The phase III NAPOLI 3 trial (NCT04083235) included 770 patients with mPDAC who were randomized (1:1) to receive liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) or nab-paclitaxel + gemcitabine (Gem+NabP) in 28-day cycles. As previously reported, at a median follow-up of 16.1 months, NALIRIFOX demonstrated statistically significant improvements in overall survival and progression-free survival versus Gem+NabP. Here, we report EORTC QLQ-C30 results from NAPOLI 3. The EORTC QLQ-C30 was completed at baseline, day 1 of each 28-day cycle and at the end of treatment. A mixed model repeated measures (MMRM) model was used to describe the global health status (GHS) evolution over time between treatment arms. Time until definitive deterioration (TUDD) was defined as the time between randomization and first occurrence of a decrease ≥ 10 points in QLQ-C30 score without further improvement of ≥ 10 points or further data due to discontinuation. Mean GHS scores at baseline were similar between treatment arms (NALIRIFOX 62.1; Gem+NabP 61.2); from week 16, there was a trend towards improvement in GHS scores in the NALIRIFOX arm relative to the Gem+NabP arm. The median TUDD of GHS was 15.7 months with NALIRIFOX and 12.2 months with Gem+NabP (stratified Cox hazard ratio 0.74 [95% confidence interval: 0.53–1.04]; nominal p = 0.08). At 6 months, 26.4% and 31.7% of patients NALIRIFOX and Gem+NabP arms, respectively, experienced definitive deterioration in GHS. The TUDD of physical, role and emotional functioning, pain, dyspnea and constipation were longer, with nominal p ≤ 0.05, in patients who received NALIRIFOX versus Gem+NabP. NALIRIFOX was associated with a trend towards improvement in GHS scores and longer TUDD in several EORTC QLQ-C30 subscales compared with Gem+NabP. However, these results should be interpreted with caution owing to the number of missing assessments.

Liposomal irinotecan and 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA and Europe for the treatment of metastatic pancreatic ductal adenocarcinoma (mPDAC) after progression with gemcitabine-based therapy. A phase 1/2 study (NCT02551991) demonstrated promising anti-tumour activity in patients with mPDAC who received first-line liposomal irinotecan 50 mg/m 2 , 5-FU 2400 mg/m2, LV 400 mg/m2 and oxaliplatin 60 mg/m 2 (NALIRIFOX). Here, we present results from NAPOLI 3 (NCT04083235), a randomized open-label phase 3 study investigating the efficacy and safety of NALIRIFOX compared with nab-paclitaxel 125 mg/m 2 + gemcitabine 1000 mg/m 2 (Gem+NabP) as first-line therapy in patients with mPDAC. Eligible patients with histopathologically/cytologically confirmed untreated mPDAC were randomized (1:1; stratified by Eastern Cooperative Oncology Group performance status, geographic region and presence/absence of liver metastases) to receive NALIRIFOX on days 1 and 15 of a 28-day cycle or Gem+NabP on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS) and overall response rate (ORR), both according to Response Evaluation Criteria in Solid Tumours version 1.1 as per investigator assessment. OS was evaluated when at least 543 events were observed using a stratified log-rank test with an overall one-sided significance level of 0.025. A sensitivity analysis of OS censored at initiation of subsequent anticancer therapy was performed using a stratified log-rank test. Overall, 770 patients (NALIRIFOX, n = 383; Gem+NabP, n = 387) comprised the intention-to-treat population. Baseline characteristics were balanced between arms. At a median follow-up of 16.1 months, 544 events had occurred. Median OS was 11.1 months in the NALIRIFOX group and 9.2 months in the Gem+NabP group (hazard ratio [HR] 0.83 [95% confidence interval [CI] 0.70–0.99], p = 0.04); survival at 18 months was 26.2% and 19.3%, respectively. Median PFS was 7.4 months for NALIRIFOX versus 5.6 months for Gem+NabP (HR 0.69 [95% CI 0.58–0.83]; p < 0.0001); at 18 months, 11.4% and 3.6% of patients receiving NALIRIFOX and Gem+NabP, respectively, were progression-free. When censored at initiation of subsequent anticancer therapy, median OS was 15.1 months in the NALIRIFOX group versus 9.2 months in the Gem+NabP group (HR 0.71 [95% CI 0.56–0.90], p < 0.005). ORR (95% CI) was 41.8% (36.8–46.9) for NALIRIFOX and 36.2% (31.4–41.2) for Gem+NabP (p = 0.11); median (95% CI) duration of response was 7.3 (5.8–7.6) and 5.0 (3.8–5.6) months, respectively. In the safety population, grade 3/4 treatment-emergent adverse events occurring in at least 10% of patients receiving NALIRIFOX (n = 370) versus Gem+NabP (n = 379) included diarrhoea (20.3% vs 4.5%), nausea (11.9% vs 2.6%), hypokalaemia (15.1% vs 4.0%), anaemia (10.5% vs 17.4%) and neutropenia (14.1% vs 24.5%). First-line NALIRIFOX demonstrated clinically meaningful and statistically significant improvement in OS and PFS compared with Gem+NabP in patients with mPDAC. The NALIRIFOX safety profile was consistent with the profiles of the regimen components and generally manageable. These results support the NALIRIFOX regimen as a new reference regimen for the first-line treatment of patients with mPDAC.

