage combination of oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, l-leucovorin 400 mg/m2 and 5-FU 2,400 mg/m2, administered as a continuous 46-h infusion.

Christmas Tree-Shaped Microneedles as FOLFIRINOX Spatiotemporal Delivery System for Pancreatic Cancer Treatment

As an effective combination chemotherapy, FOLFIRINOX regimen (fluorouracil, leucovorin, irinotecan, and oxaliplatin) has shown definite antitumor efficacy for treating pancreatic cancer (PC) nowadays. However, the traditional systematic administration of these chemotherapeutics limits the drug targeting and causes unwanted effects. Herein, we present a novel Christmas tree-shaped adhesive microneedle (MN) patch coloading fluorouracil, leucovorin, irinotecan, and oxaliplatin simultaneously to realize spatiotemporal FOLFIRINOX therapy in situ. Such MN patch was fabricated by using a layer-by-layer mold replication method, in which oxaliplatin and leucovorin are encapsulated in the top MNs, while irinotecan and fluorouracil are encapsulated in the bottom MNs. The multilayer structure imparts the MNs with enhanced adhesive ability and spatiotemporal drug release property, contributing to the antitumor effect on PC organoid models. Therefore, our Christmas tree-shaped MN patch represents an innovative approach for spatiotemporal multiple-drug delivering and realizes the combination chemotherapy for PC in a single platform.

Sequence Therapy with FOLFIRINOX and Gemcitabine/Nab-Paclitaxel for Patients with Advanced Pancreatic Cancer: A Monocentre Retrospective Cohort Study

Background and Aims: While irresectable pancreatic cancer has still a dismal overall prognosis, evidence about the optimal chemotherapy sequence is scarce. After treatment with FOLFIRINOX in first-line, gemcitabine monotherapy was established for years. As a potential treatment alternative after failure of FOLFIRINOX therapy, combination of gemcitabine and nab-paclitaxel is used. However, this combination has formally not yet been approved for second-line treatment and investigation of efficiency and treatment tolerance is the aim of this trial. Methods: Therefore, we investigated 225 patients with histologically confirmed local advanced or metastatic pancreatic cancer in this retrospective monocentre study (November 2010 – July 2019). Of this, 44 patients received FOLFIRINOX therapy and outcome was further analysed. The primary end point of this cohort was overall survival (OS), and secondary end points included progression-free survival (PFS), response rate, and safety. Results: In most of the patients, FOLFIRINOX as first-line treatment of irresectable pancreatic cancer resulted in temporary cancer control (partial response [PR]: 50% and stable disease [SD]: 18%), whereas tumour progression was observed in 23% of the patients. The median PFS time for FOLFIRINOX treatment was 7.3 months and median OS 10.3 months. Seven (16%) patients received additional local radio chemotherapy of the pancreatic tumour. During first-line therapy, in 8 (18%) patients, laparotomy was performed to proof resectability of the tumour. Hereby, in 3 patients R0- and in 3 patients R1 resection was achieved, whereas 2 patients stayed irresectable. Twenty-five of the 44 patients (57%) received second-line therapy, namely, 24 patients gemcitabine/nab-paclitaxel and 1 patient gemcitabine and erlotinib. Hereby, gemcitabine/nab-paclitaxel led again to temporary tumour control in 46% of the patients (PR: 21%, SD: 25%), while in 29% of the patients, disease progression was observed. Corresponding median PFS for gemcitabine and nab-paclitaxel treatment was 3.5 months. Patients who received second-line treatment with nab-paclitaxel and gemcitabine had a more favourable prognosis (median OS: 17 vs. 9.2 months; HR 0.32 [0.14–0.70], p < 0.001) than patients who were not eligible for second-line treatment. Moreover, in multivariate analyses association with patients’ survival and tumour response to chemotherapy in both therapeutic lines and µGT concentrations below 100 IU/L in first-line FOLFIRINOX chemotherapy were observed. Conclusion: These real-world data suggest that gemcitabine/nab-paclitaxel may be feasible after FOLFIRINOX therapy in patients with irresectable pancreatic cancer. However, prospective randomized data about the superiority to gemcitabine monotherapy are needed.

