Anlotinib plus tislelizumab for recurrent metastatic pancreas ductal adenocarcinoma with germline BRCA2 mutation: A case report.

While combined immunotherapy and anti-angiogenic therapy have demonstrated efficacy in renal cell carcinoma, non-small cell lung cancer and hepatocellular carcinoma, the efficacy of first-line treatment for pancreatic ductal adenocarcinoma (PDAC) with germline BRCA2 mutation remains unproven. We described a BRCA2-mutated patient with PDAC who presented with posterior cardiac metastasis 8 months after surgery. After receiving four cycles of anlotinib combined with tislelizumab, abdominal CT scans indicated a complete response. The patient sustained this response for over 14 months on the combination regimen, with no reported adverse events. In conclusion, the combination of tislelizumab and anlotinib may offer a viable therapeutic option for recurrent metastatic BRCA2-mutated PDAC.

High somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: prospective study.

AIMS: We previously showed that the nab-paclitaxel plus S-1 (NPS) regimen had promising effects against metastatic pancreatic ducal adenocarcinoma (mPDAC), whose efficacy however could not be precisely predicted by routine biomarkers. This prospective study aimed to investigate the values of mutations in circulating tumor DNA (ctDNA) and their dynamic changes in predicting response of mPDAC to NPS chemotherapy. METHODS: Paired tumor tissue and blood samples were prospectively collected from patients with mPDAC receiving first-line NPS chemotherapy, and underwent next-generation sequencing with genomic profiling of 425 genes for ctDNA. High mutation allelic frequency (MAF) was defined as ≥ 30% and ≥ 5% in tumor tissue and blood, respectively. Kappa statistics were used to assess agreement between mutant genes in tumor and ctDNA. Associations of mutations in ctDNA and their dynamic changes with tumor response, overall survival (OS), and progression-free survival (PFS) were assessed using the Kaplan-Meier method, multivariable-adjusted Cox proportional hazards regression, and longitudinal data analysis. RESULTS: 147 blood samples and 43 paired tumor specimens from 43 patients with mPDAC were sequenced. The most common driver genes with high MAF were KRAS (tumor, 35%; ctDNA, 37%) and TP53 (tumor, 37%; ctDNA, 33%). Mutation rates of KRAS and TP53 in ctDNA were significantly higher in patients with liver metastasis, with baseline CA19-9 ≥ 2000 U/mL, and/or without an early CA19-9 response. κ values for the 5 most commonly mutated genes between tumor and ctDNA ranged from 0.48 to 0.76. MAFs of the genes mostly decreased sequentially during subsequent measurements, which significantly correlated with objective response, with an increase indicating cancer progression. High mutations of KRAS and ARID1A in both tumor and ctDNA, and of TP53, CDKN2A, and SMAD4 in ctDNA but not in tumor were significantly associated with shorter survival. When predicting 6-month OS, AUCs for the 5 most commonly mutated genes in ctDNA ranged from 0.59 to 0.84, larger than for genes in tumor (0.56 to 0.71) and for clinicopathologic characteristics (0.51 to 0.68). Repeated measurements of mutations in ctDNA significantly differentiated survival and tumor response. Among the 31 patients with ≥ 2 ctDNA tests, longitudinal analysis of changes in gene MAF showed that ctDNA progression was 60 and 58 days ahead of radiologic and CA19-9 progression for 48% and 42% of the patients, respectively. CONCLUSIONS: High mutations of multiple driving genes in ctDNA and their dynamic changes could effectively predict response of mPDAC to NPS chemotherapy, with promising reliable predictive performance superior to routine clinicopathologic parameters. Inspiringly, longitudinal ctDNA tracking could predict disease progression about 2 months ahead of radiologic or CA19-9 evaluations, with the potential to precisely devise individualized therapeutic strategies for mPDAC.

Avelumab or talazoparib in combination with binimetinib in metastatic pancreatic ductal adenocarcinoma: dose-finding results from phase Ib of the JAVELIN PARP MEKi trial.

