First-line Gemcitabine-based Therapy Research Articles

Superior survival benefits of triple combination immunotherapy compared to standard chemotherapy as second-line treatment for advanced biliary tract cancer: a retrospective analysis.

Advanced biliary tract cancer (BTC) is associated with a poor prognosis and limited options for second-line treatment. The TOPAZ-1 and KEYNOTE-966 trials have demonstrated the benefits of combining immune checkpoint inhibitors (ICIs) with chemotherapy in treating BTC. However, the efficacy of FOLFOX as a second-line therapy is limited, highlighting the need for more effective treatment approaches. This retrospective study compared a triple regimen-comprising ICIs, tyrosine kinase inhibitors, and chemotherapy-to standard chemotherapy in patients with metastatic BTC who had progressed on first-line gemcitabine-based therapy. The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety. Of the 121 patients, 86 received the triple regimen and 35 received standard chemotherapy. The triple regimen showed a significantly higher ORR (37.2% vs. 2.8%, p < 0.0001) and DCR (89.5% vs. 71.4%). The median PFS was 6 months for the triple regimen compared to 2.0 months for standard chemotherapy (HR 0.29, p < 0.0001). The median OS was 16.0 months for the triple regimen versus 6.0 months for standard chemotherapy (HR 0.35, p < 0.0001). Treatment-related adverse events were comparable between the groups. The triple combination of immunotherapy offers superior survival benefits compared to standard chemotherapy as a second-line treatment for advanced BTC, warranting further investigation for potential clinical adoption.

Phase II study of combination pembrolizumab and olaparib in patients with advanced cholangiocarcinoma: Interim results.

452 Background: Unresectable cholangiocarcinoma (CCA) remains a cancer of dismal prognosis as these tumors tend to be highly chemotherapy-refractory, providing patients (pts) a median survival of only around nine months. We herein provide an interim update to this phase II, single-arm, open-label study, where we investigate the safety and efficacy of olaparib plus pembrolizumab in pts with CCA after first-line gemcitabine-based therapy. We hypothesize that olaparib will increase tumoral response to pembrolizumab by inducing DNA damage and increasing tumor antigen number to produce a durable immune response against CCA - thereby increasing the overall response rate (ORR) of pts from 17.5% (historic chemotherapy control) to 35%. Methods: In total, 36 histologically confirmed advanced cholangiocarcinoma pts will be enrolled onto this trial. Pts receive pembrolizumab, 200 mg, on day 1 of each 21-day cycle, and oral olaparib, 300 mg, twice daily. The primary objective is to assess ORR, while a secondary aim is to evaluate safety. Tumor biopsies are collected at baseline, the third week after treatment initiation, and disease progression; the tissue is tested for ERCC1, PD-1/PD-L1 expression, IDH1/2 mutation status, and immune cell (CD3 and CD8) response. CT or MRI is carried out every 6 weeks for the first 6 months and every 9 weeks for the next 6 months to assess clinical response. Results: At the cutoff date of September 26, 2021, 12 pts had been enrolled and received at least one dose of olaparib plus pembrolizumab. The median age is 62 years (range 47-74); most are female (N = 10) and Caucasian (N = 8). Ten pts were diagnosed with cholangiocarcinoma and 2 with gallbladder carcinoma. According to RECIST v1.1, partial response (PR) was seen in one pt (-50%), stable disease (SD) in 4 pts (one with promising ongoing response at 23% tumor shrinkage), and disease progression in 7 pts. Three pts are actively on trial (1 PR and 2 SD). Complete molecular analysis by FoundationOne CDx revealed mutations in ATM (N = 2), SKT11 (N = 1) , ARID1A (N = 2) , and IDH1 (N = 2); the full tumor profile will be presented at the ASCO-GI meeting. Primary grade 3 treatment-related adverse events (AEs) included anemia (N = 2) and diarrhea (N = 1. Grade 1/2 AEs included thrombocytopenia (N = 2), anemia (N = 1), rash (N = 1), and diarrhea (N = 1). Conclusions: Interim trial results indicate that combination olaparib and pembrolizumab has acceptable safety and manageable toxicity in pts with advanced cholangiocarcinoma. Clinical trial information: NCT04306367.

Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study

Treatment options are sparse for patients with advanced cholangiocarcinoma after progression on first-line gemcitabine-based therapy. FGFR2 fusions or rearrangements occur in 10-16% of patients with intrahepatic cholangiocarcinoma. Infigratinib is a selective, ATP-competitive inhibitor of fibroblast growth factor receptors. We aimed to evaluate the antitumour activity of infigratinib in patients with locally advanced or metastatic cholangiocarcinoma, FGFR2 alterations, and previous gemcitabine-based treatment. This multicentre, open-label, single-arm, phase 2 study recruited patients from 18 academic centres and hospitals in the USA, Belgium, Spain, Germany, Singapore, Taiwan, and Thailand. Eligible participants were aged 18 years or older, had histologically or cytologically confirmed, locally advanced or metastatic cholangiocarcinoma and FGFR2 fusions or rearrangements, and were previously treated with at least one gemcitabine-containing regimen. Patients received 125 mg of oral infigratinib once daily for 21 days of 28-day cycles until disease progression, intolerance, withdrawal of consent, or death. Radiological tumour evaluation was done at baseline and every 8 weeks until disease progression via CT or MRI of the chest, abdomen, and pelvis. The primary endpoint was objective response rate, defined as the proportion of patients with a best overall response of a confirmed complete or partial response, as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors, version 1.1. The primary outcome and safety were analysed in the full analysis set, which comprised all patients who received at least one dose of infigratinib. This trial is registered with ClinicalTrials.gov, NCT02150967, and is ongoing. Between June 23, 2014, and March 31, 2020, 122 patients were enrolled into our study, of whom 108 with FGFR2 fusions or rearrangements received at least one dose of infigratinib and comprised the full analysis set. After a median follow-up of 10·6 months (IQR 6·2-15·6), the BICR-assessed objective response rate was 23·1% (95% CI 15·6-32·2; 25 of 108 patients), with one confirmed complete response in a patient who only had non-target lesions identified at baseline and 24 partial responses. The most common treatment-emergent adverse events of any grade were hyperphosphataemia (n=83), stomatitis (n=59), fatigue (n=43), and alopecia (n=41). The most common ocular toxicity was dry eyes (n=37). Central serous retinopathy-like and retinal pigment epithelial detachment-like events occurred in 18 (17%) patients, of which ten (9%) were grade 1, seven (6%) were grade 2, and one (1%) was grade 3. There were no treatment-related deaths. Infigratinib has promising clinical activity and a manageable adverse event profile in previously treated patients with locally advanced or metastatic cholangiocarcinoma harbouring FGFR2 gene fusions or rearrangements, and so represents a potential new therapeutic option in this setting. QED Therapeutics and Novartis.

A Novel Multidrug-Resistant Cell Line from an Italian Intrahepatic Cholangiocarcinoma Patient.

Simple SummaryIntrahepatic cholangiocarcinoma (ICC) has limited prognosis and therapies. The first-line gemcitabine-based therapy provided poor benefits in terms of survival due to the development of resistance. Gemcitabine-resistance mechanisms were studied on pancreatic cancer models or cell lines derived from ICC patients of Eastern countries. Since ICC has different etiology and genetic/molecular characteristics depending on the ethnicity, appropriate preclinical models that recapitulate their biology are required. Thus, we aimed to establish and characterize an Italian ICC cell line, named 82.3. Cells were isolated from a patient-derived xenograft. After one year, immunophenotypical, biological, genetic, molecular features, and in vivo tumorigenicity in NOD/SCID mice were investigated. Furthermore, 82.3 cells displayed resistance to gemcitabine, 5-fluorouracil, carboplatin, and oxaliplatin. This model could be exploited either to investigate drug resistance mechanisms or to test alternative drugs through the identification of suitable targets to overcome drug resistance.Chemotherapy resistance is a relevant clinical issue in tumor treatment, in particular in biliary tract carcinoma (BTC), for which there are no effective therapies, neither in the first nor in the second line. The development of chemoresistant cell lines as experimental models to investigate the mechanisms of resistance and identify alternative druggable pathways is mandatory. In BTC, in which genetics and biological behavior depend on the etiology, ethnicity, and anatomical site of origin, the creation of models that better recapitulate these characteristics is even more crucial. Here we have established and characterized an intrahepatic cholangiocarcinoma (iCCA) cell line derived from an Italian patient, called 82.3. Cells were isolated from a patient-derived xenograft (PDX) and, after establishment, immunophenotypic, biological, genetic, molecular characteristics, and tumorigenicity in vivo in NOD/SCID mice were investigated. 82.3 cells exhibited epithelial morphology and cell markers (EPCAM, CK7, and CK19); they also expressed different cancer stem markers (CD44, CD133, CD49b, CD24, Stro1, PAX6, FOXA2, OCT3/4), α–fetoprotein and under anchorage-independent and serum-free conditions were capable of originating cholangiospheres. The population doubling time was approximately 53 h. In vitro, they demonstrated a poor ability to migrate; in vivo, 82.3 cells retained their tumorigenicity, with a long latency period (16 weeks). Genetic identity using DNA fingerprinting analysis revealed 16 different loci, and the cell line was characterized by a complex hyperdiploid karyotype. Furthermore, 82.3 cells showed cross-resistance to gemcitabine, 5-fluorouracil, carboplatin, and oxaliplatin; in fact, their genetic profile showed that 60% of genes (n = 168), specific for drug resistance and related to the epithelial-mesenchymal transition, were deregulated in 82.3 cells compared to a control iCCA cell line sensitive to chemotherapeutics. RNA sequencing analysis revealed the enrichment for genes associated with epithelial to mesenchymal transition (EMT), vasculature development, and extracellular matrix (ECM) remodeling, underlining an aggressive phenotype. In conclusion, we have created a new iCCA cell line of Caucasian origin: this could be exploited as a preclinical model to study drug resistance mechanisms and to identify alternative therapies to improve the prognosis of this tumor type.

