Advanced Unresectable Pancreatic Cancer Research Articles

Trends in the treatment of advanced pancreatic cancer.

Pancreatic cancer (PC) has the poorest prognosis among digestive cancers; only 15-20% of cases are resectable at diagnosis. This review explores multidisciplinary treatments for advanced PC, emphasizing resectability classification and treatment strategies. For locally advanced unresectable PC, systemic chemotherapy using modified FOLFIRINOX and gemcitabine with albumin-bound paclitaxel is standard, while the role of chemoradiation is debated. Induction chemotherapy followed by chemoradiation may be a promising therapy. Conversion surgery after initial chemotherapy or chemoradiotherapy offers favorable survival, however criteria for conversion need further refinements. For metastatic PC, clinical trials using immune checkpoint inhibitors and molecular targeted therapies are ongoing. Multidisciplinary approaches and further research are crucial for optimizing treatment and improving outcomes for advanced PC.

Trends in the treatment of advanced pancreatic cancer.

Pancreatic cancer (PC) has the poorest prognosis among digestive cancers; only 15-20% of cases are resectable at diagnosis. This review explores multidisciplinary treatments for advanced PC, emphasizing resectability classification and treatment strategies. For locally advanced unresectable PC, systemic chemotherapy using modified FOLFIRINOX and gemcitabine with albumin-bound paclitaxel is standard, while the role of chemoradiation is debated. Induction chemotherapy followed by chemoradiation may be a promising therapy. Conversion surgery after initial chemotherapy or chemoradiotherapy offers favorable survival, however criteria for conversion need further refinements. For metastatic PC, clinical trials using immune checkpoint inhibitors and molecular targeted therapies are ongoing. Multidisciplinary approaches and further research are crucial for optimizing treatment and improving outcomes for advanced PC.

Sequential neoadjuvant chemotherapy for borderline resectable and locally advanced pancreatic adenocarcinoma.

TPS4209 Background: Patients with borderline resectable (BRPC) and locally advanced unresectable (LAPC) pancreatic cancer have a median OS of 8-20 months unless they undergo margin negative resection. Despite advances in systemic therapy, the prognosis is dismal. The locoregional and distant failure rates are high in post-surgery and therefore neoadjuvant chemotherapy emerged as standard-of-care practice to select the patients for surgery and improve overall clinical outcomes. An effective and tolerable neoadjuvant regimen can facilitate R0 resection by tumor down staging and mitigating the risk for positive margins. A recent SEQUENCE-2 study on sequential treatment with combination of Gemcitabine and nab-paclitaxel (GA) GA followed by modified FOLFOX (mFOLFOX) improved OS (13.2 months) and PFS (9.5 months) in patients with metastatic PDC, compared with the standard GA regimen, with comparable safety profile. Current guidelines suggest modified FOLFIRINOX (mFFX, infusional 5-fluorouracil, oxaliplatin, irinotecan) or GA as the first-line systemic chemotherapeutic regimen in neoadjuvant, adjuvant and palliative setting. These regimens are associated with modest pathological complete response rate. However, there is significant unmet need for management of BRPC and LAPC as the optimal treatment strategy remains undefined. As both of the aforementioned regimens are active and feasible in BRPC and LAPC, we conceptualize that by using both regimens alternating in sequence the rate of R0 resection and pathological response could be improved by overcoming possible resistance to a single backbone. Methods: The aim of this study is to demonstrate the efficacy and feasibility of sequential chemotherapy (GA followed by mFFX) in patients with BRPC (n=34) and LAPC (n=30). To achieve this, we are conducting a non-randomized prospective interventional clinical study with BRPC and LAPC patients treated with alternating cycles of GA and mFFX for 4 months and assessed for clinical outcomes, feasibility and toxicity. The primary objective of this study is to evaluate the efficacy of sequential GA followed by mFFX in improving R0 resection rate in patients with BRPC and LAPC. After four months of sequential neoadjuvant therapy, the patients will proceed to surgery, radiation, or extended course of chemotherapy, off study, as determined by multidisciplinary tumor board consensus or the treating physician. These results will have high translational potential for providing mechanistic insight into tumor response, optimizing current management strategies for pancreatic cancer that could be generalizable to other stages of this cancer. The key eligibility criteria include treatment naive histologically diagnosed BRPC or LAPC with measurable disease, ECOG 0,1, optimal organ function. Clinical trial information: NCT05776524 .