Knockout lines of HepG2 and Hep3B exhibited decreased cell proliferation, migration, and in vivo tumor growth compared to wildtype. GPC-3 deficiency was associated with increased sensitivity to radiation therapy. Studies identifying the pathways through which this radiosensitivity is mediated are ongoing.

Systemic chemotherapy is the mainstay of treatment of pancreatic adenocarcinoma (PAC). Evaluating therapeutic response is essential to achieve the maximum possible benefit. We aimed to investigate the role of tissue- and blood -based biomarkers in their feasibility to predict the effect of chemotherapy in PAC patients. Between April 2019 and December 2020, a total of 238 patients were sequentially enrolled in this prospective cohort study. Among them, 112 (47%) had metastatic or recurrent PAC. Tumor tissue expression of hENT1, DCK, CES2, and SMAD4 were evaluated by immunohistochemistry, which biomarkers were reported to predict the response to gemcitabine or FOLFIRINOX chemotherapies. Germline BRCA mutations and MSI status were also tested. The concentration and fraction of KRAS mutations were determined through multiplex detection of KRAS mutations in plasma samples by use of a droplet digital PCR kit (Bio-Rad). One hundred thirty patients were received FOLFIRINOX as first-line chemotherapy, while 58 patients were treated with gemcitabine-based chemotherapy. Progression-free survival and overall survival were compared according to marker expression. There is no significant association between tissue expressions of hENT1, DCK, CES2, and SMAD4 and survival outcomes. Higher mutant KRAS concentration was significantly associated with poorer progression-free survival (HR 2.72, 95% CI 1.53-4.82; P < 0.001) and overall survival (HR 2.73, 95% CI 1.36-5.47; P < 0.01) in patient who received FOLFIRINOX. There was no predictive effect of mutant KRAS concentration in patient with gemcitabine-based chemotherapy. The preliminary results suggest that high pre-treatment KRAS mutation was associated with a negative impact on survival in patients with FOLFIRINOX. Further investigations are warranted.