Liposomal irinotecan plus fluorouracil/leucovorin versus FOLFIRINOX as the second-line chemotherapy for patients with metastatic pancreatic cancer: a multicenter retrospective study of the Korean Cancer Study Group (KCSG)

BackgroundThere is no clear consensus on the recommended second-line treatment for patients with metastatic pancreatic cancer who have disease progression following gemcitabine-based therapy. We retrospectively evaluated the clinical outcomes of liposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (FL) and FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) in patients who had failed on the first-line gemcitabine-based therapy.Patients and methodsFrom January 2015 to August 2019, 378 patients with MPC who had received nal-IRI/FL (n = 104) or FOLFIRINOX (n = 274) as second-line treatment across 11 institutions were included in this retrospective study.ResultsThere were no significant differences in baseline characteristics between groups, except age and first-line regimens. With a median follow-up of 6 months, the median progression-free survival (PFS) was 3.7 months with nal-IRI/FL versus 4.6 months with FOLFIRINOX (P = 0.44). Median overall survival (OS) was 7.7 months with nal-IRI/FL versus 9.7 months with FOLFRINOX (P = 0.13). There was no significant difference in PFS and OS between the two regimens in the univariate and multivariate analyses. The subgroup analysis revealed that younger age (<70 years) was associated with better OS with FOLFIRINOX. In contrast, older age (≥70 years) was associated with better survival outcomes with nal-IRI/FL. Adverse events were manageable with both regimens; however, the incidence of grade 3 or higher neutropenia and peripheral neuropathy was higher in patients treated with FOLFIRINOX than with nal-IRI/FL.ConclusionsSecond-line nal-IRI/FL and FOLFIRINOX showed similar effectiveness outcomes after progression following first-line gemcitabine-based therapy. Age could be the determining factor for choosing the appropriate second-line therapy.

Final results from a phase II study of infigratinib (BGJ398), an FGFR-selective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement.