Stereotactic radiotherapy plus anti PD-1 therapy in patients with locally advanced unresectable pancreatic cancer: Results from a phase 1/2 clinical trial (CA209-9KH).

649 Background: The outcomes after the treatment for pancreatic ductal adenocarcinoma (PDAC) are generally disappointing. Except for MSI high tumors, PDAC is considered to be resistant to immune checkpoint inhibitors (ICI). Radiotherapy is thought to be a potential option to foster the effect of ICI. This investigator-initiated trial evaluated safety and efficacy of combining stereotactic radiotherapy (SRT) and ICI. Methods: In this open-label, multicenter phase 1/2 study, patients (pts) aged ≥ 18 years with histologically confirmed locally advanced unresectable PDAC with no distant metastases were enrolled after initial four cycles of induction chemotherapy with FOLFIRINOX. The experimental treatment consisted of SRT (32 Gy in 4 fractions/4 weeks) and sequential nivolumab (N) therapy (3mg/kg every two weeks) administered until disease progression or unacceptable toxicity. After N discontinuation pts could continue treatment with standard chemotherapy regimens. The primary end point was safety (events graded according to NCI CTCAE 4.03 criteria). The secondary objectives were progression free survival (PFS), overall survival (OS), evaluation of selected biomarkers, and quality of life (QoL; EORTC QLQ-C30 questionnaire). The PFS and OS were defined as the time from enrollment to event (i.e., did not include 3-month of ICT and screening). Results: A total of 22 pts. were screened, and 15 pts. were enrolled. Median age was 58 (range 38-74) years, and 53 % were males. All tumors were microsatellite (MS) stable or had unknown MS status. All patients underwent SRT according to the study protocol and all started N. The median number of N cycles was 11 (range 2-17). The toxicity of SRT was low and non-significant. The toxicity of N therapy was expectable. No Grade 4-5 toxicity was observed. Three pts. discontinued therapy because of toxicity (liver test elevation in two cases and unmanageable arthralgia). Median PFS and OS were 8.1 and 13.0 months, resp.; 12-month PFS and OS were 0 % and 66.7%, resp.; and 24-month OS was 8.9 %. The level of selected biomarkers correlated with clinical or radiological disease control. The QoL assessed by pts during the therapy was acceptable, deterioration of QoL in most cases occurred with tumor progression. Conclusions: The toxicity of SRT and N therapy was low and acceptable. There was no unexpected toxicity of combination of SRT of PDAC primary tumor and N, but this regimen did not lead to any long-term treatment responses. Trial registration: EudraCT: 2017-003404-52; ClinicalTrials.gov: NCT04098432. The study was financially supported by Bristol-Meyer-Squibb. Clinical trial information: NCT04098432 .

A case of R0 resection in conversion surgery after duodenal stent placement for locally advanced unresectable pancreatic cancer with duodenal stenosis

A 67-year-old man presented to our hospital with vomiting. Esophagogastroduodenoscopy revealed duodenal stenosis and atypical epithelium. A tumor in the pancreatic head, about 30mm in size, involving the superior mesenteric artery and a superior mesenteric vein was identified using abdominal contrast computed tomography (CT). Locally advanced pancreatic cancer was diagnosed in the patient through an endoscopic biopsy. Due to the duodenal stenosis complication, duodenal stent placement was conducted. After stent placement, oral intake was resumed, and improvement of the systemic condition led to chemotherapy (modified FOLFIRINOX). After chemotherapy, CT revealed decreased carcinoma progression and vascular invasion. Conversion surgery was improved, and R0 resection was achieved. Our study showed that duodenal stent placement could enhance prognosis;as a result, it was regarded as a good choice for multidisciplinary therapy.

Intensity Modulated Radiation Therapy vs. Volumetric Modulated Arc Therapy in Locally Advanced Unresectable Pancreatic Cancer: Dosimetric Study

Intensity Modulated Radiation Therapy vs. Volumetric Modulated Arc Therapy in Locally Advanced Unresectable Pancreatic Cancer: Dosimetric Study

Multisite Is Superior to Single-Site Intratumoral Chemotherapy to Retard the Outcomes of Pancreatic Ductal Adenocarcinoma in a Murine Model.