BACKGROUND: Combinations of avelumab [anti-programmed death-ligand 1 (anti-PD-L1)] or talazoparib [poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor] with binimetinib (MEK inhibitor) were expected to result in additive or synergistic antitumor activity relative to each drug administered alone. Here, we report phase Ib results from JAVELIN PARP MEKi, which investigated avelumab or talazoparib combined with binimetinib in metastatic pancreatic ductal adenocarcinoma (mPDAC). PATIENTS AND METHODS: Patients with mPDAC that had progressed with prior treatment received avelumab 800 mg every 2 weeks plus binimetinib 45 mg or 30 mg two times daily (continuous), or talazoparib 0.75 mg daily plus binimetinib 45 mg or 30 mg two times daily (7 days on/7 days off). The primary endpoint was dose-limiting toxicity (DLT). RESULTS: A total of 22 patients received avelumab plus binimetinib 45 mg (n = 12) or 30 mg (n = 10). Among DLT-evaluable patients, DLT occurred in five of 11 patients (45.5%) at the 45-mg dose, necessitating de-escalation to 30 mg; DLT occurred in three of 10 patients (30.0%) at the 30-mg dose. Among patients treated at the 45-mg dose, one (8.3%) had a best overall response of partial response. Thirteen patients received talazoparib plus binimetinib 45 mg (n = 6) or 30 mg (n = 7). Among DLT-evaluable patients, DLT occurred in two of five patients (40.0%) at the 45-mg dose, necessitating de-escalation to 30 mg; DLT occurred in two of six patients (33.3%) at the 30-mg dose. No objective responses were observed. CONCLUSIONS: Combinations of avelumab or talazoparib plus binimetinib resulted in higher-than-expected DLT rates. However, most DLTs were single occurrences, and the overall safety profiles were generally consistent with those reported for the single agents. CLINICAL TRIAL REGISTRATION: ClinicalTrials.govNCT03637491; https://clinicaltrials.gov/ct2/show/NCT03637491.

Case Report: Anlotinib combined with PD-1 inhibitor and sequential GA regimen or FOLFIRINOX Chemotherapy in treatment of KRAS G12V mutated pancreatic ductal adenocarcinoma with liver metastasis: A case and literature review.

There is a high mortality rate associated with pancreatic cancer, and the incidence has been rising globally in recent decades. When patients are diagnosed, there is little chance that surgery will be beneficial. Systemic chemotherapy is the currently accepted treatment option for patients with metastatic advanced pancreatic cancer. However, a very limited survival improvement is possible with chemotherapy for advanced pancreatic cancer, and chemotherapy resistance plays a significant role in poor prognosis. Despite the fact that targeting growth factor receptor inhibitors such as anti-vascular endothelial growth factor (VEGFR) antibodies significantly improves survival in pancreatic cancer, only a very small number of patients benefit from the treatment. As emerging drugs, immune checkpoint inhibitors (ICIs) have demonstrated significant therapeutic effects in several tumor types, but monotherapy is not effective in pancreatic cancer. In the first-line treatment of solid tumors, combination therapy may result in remarkable outcomes. Here in, we have reported a younger patient with pancreatic ductal adenocarcinoma with liver metastasis (PDACLM) who had a long-term partial response and good tolerance to the combination of anlotinib and programmed cell death protein 1 (PD-1) inhibitor and chemotherapy. Gene analysis suggested only one mutation in the Kirsten rat sarcoma viral oncogene (KRAS) G12V gene. Consequently, there is some hope for patients with pancreatic cancer, especially for KRAS G12V gene mutated patients. Upon reviewing the literature, this patient's combination therapy is the first to have been reported.

Platinum-Based Chemotherapy in Locally Advanced or Metastatic Pancreatic Ductal Adenocarcinoma: Summary of Evidence and Application in Clinical Practice.

BACKGROUND: Different therapeutic options are available for the treatment of advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). Platinum-based multi-agent chemotherapy regimens, such as FOLFIRINOX, are important elements in the multidisciplinary management of PDAC. SUMMARY: At least one third of patients with metastatic PDAC are eligible for treatment with FOLFIRINOX. Eligibility criteria include good performance status and the absence of relevant comorbidities. However, chemotherapies can potentially be associated with serious adverse events, such as diarrhea or polyneuropathies. Here, we review relevant data from first-line, second-line, and maintenance therapy trials as well as real-world data. In addition, we address the management of possible adverse events. KEY MESSAGES: (1) Selection of a suitable treatment regime depends on patient performance status, comorbidities, and anticipated toxicity. (2) FOLFIRINOX is an appropriate treatment for patients up to 75 years of age with an ECOG PS of 0 or 1, without relevant comorbidities, normal or nearly normal bilirubin levels, and no significantly reduced DPD activity. (3) In particular, patients with germline BRCA1/2 (gBRCA1/2) or PALB2 mutations may benefit from first-line platinum-containing therapy. (4) Early and comprehensive testing of the patient's mutational status could support the first-line treatment decision-making.

