Advanced Pancreatic Cancer Pts Research Articles

Effect of pancreatic enzyme replacement therapy (PERT) on body weight in advanced pancreatic cancer (APC).

698 Background: Malnutrition/cachexia is common in PC and is associated with multiple adverse patient (pt) outcomes. Current NCCN guidelines recommend PERT in PC pts with exocrine pancreatic insufficiency (EPI). However, little evidence exists regarding the impact of PERT on clinical outcomes in PC, especially APC. Data on impact of PERT use on change in body weight is presented here. Methods: Pts in this retrospective cohort study were identified from the Virginia Mason PC database. Eligibility requirements included: 1) no upfront resection 2) no prior PC therapy 3) pancreatic stool elastase 1< 200 µg/g stool or documented clinical evidence of EPI at diagnosis 4) treatment at least to initial restaging event (8 weeks) 5) available data regarding PERT use/dosage. Weight/BMI was assessed at baseline and after 8 weeks on therapy. Two pt groups were compared; a) pts prescribed PERT for EPI at recommended package insert dose (≥ 500KU-2500/kg/meal for ≥ 3 meals/day) for ≥ 50% treatment period and b) pts who received no PERT. Pts on PERT at lower than recommended dose and /or < 50% interval between 1st treatment and reassessment were excluded from analysis. Statistical significance was determined using the T-test for continuous variables, chi-squared for categorical variables. Results: 505 total pts were study eligible; 197 (39%) pts received PERT, 308 (61%) pts did not. Pt characteristics are shown. Despite a more adverse patient population with respect to weight loss, pts receiving PERT after 8 weeks experienced less change in weight (-0.36 kg vs -1.54 kg, P = 0.025) and change in BMI ( -0.64% vs -1.96., p= 0.026). Pts with cachexia experienced a similar outcome (-0.36% vs. -2.02 %, p= 0.026). No other pt characteristics achieved statistical significance. Conclusions: Despite a more adverse population with respect to weight loss at baseline, PERT usage prescribed per package insert guidance reduced wt loss/ change in BMI loss in APC over the 1st 8 weeks of therapy. This was also true in APC pts with cachexia. Further analysis of the impact of PERT therapy in APC with respect to treatment tolerability, and toxicity, quality of life and overall survival is warranted. [Table: see text]

Metabolomics in advanced pancreatic cancer (PC) patients (pts) achieving weight stability on enteral feeding for cachexia.

e16291 Background: We previously showed that enteral feeding was associated with weight stability and compositional changes in the gut microbiome with increased abundance of the gram-negative genera Veillonella over time. Here, we evaluated the potential of plasma metabolites as predictors of weight stability and high Veillonella abundance in enteral fed pts. Methods: The PANCAX-1 (NCT02400398) prospective trial enrolled 31 cachectic advanced PC pts to receive jejunal tube peptide-based diet for 12 weeks (wks) who were planned for standard chemotherapy. In preplanned exploratory analyses, serial blood samples were collected over 12 wks of enteral feeding. Up to 219 plasma metabolites were analyzed by mass spectrometry and high-performance liquid chromatography. Analytes were compared by relative area under the curve (AUC) and differences evaluated by two-sample t-tests. Pts were stratified by weight stable (WS, defined as weight change < 0.1 kg/baseline BMI-unit over 12 wks of enteral feeding) vs. weight unstable (WU) and high (HV) vs. low Veillonella (LV) abundance (defined by dichotomizing at the mean relative abundance in WS pts). Results: Of 31 cachectic pts enrolled into PANCAX-1, a total of 55 blood samples were collected from 28 pts for plasma metabolomics. Out of 16 evaluable pts, 62.5% receiving enteral feeding met the primary endpoint of weight stability at 12 wks. Plasma metabolomics in 10 pts showed that WU pts (n = 4) had significantly decreased levels of essential amino acids (AAs, L-histidine, L-phenylalanine) and non-essential AAs (L-citrulline, L-tyrosine, all p < 0.05) than WS pts (n = 6) at the end of 12 wks of enteral feeding. In 7 WS pts with complete serial sets of blood samples available, enteral feeding over 12 wks was associated with increases in markers of muscle mass (creatinine) but decreases in nucleotide precursors (all p < 0.05) compared to baseline. Comparison of baseline metabolites between 6 WS pts with HV and 4 WU pts with LV showed that HV was associated with increases in the nucleotide dCDP and essential AA L-isoleucine but decreased TCA cycle metabolite alpha-ketoglutarate (all p < 0.05). Decreases in lactic acid was observed at 12 wks of enteral feeding in HV pts when compared to baseline (p < 0.05). Conclusions: Our findings are hypothesis-generating in that metabolites unique to weight stability and Veillonella abundance may inform future studies of anti-cachexia therapies involving enteral feeding or microbial modulation.