265 Background: Treatment options for cholangiocarcinoma (CCA) after progression on first-line gemcitabine-based therapy are limited. Fibroblast growth factor receptor 2 ( FGFR2) gene fusions occur in 13–17% of intrahepatic CCA. A single-arm, phase II study (NCT02150967) evaluated infigratinib, an ATP-competitive FGFR1–3-selective oral tyrosine kinase inhibitor, in previously-treated advanced CCA with FGFR fusions/rearrangements. Methods: Adult patients with advanced/metastatic CCA with progression on ≥1 line of systemic therapy received infigratinib 125 mg orally for 21 days of each 28-day cycle until unacceptable toxicity or disease progression. All patients received prophylaxis with the oral phosphate binder sevelamer. Primary endpoint: objective response rate (ORR) by independent central review per RECIST v1.1, with duration of response (DOR). Secondary endpoints: progression-free survival (PFS), disease control rate, overall survival, safety, pharmacokinetics. Approximately 160 patients are planned (120/20/20 patients in Cohorts 1/2/3). This analysis focuses on Cohort 1 (patients with FGFR2 gene fusions or rearrangements without receiving a prior FGFR inhibitor). Results: As of 31 March 2020, 108 patients, including 83 (77%) with FGFR2 fusions, received infigratinib: median age 53 years (range 23–81 years); 54% had received ≥2 prior treatment lines. Median follow-up was 10.6 months (range 1.1–55.9 months). 96 patients (88.9%) discontinued treatment (12 ongoing). Centrally reviewed ORR was 23.1% (95% CI 15.6–32.2) including 1 CR and 24 PRs; median DOR was 5.0 months (range 0.9–19.1 months). Among responders, 8 (32.0%) patients had a DOR of ≥6 months. Median PFS was 7.3 months (95% CI 5.6–7.6 months). Prespecified subgroup analysis: ORR was 34% (17/50) in the second-line setting and 13.8% (8/58) in the third-/later-line setting (3–8 prior treatments). Most common treatment-emergent adverse events (TEAEs, any grade) were hyperphosphatemia (76.9%), eye disorders (67.6%, excluding central serous retinopathy/retinal pigment epithelium detachment [CSR/RPED]), stomatitis (54.6%), and fatigue (39.8%). CSR/RPED occurred in 16.7% of patients (including 1 G3 event; 0 G4). Other common grade 3/4 TEAEs were stomatitis (14.8%; all G3), hyponatremia (13.0%; all G3), and hypophosphatemia (13.0%; 13 G3, 1 G4). Conclusions: Infigratinib is associated with promising anticancer activity and a manageable AE profile in patients with advanced, refractory CCA with an FGFR2 gene fusion or rearrangement. A phase III study of infigratinib versus gemcitabine/cisplatin is ongoing in the front-line setting (NCT03773302). Clinical trial information: NCT02150967.

Liposomal irinotecan plus fluorouracil/leucovorin versus FOLFIRINOX as the second-line chemotherapy for patients with metastatic pancreatic cancer: Multicenter study of the Korean Cancer Study Group (KCSG).

4624 Background: There is no clear consensus on the second-line treatment for patients with metastatic pancreatic cancer (mPC). The aim of this study was to compare the efficacy and tolerability between liposomal irinotecan (nal-IRI) plus fluorouralcil/leucovorin (FL) and FOLFIRINOX (oxaliplatin/irinotecan/leucovorin/fluorouracil) in patients who failed to first-line gemcitabine-based therapy. Methods: In this retrospective study, 378 mPC patients who received nal-IRI/FL (n = 104) or FOLFIRINOX (n = 274) as the second-line treatment across 11 institutions from January 2015 to August 2019 were analyzed. The primary end point was progression free survival (PFS), and secondary end points were overall survival (OS), overall response rate, and tolerability. Results: There were no significant differences between the two groups in terms of baseline characteristics, except first-line regimen (previous gemcitabine/nab-paclitaxel, nal-IRI/FL, 85.6% vs. FOLFIRINOX, 51.5%; previous gemcitabine monotherapy, 5.8% vs. 24.5%). The median follow-up time was 6.0 months. The median PFS (nal-IRI/FL, 3.7 months vs. FOLFIRINOX, 5.0 months) and OS (nal-IRI/FL, 7.7 months vs. FOLFRINOX, 9.7 months) were comparable between two groups (P = 0.40 and 0.13, respectively). The overall response rate was not significantly different between two groups (nal-IRI/FL, 14% vs. FOLFRINOX, 16%; P = 0.644). In multivariate analysis, poor ECOG status, presence of liver metastasis, high NLR, and high CA19-9 were independent prognostic factors for PFS and OS, but chemotherapy regimen (nal-IRI/FL vs. FOLFRINOX) was not. In a subgroup analysis of patients with liver metastasis, FOLFIRINOX exerted significant PFS (median: 2.1 months vs. 4.1 months for nal-IRI/FL vs. FOLFIRINOX, respectively; P = 0.02) and OS (median: 6.7 months vs. 8.4 months for nal-IRI/FL vs. FOLFIRINOX, respectively; P = 0.04) benefit compared with nal-IRI/FL. Grade 3 neutropenia or higher were more frequently observed in FOLFIRINOX (47.2%) than nal-IRI/FL (35%) (P = 0.033). Grade 3 peripheral neuropathy was also common in FOLFIRIONX (5.9%) group compared with nal-IRI/FL (1.0%) (P = 0.049). Conclusions: In second-line setting for mPC after progression on gemcitabine-based therapy, both nal-IRI/FL and FOLFIRINOX regimen showed comparable efficacy and acceptable safety outcomes. FOLFIRINOX regimen might be preferentially considered in patients with liver metastasis.