How to improve metastatic pancreatic ductal adenocarcinoma patients' selection: Between clinical trials and the real-world.

As underlined in the minireview by Blomstrand et al, given the poor prognosis and the paucity of data on a therapeutic sequence in pancreatic ductal adenocarcinoma (PDAC), additional randomized controlled trials and real-world evidence studies addressing current and novel regimens are needed. The real-world outcomes of first-line chemotherapy regimens such as FOLFIRINOX and gemcitabine/nab-paclitaxel are thoroughly reviewed and seem to be largely generalizable in a real-world context. Regarding second-line chemotherapy, the key question about the optimal sequence of regimens remains uncertain. Precisely in this setting, it is therefore useful to encourage the implementation of clinical studies that may contribute to the scarcity of data available up to now. We report our experience with a small group of patients treated with second-line liposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin. To improve the treatment of patients affected by PDAC, it is useful to identify subgroups of patients who may benefit from target treatments (e.g., BRCA mutant) and it is also important to focus on any prognostic factors that may affect the survival and treatment of these patients.

Nab-paclitaxel plus S-1 with or without PD-1 inhibitor in pancreatic ductal adenocarcinoma with only hepatic metastases: a retrospective cohort study.

PURPOSE: The evidence regarding programmed cell death 1 (PD-1) inhibitors on pancreatic ductal adenocarcinoma (PDAC) with metastases remains controversial. This study aimed to assess the efficacy and safety of Nab-paclitaxel plus S1 (NPS) with or without Sintilimab, a PD-1 inhibitor, in patients with PDAC with only hepatic metastases (mPDAC). METHODS: Untreated mPDAC patients who received NPS with (the combination group) or without Sintilimab (the NPS group) were retrospectively studied. Surgery was considered when the pancreatic tumor became resectable or borderline resectable on radiological examinations, and with complete metabolic response of liver metastases. RESULTS: Between October 2017 and February 2020, 32 patients were in the combination group and 34 patients in the NPS group. Successful salvage resection was achieved in 17 (25.8%) patients after tumor-downstaging (combination 12 vs. NPS 5, P = 0.03). The median overall survival (OS) was 16.8 months in the combination group and 10.0 months in the NPS group (P = 0.002). Remarkable OS benefit was observed in patients with decline in CA19-9 of ≥ 50% (16.0 vs. 6.5, P = 0.003), reduction in 18F-fluorodeoxyglucose uptake of primary tumor of ≥ 50% (16.5 vs. 10.0, P < 0. 001) and after salvage resection (20.1 vs. 11.0, P < 0. 001). No significant difference in Grade 3 or higher adverse events were seen between the two groups (40.6% vs. 32.4%, P = 0.49). CONCLUSIONS: Despite the inherent biases of this retrospective study, the addition of Sintilimab significantly improved salvage resection rates and OS compared with the NPS regimen and had a favorable safety profile in treatment naïve mPDAC patients.

A Patient with Metastatic Microsatellite Instability-High Pancreatic Ductal Adenocarcinoma with a Prolonged Response to Single-Agent Pembrolizumab.

Immunotherapy is an effective new approach in the treatment of many malignancies. However, pancreatic ductal adenocarcinoma (PDAC) does not usually respond to immunotherapy. We discuss the case of a patient with metastatic microsatellite instability-high PDAC who had a prolonged response to single-agent pembrolizumab for almost 3 years.

Phase I/II Study of LDE225 in Combination with Gemcitabine and Nab-Paclitaxel in Patients with Metastatic Pancreatic Cancer.