Locally advanced unresectable pancreatic cancer (LAPC) has a dismal prognosis, with intratumoral therapies showing limited benefits. We assume that the dense stroma within these tumors hampers drug dispersion. This study explores the efficacy of multisite intratumoral injections in improving a drug's distribution while minimizing its side effects. In mice with orthotopic LAPC tumors, weekly intratumoral injections of oxaliplatin at four separate sites reduced the tumor growth by 46% compared with saline (p < 0.003). Oxaliplatin exhibited the greatest impact on the tumor microenvironment relative to gemcitabine, Abraxane, or their combination, with increased necrosis, apoptosis, fibroblasts, inflammation, and infiltrating lymphocytes (p < 0.008). When combined with intravenous FOLFIRINOX (FFX), multisite intratumoral oxaliplatin reduced the tumor weight by 35% compared with single-site injection (p = 0.007). No additional visible toxicity was observed even at a 10-fold occurrence of intratumoral treatment. This co-modality treatment significantly improved survival compared with other groups (p = 0.007). Multisite intratumoral therapy in tandem with systemic treatment holds promise for reducing the tumor size and enhancing the overall survival in LAPC.

ROS-Sp1 axis is involved in thermochemotherapy-enhanced sensitivity of pancreatic cancer cells to gemcitabine.

Gemcitabine (GEM)-based chemotherapy represents the first choice for locally unresectable advanced pancreatic cancer, while the benefit is limited due to acquired chemoresistance or drug delivery insufficiency. Hyperthermia treatment potentially improves the clinical efficacy of GEM. However, the underlying mechanism is incompletely revealed. Our study aims to investigate the effect and involved mechanism of thermochemotherapy on cell survival. Pancreatic cancer cells PANC-1 and ASPC-1 were either treated with GEM or thermochemotherapy, then cell viability, apoptosis, migration, invasion, reactive oxygen species (ROS) production, and Sp1 expression were evaluated. The results showed that GEM dose and time-dependently affected cell viability, and 30 μM GEM achieved favorable effect in suppressing cancer cell growth. Meanwhile, hyperthermia preconditioning (43°C for 60 min) 24 h before GEM treatment yielded superior effect than other treatment sequence. GEM caused significant cell apoptosis and proapoptotic genes of both cancer cells, and thermochemotherapy further promoted apoptosis and genes transcription, accompanied by excessive ROS production. Thermochemotherapy was superior to GEM in suppressing cell migration and invasion of pancreatic cancer cells. Meanwhile, GEM significantly reduced Sp1 mRNA and protein and its downstream gene Cox-2, and thermochemotherapy further suppressed their expressions. ROS elimination with N-acetyl-l-cysteine notably neutralizes the suppressive effect of GEM and thermochemotherapy on cell growth and expressions of Sp1 and Cox-2. In conclusion, thermochemotherapy inhibited pancreatic cell viability, migration and invasion, and promoted cell apoptosis by inducing excessive ROS production, which subsequently suppressed Sp1 expression and the downstream Cox-2.

Normo- or Hypo-Fractionated Photon or Proton Radiotherapy in the Management of Locally Advanced Unresectable Pancreatic Cancer: A Systematic Review.

Clinical studies published from 2012 to 2022 were systematically reviewed using PubMed, MEDLINE (via PubMed) and Cochrane databases. Different radiotherapy-related data were extracted and analyzed. A total of 31 studies matched the inclusion criteria. Acute toxicity was less remarkable in stereotactic body radiotherapy (SBRT) compared to conventionally fractionated radiotherapy (CFRT), while in proton beam therapy (PBT) grade 3 or higher acute toxicity was observed more commonly with doses of 67.5 Gy (RBE) or higher. Late toxicity was not reported in most studies; therefore, comparison between groups was not possible. The range of median overall survival (OS) for the CFRT and SBRT groups was 9.3-22.9 months and 8.5-20 months, respectively. For the PBT group, the range of median OS was 18.4-22.3 months. CFRT and SBRT showed comparable survival outcomes with a more favorable acute toxicity profile for SBRT. PBT is a promising new treatment modality; however, additional clinical studies are needed to support its efficacy and safety.