Meta-analysis of OS for pancreatic cancer patients receiving 5FU and oxaliplatin-based therapy after failing first-line gemcitabine-containing therapy.

202 Background: Pancreatic cancer is the 3rd most common cause of cancer-related death in US. After progression on first-line gemcitabine-based therapy, guidelines suggest that 5FU with nanoliposomal irinotecan/irinotecan is the preferred regimen. Oxaliplatin (OXA) is not endorsed as prominently, as conflicting results have emerged on the efficacy of 5FU/OXA. This large variability in efficacy outcomes may be due to the heterogeneity of patient performance status (PS) or other confounding factors. We performed a meta analysis in an attempt to estimate the median (m) OS of patients receiving 5FU/OXA-containing regiments after failing first-line treatment with gemcitabine-containing therapy. Methods: A systematic review of literature and existing meta analyses for second-line treatment of pancreatic cancer was performed. Selection inclusion criteria included: prior gemcitabine treatment, second-line treatment of locally advanced or metastatic pancreatic cancer, 5FU and OXA; exclusion criteria included: oral 5FU (S1), irinotecan, capecitabine/cisplatin, no ECOG disclosure. A Bayesian fixed effect meta analysis was performed for the mOS with PS as predictor. A non-informative prior was used to establish the relationship between mOS and PS. The posterior median of OS and 95% predictive interval (PI) were summarized. Results: Eleven studies (454 patients) met the selection criteria for analysis. Median OS for patients receiving second-line 5FU and OXA-based therapy with ECOG PS 0-1 was 6.2 months (95% PI 5.4, 7.1). Restricting to FOLFOX (6 studies, 258 patients), mOS was 6.3 months (95% PI, 5.4, 7.4). Median OS were comparable to those observed with nanoliposomal irinotecan (NAPOLI-1) where 90% patients had ECOG 0-1. Some of the most frequent ( &gt; 10%) grade 3-4 AEs for 5FU and OXA included neutropenia, thrombocytopenia, anemia, and fatigue, comparable to that reported with irinotecan-based therapy. Conclusions: This meta analysis suggests that after progression on a first-line gemcitabine containing regimen, 5FU and OXA-based therapy (eg. FOLFOX) may be a viable and acceptable treatment for patients with pancreatic cancer with good PS.

Association of MDM2 expression with shorter progression-free survival and overall survival in patients with advanced pancreatic cancer treated with gemcitabine-based chemotherapy.

This study evaluated the prognostic roles of murine double minute 2 (MDM2) and p53 in pancreatic cancer patients treated with gemcitabine-based chemotherapy. A total of 137 advanced or recurrent adenocarcinoma patients who were treated with gemcitabine-based palliative chemotherapy were reviewed, selected from 957 patients with pancreatic malignancy between 2008 and 2013 at our hospital. Immunohistochemical staining for MDM2 and p53 with formalin-fixed, paraffin-embedded tumor tissues was independently reviewed. Nuclear or cytoplasmic expression of MDM2 and p53 was found in tumor cells of 30 (21.9%) and 71 (51.8%) patients, respectively. Patients with MDM2 expression had shorter median overall survival (OS) (3.7 vs 5.8 mo; P = .048) and median progression-free survival (PFS) (1.5 vs 2.5 mo; P < .001); by contrast, p53 expression was not correlated with OS or PFS. In the multivariate analysis, MDM2 expression (hazard ratio = 1.731; P = .025) was an independent and unfavorable prognostic factor of OS. Additionally, MDM2 expression was significantly associated with progressive disease (PD) and death (P = .015) following first-line gemcitabine-based therapy. In advanced pancreatic cancer patients, MDM2 expression is associated with shorter OS and PFS after gemcitabine-based chemotherapy.

Best practices for the treatment of metastatic pancreatic adenocarcinoma: the therapeutic landscape in 2017.