BACKGROUND: Desmoplasia is a central feature of the tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC). LDE225 is a pharmacological Hedgehog signaling pathway inhibitor and is thought to specifically target tumor stroma. We investigated the combined use of LDE225 and chemotherapy to treat PDAC patients. METHODS: This was a multi-center, phase I/II study for patients with metastatic PDAC establishing the maximum tolerated dose of LDE225 co-administered with gemcitabine and nab-paclitaxel (phase I) and evaluating the efficacy and safety of the treatment combination after prior FOLFIRINOX treatment (phase II). Tumor microenvironment assessment was performed with quantitative MRI using intra-voxel incoherent motion diffusion weighted MRI (IVIM-DWI) and dynamic contrast-enhanced (DCE) MRI. RESULTS: The MTD of LDE225 was 200 mg once daily co-administered with gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2. In phase II, six therapy-related grade 4 adverse events (AE) and three grade 5 were observed. In 24 patients, the target lesion response was evaluable. Three patients had partial response (13%), 14 patients showed stable disease (58%), and 7 patients had progressive disease (29%). Median overall survival (OS) was 6 months (IQR 3.9-8.1). Blood plasma fraction (DCE) and diffusion coefficient (IVIM-DWI) significantly increased during treatment. Baseline perfusion fraction could predict OS (>222 days) with 80% sensitivity and 85% specificity. CONCLUSION: LDE225 in combination with gemcitabine and nab-paclitaxel was well-tolerated in patients with metastatic PDAC and has promising efficacy after prior treatment with FOLFIRINOX. Quantitative MRI suggested that LDE225 causes increased tumor diffusion and works particularly well in patients with poor baseline tumor perfusion.

Early dose reduction/delay and the efficacy of liposomal irinotecan with fluorouracil and leucovorin in metastatic pancreatic ductal adenocarcinoma (mPDAC): A post hoc analysis of NAPOLI-1.

BACKGROUND: Chemotherapy dose modification to manage adverse events is commonplace in clinical practice. This exploratory analysis evaluates the impact of liposomal irinotecan dose modification on overall survival (OS) and progression-free survival (PFS) in the NAPOLI-1 clinical trial (NCT01494506). METHODS: Analysis includes only patients enrolled under protocol version 2 who received at least the first 2 scheduled doses of study drug. Within the liposomal irinotecan +5 fluorouracil/leucovorin (5 FU/LV) arm, patients were grouped according to whether or not they had a dose modification within the first 6 weeks. Dose reduction was defined as any decrease from initial dose; dose delay was any dosing delay >3 days from target date. OS and PFS (Kaplan-Meier estimates) were compared within the liposomal irinotecan+5-FU/LV arm and between treatment arms. Unstratified hazard ratios (HRs) were calculated using Cox regression analysis. RESULTS: Of the 93 patients from the liposomal irinotecan+5 FU/LV arm included in the analysis, 53 experienced a dose modification (both delay and reduction, n = 30; delay only, n = 19; reduction only, n = 4). No apparent difference in median OS or PFS was observed between patients who did versus patients who did not have a dose modification (OS: 8.4 vs 6.7 months; HR, 0.89; PFS: 4.2 vs 3.1 months; HR, 0.74). CONCLUSION: An early dose reduction or delay of liposomal irinotecan+5-FU/LV in the first 6 weeks does not significantly impact OS or PFS compared to patients without dose modifications. This finding suggests that tolerability-guided dose modification of liposomal irinotecan does not adversely affect efficacy outcomes.

Durable Response and Good Tolerance to the Triple Combination of Toripalimab, Gemcitabine, and Nab-Paclitaxel in a Patient With Metastatic Pancreatic Ductal Adenocarcinoma.

Background: The performance of immune checkpoint inhibitor (ICI) monotherapy was proved to be disappointing in pancreatic ductal adenocarcinoma (PDAC). Increasing evidence has shown the promising efficacy of ICIs combined with systemic therapy in the first-line treatment in solid tumors. Case presentation: We reported a case of a metastatic PDAC patient who had a long-term partial response and good tolerance to the combined approach of toripalimab (a novel PD-1 inhibitor) and gemcitabine plus nab-paclitaxel (GA). PD-L1 positive expression was detected in his liver metastases. Besides, we described a phenomenon of pseudo-progression of this patient during the course of therapy. Conclusion: As the first-line treatment of metastatic PDAC patients, GA plus toripalimab may provide a novel combined approach with favorable response and manageable toxicity. Further clinical trials are needed to confirm the results. Pseudo-progression requires special attention and to be differentiated with true progression in patients undergoing immunotherapy.