Neoadjuvant FOLFIRINOX Therapy Is Associated with Increased Effector T Cells and Reduced Suppressor Cells in Patients with Pancreatic Cancer.

FOLFIRINOX has demonstrated promising results for patients with pancreatic ductal adenocarcinoma (PDAC). Chemotherapy-induced immunogenic cell death can prime antitumor immune responses. We therefore performed high-dimensional profiling of immune cell subsets in peripheral blood to evaluate the impact of FOLFIRINOX on the immune system. Peripheral blood mononuclear cells (PBMC) were obtained from treatment-naïve (n = 20) and FOLFIRINOX-treated patients (n = 19) with primary PDAC tumors at the time of resection. PBMCs were characterized by 36 markers using mass cytometry by time of flight (CyTOF). Compared with treatment-naïve patients, FOLFIRINOX-treated patients showed distinct immune profiles, including significantly decreased inflammatory monocytes and regulatory T cells (Treg), increased Th1 cells, and decreased Th2 cells. Notably, both monocytes and Treg expressed high levels of immune suppression-associated CD39, and the total CD39+ cell population was significantly lower in FOLFIRINOX-treated patients compared with untreated patients. Cellular alterations observed in responders to FOLFIRINOX included a significantly decreased frequency of Treg, an increased frequency of total CD8 T cells, and an increased frequency of CD27-Tbet+ effector/effector memory subsets of CD4 and CD8 T cells. Our study reveals that neoadjuvant chemotherapy with FOLFIRINOX enhances effector T cells and downregulates suppressor cells. These data indicate that FOLFIRINOX neoadjuvant therapy may improve immune therapy and clinical outcome in patients with PDAC.

Organoids Derived from Neoadjuvant FOLFIRINOX Patients Recapitulate Therapy Resistance in Pancreatic Ductal Adenocarcinoma.

We investigated whether organoids can be generated from resected tumors of patients who received eight cycles of neoadjuvant FOLFIRINOX chemotherapy before surgery, and evaluated the sensitivity/resistance of these surviving cancer cells to cancer therapy. We generated a library of 10 pancreatic ductal adenocarcinoma (PDAC) organoid lines: five each from treatment-naïve and FOLFIRINOX-treated patients. We first assessed the histologic, genetic, and transcriptional characteristics of the organoids and their matched primary PDAC tissue. Next, the organoids' response to treatment with single agents-5-FU, irinotecan, and oxaliplatin-of the FOLFIRINOX regimen as well as combined regimen was evaluated. Finally, global mRNA-seq analyses were performed to identify FOLFIRINOX resistance pathways. All 10 patient-derived PDAC organoids recapitulate histologic, genetic, and transcriptional characteristics of their primary tumor tissue. Neoadjuvant FOLFIRINOX-treated organoids display resistance to FOLFIRINOX (5/5), irinotecan (5/5), and oxaliplatin (4/5) when compared with treatment-naïve organoids (FOLFIRINOX: 1/5, irinotecan: 2/5, oxaliplatin: 0/5). 5-Fluorouracil treatment responses between naïve and treated organoids were similar. Comparative global transcriptome analysis of treatment-naïve and FOLFIRINOX samples-in both organoids and corresponding matched tumor tissues-uncovered modulated pathways mainly involved in genomic instability, energy metabolism, and innate immune system. Resistance development in neoadjuvant FOLFIRINOX organoids, recapitulating their primary tumor resistance, suggests continuation of FOLFIRINOX therapy as an adjuvant treatment may not be advantageous for these patients. Gene-expression profiles of PDAC organoids identify targetable pathways involved in chemoresistance development upon neoadjuvant FOLFIRINOX treatment, thus opening up combination therapy possibilities.