Plasma metabolomics to predict chemotherapy (CTX) response in advanced pancreatic cancer (PC) patients (pts) on enteral feeding for cachexia.

600 Background: We evaluated the potential of plasma metabolites as predictors of response to CTX in a prospective cohort of pts who received enteral feeding for cachexia and advanced PC. Methods: The PANCAX-1 (NCT02400398) prospective trial enrolled 31 cachectic advanced PC pts to receive jejunal tube peptide-based diet for 12 weeks (wks) who were planned for palliative CTX. Out of 16 evaluable pts, 62.5% receiving enteral feeding met the primary endpoint of weight stability at 12 wks. As part of an exploratory analysis of the PANCAX-1 trial, serial blood samples were collected at 3 predefined timepoints over 12 wks of enteral feeding. Up to 219 plasma metabolites were analyzed by mass spectrometry and high-performance liquid chromatography. Analytes were compared by relative area under the curve (AUC) and differences evaluated by two-sample t-tests. The mean AUC was used in pts with metabolites measured from > 1 timepoint of collection. Pts were stratified by stable disease (SD), partial response (PR), or progressive disease (PD) as best overall response to standard CTX. Results: Of 31 pts with advanced PC prospectively enrolled for enteral feeding, there were 55 blood samples collected from 28 pts available for plasma metabolomics. 20/28 (71%) pts received first-line CTX, the majority of whom (90%) received gemcitabine-based CTX. There were 2 PRs (7%) and 10 with SD (36%) as best response to CTX. Overall, there were statistically significant differences in levels of intermediates involved in multiple metabolic pathways including glycolysis, the tricarboxylic acid (TCA) cycle, fatty acid synthesis, and nucleoside synthesis in pts with PR/SD vs. PD to CTX (all p < 0.05). When stratified by CTX regimen, PD to 5-fluorouracil-based CTX (e.g., FOLFIRINOX) was associated with decreased levels of essential amino acids (AAs, L-leucine, L-methionine, L-tryptophan) and non-essential AAs (L-arginine, L-serine, L-tyrosine, all p < 0.05). For gemcitabine-based CTX (e.g., gemcitabine/nab-paclitaxel), PD was associated with increased levels of intermediates of glycolysis (pyruvate), TCA cycle (L-glutamate), nucleoside synthesis (xanthine), and bile acid metabolism (taurocholic acid, all p < 0.05). Conclusions: We are the first to demonstrate the feasibility of plasma metabolomics in a prospective cohort of advanced PC pts on enteral feeding as their primary source of nutrition. Metabolic signatures unique to FOLFIRINOX or gemcitabine/nab-paclitaxel may be predictive of response and warrant further study.

P-74 The impact of first-line chemotherapy in elderly patients with advanced pancreatic cancer: A mono-institutional retrospective study

Pancreatic cancer median age at diagnosis is 70 years old. However, elderly patients (pts) are underrepresented in randomized clinical trials (RCTs) and chemotherapy efficacy and safety data in this population are limited. Herein, we present a retrospective analysis of an elderly population treated at our institution, investigating the role of baseline clinical factors in guiding treatment decision-making. Pts aged ≥70 years old receiving first-line chemotherapy for advanced pancreatic cancer (APC) were included in the analysis. The primary end-points were progression-free survival (PFS) and overall survival (OS). The following variables were collected: gender; age (≥ 70 and < 75 years vs ≥ 75 years); baseline ECOG PS (0-1 vs 2-3); site of primary tumor (head/uncinate process vs body/tail); disease stage (locally advanced vs metastatic); baseline CA 19.9 (< vs ≥ 200); chemotherapy regimen; comorbidities (yes vs no); number of comorbidities (0-1 vs ≥ 2). Univariate and multivariate analysis for PFS and OS were performed. A total of 169 APC pts aged ≥70 years old, receiving first-line chemotherapy between March 2015 and August 2020, were included in the analysis. The median age was 76 years (70-89), ECOG PS was 0-1 in 77% of pts; 70% were metastatic; 70% of pts had a head/uncinate process primary tumor; 25% had baseline CA 19.9 ≥ 200; 9.4% of pts had no comorbidities and 50% had ≥2 comorbidities. The majority of pts received gemcitabine nab-paclitaxel (60%), other regimes included gemcitabine (28%), FOLFIRINOX (5%), capecitabine (4%), FOLFOX (2%) and FOLFIRI (1%). The overall population median PFS and OS were 6.5 (median follow-up 19.1 months) and 11 months (median follow-up 21.8 months), respectively. Out of 164 pts evaluable, 38 (23%) pts achieved a partial response and 58 (35%) a stable disease, with a disease control rate of 58%. At the multivariate analysis, ECOG PS 0-1 was independently associated with both improved PFS (p=0.005) and OS (p=0.0084). At the multivariate analysis for PFS, locally advanced stage was also significantly associated with better PFS (p=0.036). In pts with ECOG PS 0-1 vs 3-4 the median PFS was 6.7 vs 3.3 months (p=0.0004) and median OS was 11.3 vs 5.5 moths (p=0.003), respectively. Despite the retrospective nature of the analysis and the limited sample size, we observed that elderly APC pts can benefit from first-line treatment, achieving survival outcomes comparable to the ones reported for younger pts in RCTs. On the basis of our results, the baseline ECOG PS can be considered a prognostic factor for both PFS and OS. In conclusion, elderly pts should not be precluded from active treatment, and careful patient selection, mainly according to baseline ECOG PS, should guide treatment indication.