Introduction: Pancreatic cancer is the 4th deadliest cancer in Europe, with more than 95% of those affected dying from the disease and it is set to become the second greatest cause of death from cancer by 2020 (ECPC, European Cancer Patient Coalition). Less than 20% of pancreatic cancer patients are diagnosed with a resectable and potentially curable disease as the vast majority of patients have advanced disease at the time of diagnosis with a median survival of approximately 6 months. EndoTAG-1 is a novel formulation of cationic liposomes for the treatment of solid tumors, carrying paclitaxel embedded in the liposome membrane. EndoTAG-1 specifically displays antivascular and antiangiogenic activity. Cationic liposomes are known to bind and internalize at tumor endothelial cells after intravenous administration, which is the basis for the new mode of action of EndoTAG-1. Using a cationic liposome formulation, the cytostatic and cytotoxic activities of paclitaxel are targeted to the activated tumor endothelial cells. FOLFIRINOX regimen is the standard first-line treatment for pancreatic cancer patients with good performance status. However, the optimal management strategy for patients who fail initial FOLFIRINOX remains undefined. There is still no standard of care in second-line therapy for patients with disease progression. Methods: A total of 218 subjects will be enrolled and randomized in a 1:1 ratio to Arm A (EndoTAG-1 plus gemcitabine) and Arm B (gemcitabine monotherapy). Based on the sample size calculation, the primary endpoint analysis will require 167 events (deaths) for 196 subjects. This sample size is sufficient to detect a 40% reduction in the risk of death in Arm A, as compared with Arm B (hazard ratio, 0.60) using a 2-sided log-rank test with 90% power and an overall significance level of 0.05 two-sided test. The overall survival assumption for the sample size is based on published literature data comparing the therapeutic effects of gemcitabine monotherapy and gemcitabine combination regimen on patients with advanced pancreatic cancer after previous FOLFIRINOX treatment. The hazard ratio for death of 0.60 with median overall survival of 4.4 months for gemcitabine monotherapy (Conroy et al. 2011) and 7.3 months for gemcitabine + paclitaxel combination (Portal et al. 2015) was used for the sample size calculation.

Small cell lung cancer (SCLC) is an aggressive cancer. Although sensitive to initial therapy, recurrence is almost inevitable. The molecular mechanisms underlying recurrence are unknown. We have previously demonstrated that complex genomic and T cell receptor (TCR) intratumor heterogeneity (ITH) was associated with increased risks of relapse in non-small cell lung cancers (NSCLC). Genomic ITH and TCR architecture of SCLC and its clinical impact have not been well studied, largely due to lack of tumor specimens as surgery is rarely used to treat SCLC. We performed multiregion whole-exome sequencing and TCR sequencing of 49 tumor samples from 18 resected limited-stage SCLCs to delineate the immunogenomic ITH of SCLC. We compared the results to those in NSCLC and assessed the association of genomic and TCR attributes with patient's survival. On average, 544 mutations/sample were detected. The median proportion of trunk mutations (mutations identified in all regions within the same tumors) was 80.4% versus 70% in NSCLC (TRACERx, Jamal-Hanjani, NEJM, 2017, p=0.08) and all TP53 and RB1 mutations were trunk mutations, suggesting these mutations were early events during carcinogenesis of this cohort of SCLCs. A higher non-synonymous tumor mutational burden (TMB) was associated with a higher T cell density (infiltration) in the tumor (r=0.46, p=0.005). Compared to the TCR repertoire of NSCLC (Reuben, WCLC, 2017), these SCLC tumors demonstrated significantly lower T-cell density (0.05 versus 0.24, p<0.0001), richness (diversity, 1,043 versus 3,666, p<0.0001) and clonality (reactivity, average 0.02 versus 0.15, p<0.0001) despite similar non-synonymous TMB (average 187 in SCLC versus 176 mutations/sample in NSCLC). Only 0.2% to 14.6% of T cells were detectable across all regions from the same tumors, suggesting substantial TCR ITH. Jaccard index (JI), a parameter quantifying TCR ITH was significantly lower in SCLC than in NSCLC (0.06 versus 0.1, p<0.0001) implying higher level of TCR ITH in SCLC than NSCLC. Interestingly, higher T-cell density, richness or clonality appeared to be associated with lower risk of recurrence numerically. Furthermore, higher TCR JI (less degree of ITH) was associated with significantly longer overall survival (HR=0.15, p=0.04). Limited-stage SCLC tumors have distinct TCR repertoire and genomic ITH architecture. Overall, SCLC may have a more pronounced immunosuppressive microenvironment and higher level of TCR repertoire ITH than NSCLC. Nevertheless, higher degree of T cell infiltration and clonal expansion as well as more homogeneous T cell response may be associated with more favorable clinical outcome in patients with limited-stage SCLC.