Amplification of mutant KRASG12D in a patient with advanced metastatic pancreatic adenocarcinoma detected by liquid biopsy: A case report.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancer types. Activating oncogenic KRAS mutations are commonly observed in PDAC; however, oncogenic KRAS amplification is rarely observed, and its significance in prognosis and resistance to therapy remains poorly characterized. The present report describes the case of a 52-year-old male patient diagnosed with advanced PDAC with liver metastasis. The patient received modified FOLFIRINOX (mFFX) therapy to which the patient became intolerant with a strong inflammatory response. Subsequent treatment with gemcitabine plus nab-paclitaxel failed to control the disease. Targeted genetic analysis revealed KRASG12D and TP53R248Q mutations in the primary tumor and liver metastases. Analysis of circulating tumor DNA (ctDNA) before the first line of treatment confirmed these genetic findings and revealed a >4-fold amplification of the mutant KRASG12D not detected in the primary tumor. Additionally, subsequent analysis confirmed a 5-fold amplification of the KRASG12D allele in liver metastasis. Consecutive monitoring of ctDNA revealed an initial decrease in the tumor burden 2 weeks after the first cycle of mFFX. However, coinciding with treatment intolerance, a sharp increase in tumor mutational levels and KRASG12D amplification was observed 1 month later. The patient died 70 days after treatment initiation. Overall, amplification of oncogenic KRASG12D was not only associated with an aggressive phenotype, but also supported cancer resistance to chemotherapy. Importantly, this case suggests that plasma detection of KRASG12D amplification is feasible in the clinical routine and constitutes a powerful tool for assessing tumor aggressiveness.

A phase II trial combining tumor-targeting TP53 gene therapy with gemcitabine/nab-paclitaxel as a second-line treatment for metastatic pancreatic cancer.

4139 Background: Nearly all stage IV pancreatic adenocarcinoma (PAC) patients progress after first-line treatment, and second-line options are limited. SGT-53 is an investigational product for tumor-targeted TP53 gene therapy that has completed phase Ia/Ib trials [Senser et al (2013), Mol Ther 21:1096; Pirollo et al (2016) Mol Ther 24:1697]. Methods: Here we provide an interim analysis of a Phase II trial (SGT53-02-1; NCT02340117) combining SGT-53 with gemcitabine/nab-paclitaxel (GEM/ABX). Eligible were first-line patients or those who had progressed after FOLFIRINOX (FFX) and/or gemcitabine-based therapy (second-line). In a 7-week treatment cycle, SGT-53 (3.6 mg DNA) was given once or twice weekly with GEM/ABX (1000 mg/m2/wk and 125 mg/m2/wk, respectively, for 3 of 4 weeks). Progression-free survival (PFS) and objective response rate (ORR) are primary endpoints.Overall survival (OS) and PFS are estimated by Kaplan-Meier analysis. Results: Of all evaluable patients (n=20), best response in 7 patients was determined to be partial response (PR) and 13 had stable disease (SD); none had progressive disease. In the second-line patients (n=11) there were 5 PR and 6 SD after 9 had failed FFX treatment, 3 had failed gemcitabine-based treatment and 1 had failed both. For patients with elevated CA19-9, SGT-53 + GEM/ABX resulted in marked reductions in the tumor marker. Published data for patients with PAC after therapy failure [Mita et al (2019) J Clin Med 8: 761; Portal et al (2015) Br J Cancer 113:989; Wang-Gillam et al (2016) Lancet 387:545] are shown for comparison. Notably, mPFS in our second-line patients was 7.4 months versus 3.1 months for the approved second-line therapy [Wang-Gillam et al (2016)]. This improvement in PFS exceeds the benchmark proposed to predict a clinically meaningful Phase III trial [Rahib et al (2016) Lancet Oncol 2:1209]. Conclusions: Our data suggest a clinically meaningful benefit of adding SGT-53 to GEM/ABX particularly for second-line PAC patients, most of whom had failed prior FFX treatment. Clinical trial information: NCT02340117. [Table: see text]