Applied precision medicine in metastatic pancreatic ductal adenocarcinoma.

BACKGROUND: Metastatic pancreatic ductal adenocarcinoma (mPDAC) bears a dismal prognosis due to the limited activity of systemic chemotherapy. In our platform for precision medicine, we aim to offer molecular-guided treatments to patients without further standard therapy options. METHODS: In this single center, real-world retrospective analysis of our platform, we describe the molecular-based therapy approaches used in all 50 patients diagnosed with therapy-refractory mPDAC. A molecular portrait of the tumor specimens was created by next-generation sequencing, immunohistochemistry (IHC), microsatellite instability (MSI) testing, and fluorescence in situ hybridization. RESULTS: In total, we detected 123 mutations in 50 patients. The five most frequent mutations were KRAS (n = 40; 80%), TP53 (n = 29; 58%), CDKN2A (n = 8; 16%), SMAD4 (n = 4; 8%), and NOTCH1 (n = 4; 8%), which together accounted for 40.2% of all mutations. Two patients had gene fusions, namely, TBL1XR1-PIK3CA and EIF3E-RSPO2. IHC detected expression of EGFR, phosphorylated mTOR, and PTEN in 36 (72%), 33 (66%), and 17 patients (34%), respectively. For 14 (28%) of the 50 patients, a targeted therapy was suggested based on the identified molecular targets. The recommended treatments included the mTOR inhibitor everolimus (n = 3), pembrolizumab (n = 3), palbociclib (n = 2), nintedanib (n = 2), and cetuximab, crizotinib, tamoxifen, and the combination of lapatinib and trastuzumab, in one patient each.Finally, five patients received the recommended therapy. Four patients died due to disease progression before radiological assessment. One patient was treated with nintedanib and achieved stable disease for 6 months. CONCLUSION: Based on our observations, precision medicine approaches are feasible and implementable in clinical routine and may provide molecular-based therapy recommendations for mPDAC.

Peritumoral/vascular expression of PSMA as a diagnostic marker in hepatic lesions.

BACKGROUND: The differential diagnosis between primary cholangiocarcinoma and metastatic pancreatobiliary adenocarcinoma is histologically challenging due to lack of distinct morphological features and reliable molecular markers. Prostate-specific membrane antigen (PSMA) is expressed in prostate epithelium and upregulated on the surface of prostatic adenocarcinoma cells. Studies have shown PSMA enzymatic activity is involved in malignancy-driven neoangiogenesis in the endothelium of tumor-associated neovasculature in breast, lung, thyroid, hepatocellular carcinoma (HCC) and urothelial cancer. Recently, PSMA-targeted imaging technology (PSMA PET-CT) detected the presence of PSMA in primary cholangiocarcinoma. However histological correlation with PSMA expression other mass lesions in the liver has not yet been studied. METHODS: 72 cases of liver mass resection were collected at a tertiary hospital from 2011 to 2019. Immunohistochemical stains for PSMA and CD34 were performed. The expression of PSMA in tumor cells and associated neovascular endothelium were analyzed separately and the locations of vascular structures were confirmed by CD34 expression. RESULTS: Among 72 cases, 28 cases (22/72, 38.9%) showed PSMA peritumoral/vascular expression only, 3 cases (3/72, 4.2%) showed tumor cell expression only, and 2 cases (2/72, 2.8%) showed both tumor cell and peritumoral/vascular expression. The remainder (39/72, 54.2%) showed no expression. Particularly, most of primary cholangiocarcinoma showed PSMA vascular expression (13/15, 86.7%), while none of the 18 cases of metastatic pancreatobiliary adenocarcinoma were positive for PSMA (0/18, 0%) (p < 0.01). Outside of pancreatobiliary adenocarcinoma, none of the metastatic tumors, including colon and lung cancers, expressed PSMA. In 8 cases of metastatic prostate carcinoma, 3 showed PSMA expressions in tumor cells only (3/8, 37.5%) and 2 expressed PMSA in both tumor cells and neovasculature (2/8, 25.0%). Out of 22 HCC cases, 15 (15/22, 68.2%) were positive for PSMA in tumor vasculature. None of the 5 hepatic adenoma expressed PSMA (0/5, 0%). CONCLUSION: Significantly enhanced tumor-associated neovascular PSMA expression was identified in primary cholangiocarcinoma, compared to metastatic pancreatobiliary adenocarcinoma. Our findings potentially provide a sensitive marker in differential diagnosis between otherwise morphologically indistinguishable cases.