Induction Chemotherapy Followed by Concomitant Chemoradiation using Intensity Modulated Radiotherapy Technique in Locally Advanced Unresectable Pancreatic Cancer patients

Induction Chemotherapy Followed by Concomitant Chemoradiation using Intensity Modulated Radiotherapy Technique in Locally Advanced Unresectable Pancreatic Cancer patients

Carbon-Ion Radiotherapy Combined with Concurrent Chemotherapy for Locally Advanced Pancreatic Cancer: A Retrospective Case Series Analysis

Systemic chemotherapy has significantly improved in recent years. In this study. the clinical impact of carbon-ion radiotherapy (CIRT) with concurrent chemotherapy for locally advanced unresectable pancreatic cancer (URPC) was evaluated. Methods: Patients with URPC who were treated with CIRT between January 2016 and December 2020 were prospectively registered and analyzed. The major criteria for registration were (1) diagnosed as URPC on imaging; (2) pathologically diagnosed adenocarcinoma; (3) no distant metastasis; (4) Eastern Cooperative Oncology Group performance status of 0–2; (5) tumors without gastrointestinal tract invasion; and (6) available for concurrent chemotherapy. Patients who received neoadjuvant chemotherapy (NAC) for more than one year prior to CIRT were excluded. Results: Forty-four patients met the inclusion criteria, and thirty-seven received NAC before CIRT. The median follow-up period of living patients was 26.0 (6.0–68.6) months after CIRT. The estimated two-year overall survival, local control, and progression-free survival rates after CIRT were 56.6%, 76.1%, and 29.0%, respectively. The median survival time of all patients was 29.6 months after CIRT and 34.5 months after the initial NAC. Conclusion: CIRT showed survival benefits for URPC even in the multiagent chemotherapy era.

Combination L-Glutamine with Gemcitabine and Nab-Paclitaxel in Treatment-Naïve Advanced Pancreatic Cancer: The Phase I GlutaPanc Study Protocol.

Advanced pancreatic cancer is underscored by progressive therapeutic resistance and a dismal 5-year survival rate of 3%. Preclinical data demonstrated glutamine supplementation, not deprivation, elicited antitumor effects against pancreatic ductal adenocarcinoma (PDAC) alone and in combination with gemcitabine in a dose-dependent manner. The GlutaPanc phase I trial is a single-arm, open-label clinical trial investigating the safety of combination L-glutamine, gemcitabine, and nab-paclitaxel in subjects (n = 16) with untreated, locally advanced unresectable or metastatic pancreatic cancer. Following a 7-day lead-in phase with L-glutamine, the dose-finding phase via Bayesian design begins with treatment cycles lasting 28 days until disease progression, intolerance, or withdrawal. The primary objective is to establish the recommended phase II dose (RP2D) of combination L-glutamine, gemcitabine, and nab-paclitaxel. Secondary objectives include safety of the combination across all dose levels and preliminary evidence of antitumor activity. Exploratory objectives include evaluating changes in plasma metabolites across multiple time points and changes in the stool microbiome pre and post L-glutamine supplementation. If this phase I clinical trial demonstrates the feasibility of L-glutamine in combination with nab-paclitaxel and gemcitabine, we would advance the development of this combination as a first-line systemic option in subjects with metastatic pancreatic cancer, a high-risk subgroup desperately in need of additional therapies.

Abstract 5397: Prediction of conversion surgery completion following neoadjuvant modified FOLFIRINOX in borderline resectable and locally advanced pancreatic adenocarcinoma: machine learning algorithm analysis