The vast majority of patients diagnosed with pancreatic adenocarcinoma have inoperable, most commonly metastatic, disease at the time of initial presentation, at which point systemic therapy becomes the mainstay of treatment. Although survival rates remain very poor in this clinical setting, patients currently have a greater number of therapeutic options available to them than ever before, and consequently individuals are more frequently able to be sequenced through multiple lines of treatment. In this review, we will provide an overview of the current treatment landscape for metastatic pancreatic cancer in 2017, focusing on best practices and the various factors that should be considered in selecting the most appropriate regimen for a given individual. Options for front-line therapy include both infusional 5-fluorouracil, leucovorin, irinotecan, oxaliplatin (FOLFIRINOX) and the combination of gemcitabine plus nab-paclitaxel; however, how to choose between these two regimens can sometimes pose a challenging problem, and some patients may not be suitable candidates for either. For patients who are robust enough to receive second-line therapy (and beyond), the selection of treatment depends in part on their prior treatment exposure; newer drugs such as nanoliposomal irinotecan (nal-IRI) (in combination with infusional 5-fluorouracil and leucovorin) are now approved by the United States Food and Drug Administration (FDA) specifically for use following disease progression on first-line gemcitabine-based therapy. Despite these welcome advances in standard of care treatment, patients should still be encouraged to participate in clinical trials whenever possible.

Second-line systemic treatment for advanced cholangiocarcinoma.

Gemcitabine plus platinum (GEM-P) combination chemotherapy is standard treatment for first-line advanced cholangiocarcinoma (aCC). GEM-P first-line therapy reports a progression-free survival (PFS) of 8 months and overall survival (OS) of 11.7 months. Treatment in the second-line setting is less clear. Five-year survival for aCC remains dismal at 5-10%. The purpose of this study was to describe the outcomes with second-line systemic treatment at our institution. This study was a single institution retrospective chart review of aCC patients who initiated second-line systemic treatment during 1/1/2009 to 12/31/2012. The primary objective was to evaluate PFS with second-line systemic treatment. Secondary objectives were OS and disease control rate. Second-line systemic regimens were classified into four treatment groups: GEM-P, gemcitabine + fluoropyrimidine (GEM-FU), other FU combination (FU-combo), and others. Fifty-six patients were included and the majority had intrahepatic aCC. A total of 80% received first-line gemcitabine-based therapy. Second-line therapy consisted of GEM-P (19.6%), GEM-FU (28.6%), FU-combo (37.5%), and others (14.3%). Median PFS was 2.7-month (95% CI, 2.3-3.8 months) with a median OS of 13.8 months (95% CI, 12-19.3 months) and a disease control rate of 50%. No significant difference in survival was identified between the four treatment groups. This study revealed a 2.7-month PFS, 50% disease control rate, and potential survival benefit with second-line treatment. Options for second-line systemic therapy include GEM-FU, FU-combo, GEM-P if not given in the first-line setting. Targeted therapy with erlotinib or bevacizumab could be considered in addition to chemotherapy.

Sequential gemcitabine and platinum versus first-line combination of gemcitabine and platinum for advanced pancreatic cancer treatment: a retrospective study

The purpose of this study was to investigate the impact of combinational versus sequential gemcitabine and platinum on prognosis of advanced pancreatic cancer. Two hundred and three patients with advanced pancreatic cancer were selected. They were divided into GemP (first-line gemcitabine and platinum), Gem-then-P(sequential gemcitabine and platinum), Gem/other (first-line gemcitabine-based therapy without subsequent platinum),and Gem (first-line gemcitabine-based therapy without subsequent systemic therapy) groups. The Kaplan–Meier method and log-rank test were used for survival analyses. Cox regression model and propensity score matching were used for prognostic analyses. The median survival was 12.5 months [95 %confidence interval (CI), 11.2-13.7] in the GemP group(N = 65), 8.3 months (95 % CI 5.0-11.7) in the Gem-then-P group (N = 35), 11.6 months (95 % CI 4.6–18.5) in the Gem/other group (N = 26), and 4.7 months (95 % C I3.3-6.0) in the Gem group (N = 77) (P<0.001). Considering the GemP and Gem-then-P groups, performance status, serum creatinine, and response to first-line treatment were independent prognostic factors for overall survival in the multivariate analysis. No specific factors were identified for predicting the choice between GemP and Gem-then-P. First-line gemcitabine and platinum-based combinations were not superior to sequential gemcitabine and platinum for overall survival. The best sequence of chemotherapy for advanced pancreatic cancer should be explored in future clinical trials.