The impact of first-line chemotherapy in elderly patients (pts) with advanced pancreatic cancer (APC): A mono-institutional retrospective study.

e16229 Background: Pancreatic cancer median age at diagnosis is 70 years old. However, elderly pts are underrepresented in randomized clinical trials (RCTs) and chemotherapy efficacy and safety data in this population are limited. Herein, we present a retrospective analysis of an elderly population treated at our Institution, investigating the role of baseline clinical factors in guiding treatment decision making. Methods: Pts aged ≥70 years old receiving a first-line chemotherapy for APC were included in the analysis. The primary end-points were progression-free survival (PFS) and overall survival (OS). The following variables were collected: gender; age (≥ 70 and &lt; 75 years vs ≥ 75 years); baseline ECOG PS (0-1 vs 2-3); site of primary tumor (head/uncinate process vs body/tail); disease stage (locally advanced vs metastatic); baseline CA 19.9 ( &lt; vs ≥ 200); chemotherapy regimen; comorbidities (yes vs no); number of comorbidities (0-1 vs ≥ 2). Univariate and multivariate analysis for PFS and OS were performed. Results: A total of 169 APC pts aged ≥70 years old, receiving first-line chemotherapy between March 2015 and August 2020, were included in the analysis. The median age was 76 years (70-89), ECOG PS was 0-1 in 77% of pts; 70% were metastatic; 70% of pts had a head/uncinate process primary tumor; 25% had baseline CA 19.9 ≥ 200; 9.4% of pts had no comorbidities and 50% had ≥2 comorbidities. The majority of pts received gemcitabine nab-paclitaxel (60%), other regimes included gemcitabine (28%), FOLFIRINOX (5%), capecitabine (4%), FOLFOX (2%) and FOLFIRI (1%). The overall population median PFS and OS were 6.5 (median follow-up 19.1 months) and 11 months (median follow-up 21.8 months), respectively. Out of 164 pts evaluable, 38 (23%) pts achieved a partial response and 58 (35%) a stable disease, with a disease control rate of 58%. At the multivariate analysis, ECOG PS 0-1 resulted independently associated both with improved PFS (p 0.005) and OS (p 0.0084). At the multivariate analysis for PFS, also locally advanced stage resulted significantly associated with better PFS (p = 0.036). In pts with ECOG PS 0-1 vs 3-4 the median PFS was 6.7 vs 3.3 months (p 0.0004) and median OS was 11.3 vs 5.5 moths (p 0.003), respectively. Conclusions: Despite the retrospective nature of the analysis and the limited sample size, we observed that elderly APC pts can benefit from a first-line treatment achieving survival outcomes comparable to the one reported for younger pts in RCTs. On the basis of our results, the baseline ECOG PS can be considered a prognostic factor for both PFS and OS. In conclusion, elderly pts should not be precluded from an active treatment and careful patient selection, mainly according to baseline ECOG PS, should guide treatment indication.