Abstract Background: Neoadjuvant modified (m) FOLFIRINOX is a standard therapy for medically fit patients with borderline resectable pancreatic cancer (BRPC) and locally advanced unresectable pancreatic cancer (LAPC). Completion of conversion surgery following mFOLFIRINOX is an important prognostic factor. In this study, we evaluated multiple machine learning models to predict completion of conversion surgery following neoadjuvant mFOLFIRINOX in BRPC and LAPC. Methods: Between January 2017 and December 2020, a total of 647 patients with BRPC and LAPC treated with neoadjuvant mFOLFIRINOX at Asan Medical Center, Seoul, South Korea were enrolled. All demographic and clinicopathological data were retrospectively collected; age, ECOG performance status, BMI, resectability as per the NCCN guidelines, tumor location, tumor size, maximum standardized uptake value assessed by 18F-FDG PET/CT, number of cycles of mFOLFIRINOX, tumor response to mFOLFIRINOX, and serum CA 19-9. Several machine learning models, such as logistic regression and random forest classifier, were trained to predict curative-intent resection and were then internally validated. The relative importance of each variable was analyzed using both Gini importance and permutation importance. Results: Among 647 patients, 173 (26.7%) underwent curative-intent conversion surgery (R0 or R1) following mFOLFIRINOX. The patients who underwent surgery showed significantly better overall survival (median 42.1 vs 17.2 months, P&amp;lt;0.0001) than those who did not. In multivariable analysis using logistic regression, age, resectability as per the NCCN guidelines, tumor size, number of cycles of mFOLFIRINOX, tumor response to mFOLFIRINOX, and CA 19-9 change rate (percentage change in CA 19-9 after mFOLFIRINOX) were significantly correlated to tumor removal with curative-intent conversion surgery. Random forest classifier showed the best predictive capability with AUC at 0.832. The most important feature was the CA 19-9 change rate. Conclusions: In this large cohort-based analysis, completion of conversion surgery could be predicted successfully in BRPC and LAPC patients treated with neoadjuvant mFOLFIRINOX using machine learning models. Further external validation is necessary for generalization. Citation Format: Hyunseok Yoon, Kyu-Pyo Kim, Inkeun Park, Jae Ho Jeong, Heung-Moon Chang, Baek-Yeol Ryoo, Changhoon Yoo. Prediction of conversion surgery completion following neoadjuvant modified FOLFIRINOX in borderline resectable and locally advanced pancreatic adenocarcinoma: machine learning algorithm analysis. [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 5397.

Association between Survival Duration of Older Patients with Advanced Unresectable Pancreatic Cancer and Appetite Loss: A Retrospective Cohort Study.

This retrospective cohort study clarified associations between trajectories in palliative care and appetite loss among older patients with advanced unresectable pancreatic cancer and reviewed pancreatic cancer diagnosis among these populations in rural community hospitals. Patients aged &gt;65 years and with pancreatic cancer in a rural community hospital were enrolled. The primary outcome was survival duration from the time of pancreatic cancer diagnosis. Participants were divided into those with and without appetite loss. Cumulative event-free survival rates were calculated using the Kaplan-Meier method, analyzed using the log-rank test, and stratified by factors with statistically significant between-group differences (serum albumin). The mean participant age was 84.14 (SD, 8.34) years; 31.4% were men. Significant between-group differences were noted in albumin concentration and survival duration. Kaplan-Meier curves showed a significant between-group difference in survival probability (p &lt; 0.001). Survival duration significantly differed after stratification by albumin level (p &lt; 0.001). Appetite loss may be a useful symptom for predicting mortality among older patients with unresectable pancreatic cancer, and hypoalbuminemia may accelerate deterioration in their conditions. Accordingly, subjective appetite loss observed by patients and families should be assessed to predict mortality, and it is advisable for physicians to promptly discuss relevant and advanced directives at appropriate timings.

The efficacy and safety of modified FOLFIRINOX for unresectable advanced pancreatic cancer in elderly versus young patients: A multicenter retrospective cohort study