Second-line pemetrexed–oxaliplatin combination for advanced pancreatic adenocarcinoma

e15597 Background: Few regimens showed efficacy in advanced pancreatic cancer patients (pts) who had failed a first-line gemcitabine-based therapy. However, there is growing evidence suggesting that second-line treatment may provide further disease control in selected pts. Both pemetrexed and oxaliplatin demonstrated activity in this setting, and their combination resulted safe and tolerable.Methods: Pancreatic cancer pts with advanced disease, PS&gt;60, age&gt;18 years, who progressed after a gemcitabine-based therapy were enrolled in a phase II trial, and treated with pemetrexed 500 mg/mq followed by oxaliplatin 120 mg/mq, day 1 every 3 weeks, together with adequate oral folinic acid and intramuscular vitamin B12 supplementation. Accordingly to the Simon Minimax two-stage study design, an accrual of 31 patients was planned, with a minimum response rate considered of interest of 25%, α level 0.10 and β level 0.10. Results: To date, 16 patients have been treated. Of them, 12 progressed during or shortly after gemcitabine (13) or gemcitabine-cisplatin combination (3), with a median time to progression of 186 days. 62 cycles were delivered, with a median of 4 cycles per patient (range 2–8). Overall, the regimen was well tolerated: most common adverse events were mild-to-moderate sensory neurotoxicity and gastrointestinal disturbances. We reported grade 3 anemia, grade 3 thrombocytopenia, and grade 3 fatigue in 1 patient each. Three among the treated patients died within 30 days from last delivered cycle due to progressive disease. Confirmed partial (3) or minor responses (6) were observed in 9 out of 15 evaluable pts, with a median decrease in the Ca 19.9 value of 43% among those who responded. Median progression-free survival was 99 days. At the time of analysis, 3 out of 16 patients are still on treatment.Conclusions: The preliminary results suggest that second-line pemetrexed-oxaliplatin combination is well tolerated and reasonably active, and allow the continuation of the study until the full sample of 31 pts. No significant financial relationships to disclose.

A phase II study of erlotinib in combination with capecitabine in previously treated patients with metastatic pancreatic cancer

4099 Background: Patients with advanced pancreatic cancer who fail first-line gemcitabine-based therapy have no standard treatment options. Capecitabine (CAPE) has activity in patients with previously untreated pancreatic cancer, and is commonly used in the second line setting. Erlotinib (OSI-774, Tarceva) is a tyrosine kinase inhibitor directed against the epidermal growth factor receptor (EGFR). EGFR is overexpressed in more than 90% of pancreatic cancers and is therefore an attractive treatment target for this malignancy. We performed a phase II study of erlotinib and CAPE in patients with advanced pancreatic cancer who had failed first-line therapy with a gemcitabine-containing regimen. Methods: Eligibility criteria included metastatic pancreatic carcinoma (excluding neuroendocrine tumors), failure of first-line therapy with a gemcitabine-containing regimen, no more than one prior regimen for metastatic disease, and adequate hematologic, renal and hepatic function. Patients received CAPE 1000 mg/m2 PO BID (total dose 2000 mg/m2 QD) for 14 days followed by a one week break, and erlotinib 150 mg PO QD. Treatment cycles repeated every 21 days. Patients were followed for toxicity, response, and overall survival. Results: Thirty patients have been enrolled with the following characteristics: median age 54 (range 41–78); M:F=12:18; ECOG PS 0/1=6/24. Two patients did not initiate protocol therapy. The remaining twenty-eight patients have received a median of 3.8 3-week treatment cycles and are evaluable for toxicity, response, and survival. Treatment was generally well tolerated; the most common grade 3–4 toxicities included: diarrhea 4 (14%); rash 4 (14%); hand-foot syndrome 3 (11%); stomatitis 2 (7%); and thrombosis 2 (7%). Three patients (11%) experienced PR, 16 (57%) experienced stable disease, and 9 (32%) experienced progressive disease as their best response. The median survival time, measured from initiation of protocol therapy is 202 days (6.7 months). Conclusions: The combination of erlotinib and CAPE is associated with antitumor activity and an encouraging median survival time in the second-line treatment of patients with advanced pancreatic cancer. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration OSI Genentech, Roche