Primary tumor resection and lymph node dissection improve survival in de novo metastatic pancreatic ductal adenocarcinoma: an inverse probability of treatment weighting analysis.

BACKGROUND: Primary tumor resection (PTR) and lymph node dissection (LND) may be performed occasionally in patients with de novo metastatic pancreatic ductal adenocarcinoma (mPDAC). However, the role of PTR and LND in such cases remains unclear. Thus, we aimed to test the effect of PTR and LND on overall survival (OS) and cancer-specific survival (CSS) in mPDAC patients. METHODS: Patients with de novo mPDAC were identified from the Surveillance Epidemiology and End Results (SEER) database (2010-2015). The inverse probability of treatment weighting (IPTW) method was used to minimize the selection bias. IPTW-adjusted Kaplan-Meier curves and Cox proportional hazards models were used to compare OS and CSS in different treatment groups. RESULTS: A total of 10,036 patients met the inclusion criteria. Of these patients, 275 (2.7%) underwent PTR, while 217 (2.2%) also underwent LND with a median of 16 nodes removed. In the IPTW-adjusted Kaplan-Meier analysis, the median OS was 13 versus 6 months (P<0.001) for the PTR and non-PTR groups, respectively, and 15 versus 5 months (P=0.007) for the LND and non-LND groups, respectively. In the IPTW-adjusted Cox regression analysis, PTR was independently associated with better OS [hazard ratio (HR) 0.483, 95% confidence interval (CI): 0.468-0.498, P<0.001], as was LND (HR 0.286, 95% CI: 0.228-0.358, P<0.001). Similar results were observed in the analysis of CSS. In the LND group, the extent of LND was not associated with either OS or CSS. CONCLUSIONS: PTR and LND were independent prognostic factors that prolonged OS and CSS in de novo mPDAC patients. These findings must be validated in prospective randomized studies.

Real life triplet FIr/FOx chemotherapy in first-line metastatic pancreatic ductal adenocarcinoma patients: recommended schedule for expected activity and safety and phase II study.

BACKGROUND: Gemcitabine/nab-paclitaxel and FOLFIRINOX demonstrated significantly increased survival compared with gemcitabine in metastatic pancreatic ductal adenocarcinoma (PDAC): objective response rate (ORR) 23 and 31.6%, progression-free survival (PFS) 5.5 and 6.4 months, overall survival (OS) 8.7 and 11.1 months. Present phase II study evaluated recommended first-line triplet FIr/FOx schedule. METHODS: Simon two-step design: p010%, p130%, power 80%, α5%, ß20%. Projected ORR: I step, 1/10; II 5/29. Schedule: 12h-timed-flat-infusion/5-fluorouracil 750-800-900 mg/m2 d1-2,8-9,15-16,22-23; irinotecan 120-140-160 mg/m2 d1,15; oxaliplatin 70-80 mg/m2 d8,22; every 4 weeks, according to clinical parameters (age, comorbidities, performance status (PS), liver function). Activity and efficacy were evaluated, and compared using log-rank; limiting toxicity syndromes (LTS), using chi-square. RESULTS: Twenty-nine consecutive patients were enrolled, according to primary/intermediate/secondary Cumulative Illness Rating Scale (CIRS). Median age 62; elderly 13 (44.7%); PS2 3 (10.4%), secondary CIRS 5 (17.2%). Primary endpoint was met: ORR 53% (7/13 patients) as-treated, 50% intent-to-treat. Cumulative G3-4 toxicities: diarrhea 17%, asthenia 14%, hypertransaminasemy 7%, mucositis 7%, vomiting 3%, anemia 3%, thrombocytopenia 3%. LTS were 27.5% overall, 38.4% in elderly. At 3 months median follow-up, PFS 4 months, OS 11 months. PS2 patients showed significantly worse OS (P 0.022). CONCLUSION: Intensive first-line triplet FIr/FOx is tolerable at modulated doses, and confirms high activity/efficacy in metastatic PDAC. Patients' careful selection, and exclusion of PS2, can maintain safety profile and efficient dose intensity.