In the treatment of advanced pancreatic cancer (APC), FOLFIRINOX (FX), including its dose-modified regimen (mFX), is considered an effective regimen; however, FX is also known to be associated with a high incidence of adverse events due to its multi-agent combination regimen. The efficacy and safety in elderly patients with APC have not been well studied. AimTo compare the safety and efficacy of first-line mFX for unresectable APC in elderly and young patients. MethodsThis was a multicenter retrospective cohort study included patients who received first-line mFX for unresectable APC. A total of 151 patients were included and divided into the elderly (≥65 years old; 76 patients) and young (<65 years old; 75 patients) groups. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS) and adverse events (AEs). ResultsThe median OS and PFS were similar between the two groups (OS: 14.4 months versus 13.9 months, p = 0.42; PFS: 7.4 months versus 6.6 months, p = 0.65). Although severe AEs (≥ grade 3) were observed frequently in both groups (80% versus 84.2%, p = 0.53), there was no significant difference in any of the events between the groups. In the multivariate analysis evaluating the factors affecting OS and febrile neutropenia, age was not significant factors in both analyses. ConclusionFirst-line mFX for APC in elderly patients was as safe and effective as in younger patients if performance status was good. Further evaluation in a larger cohort is required to confirm our findings.

Multi-Institutional Comparison of Ablative Radiation Therapy in 5 Versus 15-25 Fractions for Locally Advanced Pancreatic Cancer

<h3>Purpose/Objective(s)</h3> Ablative RT doses ∼100Gy BED₁₀ are associated with improved overall survival (OS) in patients with locally advanced unresectable pancreatic cancer (LAPC), but the optimal fractionation scheme remains unknown. <h3>Materials/Methods</h3> We performed a retrospective analysis of consecutive LAPC patients treated at 2 high-volume institutions with either 50 Gy in 5 fractions using a 0.35T MR Linac and online adaptive replanning between 2018-2021 or 67.5-75 Gy in 15-25 fractions using CBCT guidance and selective offline adaptive replanning between 2016-2019. All were treated with breath hold or gating. Elective nodal coverage was used in 94%. Clinical characteristics between the groups were compared using Fisher's exact test. Freedom from local progression (FFLP) by RECIST and OS were estimated from time of RT with the Kaplan-Meier method. Log-rank test and Cox proportional hazards regression model were used for univariate (UVA) and multivariate (MVA) analyses. <h3>Results</h3> 183 patients were evaluated including 62 (34%) treated with 50 Gy in 5 fractions, 23 (123%) treated with 67.5 Gy in 15 fractions, and 98 (54%) treated with 75 Gy in 25 fractions. Median age was 67 years (range 35 to 91), 53% were male, 72% had a head tumor location, 81% were T3/4 with a median tumor size of 3.8 cm (range 1.4-7.4 cm) and 38% were lymph node positive. Patients receiving 5 fractions were more likely to be N0 than patients receiving 15-25 fractions (69.3% vs 44.6%, p=0.0219), and there were no other clinical differences between the groups. 98% received induction chemotherapy for a median of 3.9 months (FOLFIRINOX 61%, Gemcitabine/Nab-paclitaxel 29%, other 10%). Median follow-up was 38 months. Median FFLP and OS were 31 and 18 months, with 2-yr FFLP and 2-yr OS of 62.9% (95%CI 47.9 – 69.3%) and 36.2% (26.0 – 40.9%), respectively. There were no significant differences in FFLP (HR= 1.493, 95%CI 0.8030 – 2.775, p=0.1598) or OS (HR=1.321, 95%CI 0.8835 – 1.974, p=0.1580) between patients receiving 5 vs 15-25 fractions, respectively, on UVA. Likewise, after adjusting for T stage, nodal status, tumor size, chemotherapy type and duration, there were no significant differences in OS between the groups on MVA (HR=1.234, 95%CI 0.8151 – 1.833, p=0.3070). The rate of grade 3+ GI bleeding was 4.8% and 8% (p=0.5476) in patients receiving 5 vs 15-25 fractions, respectively. <h3>Conclusion</h3> In appropriately selected LAPC patients, ablative RT (BED₁₀ ∼100 Gy) in 5 fractions delivered with MR guidance and online adaptive replanning or 15-25 fractions delivered with CT guidance and selective offline adaptive replanning both appear to achieve excellent efficacy and minimal severe toxicity. Choice of fractionation scheme should be based on anatomical considerations and available technology.

Impact of First-Line FOLFIRINOX-Induced Peripheral Neuropathy on the Efficacy of Second-Line GnP in Patients with Unresectable Advanced Pancreatic Cancer.