Non-small cell lung cancer (NSCLC) is characterized by a high mutational load. Accordingly, it is also among the tumor types responding to immune checkpoint blockade, likely through harnessing of the anti-tumor T cell response. However, the lung is continuously exposed to the outside environment, which may result in a continuous state of inflammation against outside pathogens unrelated to the tumor microenvironment. Therefore, further investigation into the T cell repertoire and T cell phenotypes across normal lung and tumor is warranted. We performed T cell receptor (TCR) sequencing on peripheral blood mononuclear cells (PBMC), normal lung, and tumor from 225 NSCLC patients, among which, 96 patients were also subjected to whole exome sequencing (WES) of PBMC, tumor and normal lung tissues. We further performed Cytometry by Time-of-Flight (CyTOF) on 10 NSCLC tumors and paired normal lung tissues to phenotype immune and T cell subsets. Comparison of the T cell repertoire showed 9% (from 4% to 15%) of T cell clones were shared between normal lung and paired tumor. Furthermore, among the top 100 clones identified in the tumor, on average 57 (from 0 to 95) were shared with paired normal lung tissue. Interestingly, T cell clonality was higher in the normal lung in 89% of patients suggesting potential differences in the immune response and immunogenicity. A substantial number of somatic mutations were also identified not only in NSCLC tumors (average 566; from 147 to 2819), but also in morphologically normal lung tissues (average 156; from 50 to 2481). CyTOF demonstrated striking differences in the immune infiltrate between normal lung and tumor, namely a lower frequency of PD-1+CD28+ T cells (both CD4+ and CD8+) in the normal lung (2.7% versus 3.0% in tumor). In addition, a unique GITR+ T cell subset (0.96%) was entirely restricted to the normal lung. Conversely, increases in regulatory T cell frequency (CD4+FoxP3+) were observed in the tumor (10.4% vs 1.7% in normal lung), further highlighting the differences in T cell phenotype and response across normal lung and tumor. These results suggest that a substantial proportion of infiltrating T cells in NSCLC tumors may be residential T cells associated with response to environmental factors. However, normal lung and NSCLC tumors carry T cells of distinct phenotypes including increases in immunosuppressive T cells within the tumor which may further highlight the differences in the anti-tumor immune response.

Purpose: Current pancreatic cancer marker, CA19-9 has limited diagnostic accuracy. we aimed to identify a multiple marker panel capable of detecting pancreatic cancer in early stages eligible for surgical treatment, with high sensitivity and specificity. Methods: Pancreatic cancer biomarker candidates were screened through data mining from several databases and gene chip microarray experiment. Selected 1000 proteins' blood levels were measured using Multiple Reaction Monitoring Mass Spectrometry in 50 pancreatic ductal adenocarcinoma (PDAC) and 50 control samples. 54 proteins with high ranked diagnostic performance were selected for external validation. The validation test was performed in 1000 patients as well as control group. The best performing biomarker panel was validated using immunoassays. Results: A panel comprising CA19-9, LRG1 and TTR was determined to be the best biomarker and the results were validated using immunoassay. The AUC of the panel was 0.941 and the sensitivity was 0.850 whereas those of CA19-9 alone were 0.847 and 0.746, respectively. This panel showed 20% increased sensitivity in fixed 90% specificity especially in stage I-II PDAC. Additionally our maker showed 30% increase of AUC even in normal CA 19-9 patents with PDAC. Also, our marker was highly selective for PDAC than that of CA19-9 to differentiate between PDAC from other cancers. Conclusion: A new diagnostic panel showed advantages over CA19-9 in terms of sensitivity and selectivity for pancreatic cancer. Noticeably, this panel shows good performance to detect early stage pancreatic and could be useful even in CA19-9 negative patients.