Modified FOLFIRINOX (mFFX) and Gemcitabine plus nab-paclitaxel (GnP) are effective first-line chemotherapies for unresectable advanced pancreatic cancer (APC); however, both lead to peripheral neuropathy (PN). Aims: To evaluate the impact of first-line mFFX-induced PN on the efficacy of second-line GnP in patients with APC. Methods: A database containing patients with APC was retrospectively analyzed to evaluate patients who received second-line GnP after first-line mFFX failure between September 2014 and January 2021. The efficacy and safety of GnP were compared between patients with PN ≥ Grade 2 (PN group) and PN ≤ Grade 1 (non-PN group) at the start of second-line GnP. Cox proportional hazards analysis was also performed to examine the effect on overall survival (OS) and time-to-treatment failure (TTF). Results: Fifty-nine patients (PN group, 18 patients; non-PN group, 41 patients) were included. Median OS and TTF in the PN versus non-PN group were 7.7 versus 5.7 months (p = 0.19) and 3.8 versus 2.7 months (p = 0.18), respectively. Multivariate analysis showed that PN (≥Grade 2) was not a significant factor affecting either OS (hazard ratio (HR) 0.66, 95% confidence interval [CI] 0.33–1.31, p = 0.24) or TTF (HR 0.71, 95% CI 0.38–1.33, p = 0.28). No significant difference was observed in the relative dose intensity of GEM or nab-PTX, and incidence of adverse events. Conclusions: mFFX-induced PN has little impact on the efficacy and safety of second-line GnP in patients with APC. Second-line GnP could be a possible treatment option regardless of the presence of PN.

Efficacy and Safety of the Combination of Nano-Liposomal Irinotecan and 5-Fluorouracil/L-Leucovorin in Unresectable Advanced Pancreatic Cancer: A Real-World Study

Introduction: This retrospective study investigated the efficacy and safety of nano-liposomal irinotecan (nal-IRI) plus 5-fluorouracil/L-leucovorin (5-FU/l-LV) treatment in the second-line or later setting for advanced pancreatic cancer under real-world conditions. Methods: Between June 2020 and September 2021, a total of 44 patients with unresectable advanced pancreatic cancer treated with nal-IRI + 5-FU/l-LV in our affiliated hospitals were included. The prognosis, predictive factors (including systemic inflammation-based prognostic indicators), and adverse events were investigated. Results: The median age was 68 (interquartile range 62–73) years old, and 22 patients (50.0%) were male. Concerning tumor factors, 9 patients (20.5%) had local advanced disease and 35 patients (79.5%) had metastases. Twenty-five of the 44 patients were receiving second-line treatment, and 19 were receiving third-line or later treatment. The median overall survival (OS) and progression-free survival were 9.0 (range, 0.7–15.4) months and 4.4 (range, 0.6–15.4) months, respectively. The overall response rate was 5.3%. The disease control rate was 44.7%. Patients with a neutrophil-to-lymphocyte ratio of ≥2.7 had a significant risk of a poor OS (HR = 0.275, p = 0.017). Adverse events were manageable, although gastrointestinal symptoms and neutropenia were observed. The most common grade ≥3 adverse event was neutropenia, which was reported in 20% of patients. Conclusions: Nal-IRI + 5-FU/l-LV therapy was considered to be a useful regimen as second-line or later treatment for unresectable advanced pancreatic cancer, even in clinical practice.

A multicenter, randomized, double-blind phase III clinical study to evaluate the efficacy and safety of KN046 combined with nab-paclitaxel and gemcitabine versus placebo combined with nab-paclitaxel and gemcitabine in patients with advanced pancreatic cancer (ENREACH-PDAC-01).

TPS4189 Background: Pancreatic cancer is biologically aggressive, and the majority of pts was diagnosed as locally advanced or metastatic disease. Nab-paclitaxel and gemcitabine is a frequently used regimen for advanced pancreatic cancer, but chemoresistance is unavoidable. The combination of immunotherapy with chemotherapy have shown efficacy for certain types of cancer, but no similar results have been obtained in pancreatic cancer. KN046, a novel recombinant humanized bispecific antibody, can simultaneously block PD-1/PD-L1 and CTLA-4 pathways and restore T-cell immune response to tumor. In a phase Ⅱ clinical trial (NCT04324307), as of August 10, 2021, 53 pts with unresectable advanced pancreatic cancer had received one cycle KN046 combined AG regimen treatment and 31 subjects had received post-baseline tumor assessment at least once. Objective response rate (ORR) was 45.2% (95% CI: 27.3%, 64.0%) and disease control rate (DCR) was 93.5% (95% CI: 78.6%, 99.2%)，excellent preliminary results have been achieved. Based on this, a phase III pivotal study (ENREACH-PDAC-01) is conducting now in China to verify the efficacy and safety of KN046 plus nab-paclitaxel and gemcitabine as first-line treatment for advanced pancreatic cancer (NCT05149326). Methods: This nationwide multicenter phase III clinical trial enrolled pts with histologically or cytologically confirmed unresectable locally advanced or metastatic pancreatic ductal adenocarcinomas with a WHO performance score of 0 or 1 and expected survival period of more than 3 months. Eligible pts will be randomized 1:1 to intervention group or control group and receive 4-6 cycles of KN046 (5mpk Q2W) or placebo combined with nab-paclitaxel (initial dose: 125mg/m2 D1,8,15 Q4W) and gemcitabine (initial dose: 1000mg/m2 D1,8,15 Q4W) followed by KN046 (5mpk Q2W) or placebo with gemcitabine（QW × 3, 1 week off） maintenance therapy. Treatment will continue until disease progression or intolerable toxicity, withdrawal of consent, loss to follow-up or death, end of study, whichever occurs first. The primary endpoint is overall survival (OS). Key secondary endpoints are ORR and progression free survival (PFS). PFS and ORR will be assessed independently per RECIST v1.1 at screening, every 8 weeks for 1 year and then every 12 weeks until disease progression. Tumor and blood samples will be collected at baseline and during study treatment for pharmacokinetic, immunogenicity and biomarker assessment. The first patient was enrolled in early February 2022. Clinical trial information: NCT05149326.

Real-world evaluation of AG plus PD-1 antibody in old patients with advanced unresectable pancreatic cancer.

e16226 Background: Unresectable pancreatic cancer (PC) is associated with fatal outcomes despite chemotherapy and radiation. PD-1 antibodies might provide favorable long-term survival in combination with chemotherapy according to previous clinical trials and pilot studies. In this study, we conducted a real-world evaluation of PD-1 antibody in old patients with unresectable PC. We also aimed to explore biomarkers for the early prediction of PD-1 antibodies response. Methods: This is a single-arm, single-center, real-world study. Primary Objectives: ORR. Secondary Objectives: DCR, OS, PFS, Safety(CTCAE). Exploratory Objectives: The alteration of molecular biomarkers to PD-1 antibodies treatment including IL-2, IL-4, IL-10, IL-16, TNF¦Á and IFN-¦Ã, ect. Key eligibility criteria: Histopathologically confirmed advanced unresectable PC; Without systematic treatment; ¡Ý60 years old; ECOG PS 0 or 1; Evaluated by mRECIST PD-1 plus AG, Q3W Surgery Until disease progression, unacceptable toxicity, or up to 2 years. Results: From Jan 2021 to Dec 2021, 10 unresectable PC patients were enrolled in Yuhang campus, the first affiliated hospital, Zhejiang university school of medicine, which their baseline characteristics were listed in Table. A total of 9 patients were finally included and analyzed. Clinical decisions were made by multi-disciplinary team. The treatment efficacy was evaluated by mRECIST. A total of 9 patients were assessable for response. ORR was 33.3%, with 3/9 partial response (PR). 5/9 patients were stable disease (SD), and DCR was 88.9%. Conversion therapy uses rational immunotherapy and chemotherapy and so on combined with MDT assessment to translate initial unresectable case to resectable one, which obviously prolongs survival time and improves quality of life. For patients with surgically unresectable PC 2 patients were successfully transformed. The rate of overall surgical conversions was 22.2%. The most common adverse events were anemia (6 [60%] patients). There were no treatment-related level 4 and 5 adverse events. There was no treatment-related cardiotoxicity. No patients were interrupted due to adverse events. Conclusions: PD-1 antibody plus Chemotherapy demonstrates significant clinical activity and favorable tolerability in old patients with advanced unresectable PC, and DCR was 88.9%.[Table: see text]