Sindilimab combined with nab-paclitaxel plus gemcitabine as first-line treatment for patients with advanced pancreatic cancer.

e16257 Background: This study aimed to evaluate the efficacy and safety of Sindilimab combined with nab-paclitaxel plus gemcitabine as first-line treatment for advanced pancreatic cancer. Methods: This was a single-arm, simple-center, exploratory trial, which included advanced pancreatic cancer pts. Patients received Sindilimab combined with nab-paclitaxel plus gemcitabine. Combined chemotherapy lasted for no more than 12 cycles. Once chemotherapy intolerance occurred or at end of 12-cycle combined chemotherapy, pts with stable disease or objective response would continue to take Sindilimab as single agent until disease progression or intolerable toxicity. Response was assessed every 8 weeks. Results: 16 eligible patients were enrolled and 14 pts were evaluable for efficacy analysis. Baseline characteristics are shown in Table 2. Conclusions: This study has showed high anti-tumor efficacy and tolerant toxicity in first-line regimen for advanced pancreatic cancer. Furthermore, it is needed to be proved in update results and large scale studies. Efficacy As shown in Table 3, among 14 evaluable pts, unconfirmed ORR was 57.1% and DCR was 92.8%. 8 pts got partial response (PR), 5 pts stable disease (SD) and 1 pts progressive disease(PD) at best. PFS: The primary endpoint 6-month PFS rate was 2%(95% CI 50.4%-72.4%). Which indicated that the primary endpoint of the study was reached. And mPFS was 7.3 months(95% CI 5.9-8.1). OS: Median OS was not reached and 6m-OS rate was 85.7% (95%CI 5%-91.3%). Safety. All 16 pts were included in the safety analysis (Table 4). The overall AE incidence rate was 93.75% .≥Grade 3 irAE included GGT increased (37.5%) and peripheral neuropathy (6.25%). No TRAE led to death.[Table: see text][Table: see text][Table: see text][Table: see text]

P-164 The role of response as a predictor of improved outcome in advanced pancreatic cancer patients treated with first-line gemcitabine plus nab-paclitaxel

Gemcitabine plus nab-paclitaxel (GemNab) is one of the first-line standard treatments (tx) of advanced pancreatic cancer (APC). To date, no predictive factors, both clinical and molecular, of benefit from this regimen exist. Two retrospective studies showed that early tumor shrinkage (ETS) can predict an improved outcome in APC pts receiving a first-line tx with FOLFIRINOX or GemNab. However, data regarding GemNab, limited to a small population of only 57 pts, seem to not confirm the association of ETS with a better outcome.

The impact of 2nd-line treatment (tx) after 1st-line Gemcitabine plus Nab-paclitaxel (GemNab) in advanced pancreatic cancer (APC) patients (pts).

e16759 Background: Three main phase III randomized studies investigated the role of 2nd-line tx in APC pts. The PANCREOX study failed to demonstrate a survival advantage of mFOLFOX vs 5FU/LV. Conversely, the CONKO-003 and NAPOLI-1 trials, demonstrated a significant survival improvement from the combination regimen OFF and 5FU+Nal-IRI, respectively, in comparison to 5FU/LV alone. Recently, final OS analysis from NAPOLI-1 demonstrated an association of specific characteristics (ECOG PS, age, Ca 19.9 baseline level, neutrophil-to-lymphocyte ratio and no liver metastases (m)) with OS &gt; 1 year. The main limit of all these studies was due to the period they were carried out: no pts received 1st-line GemNab. Hence, we retrospectively analysed an homogeneous population of APC treated with 1st-line GemNab at our Institution, investigating the impact of 2nd-line tx. Methods: APC pts receiving a 2nd-line tx after 1st-line GemNab were included in the analysis. The following variables were collected: gender; age ( &gt; vs ≤ 55 years and ≥ vs &lt; 70 years ); baseline ECOG PS (0-1 vs 2-3); Ca 19.9 baseline level (≥ vs &lt; 200); anamnesis of diabetes; site of primary tumor (head/uncinate process vs body/tail); number of m sites (1 vs &gt; 1); m sites (liver, peritoneum, lung, nodes); RECIST response and ETS during 1-line GemNab. Univariate and multivariate analyses for PFS and OS were performed. Results: Out of 167 APC pts progressed to 1st-line GemNab, 93 (56%) pts received a 2nd-line tx, specifically 58 pts received an oxa-based regimen, 11 FOLFIRINOX, 8 FOLFIRI and 16 pts received other tx. Median 2nd-line PFS and OS were 3.3 and 5.6 months, respectively. Out of 87 pts evaluable for response, 7 pts achieved a partial response and 27 a stable disease, with a RR and a disease control rate (DCR) of 8% and 39%, respectively. Pts with baseline ECOG PS 0-1 had a significant better outcome in comparison to pts with PS 3-4 (PFS 4.2 vs 1.2 months, p &lt; 0.0001; OS 7.2 vs 2.6 months, p = 0.0001). This significant association with survival parameters and ECOG PS was confirmed at the multivariate analysis. Conclusions: Despite the limited number of pts evaluated and the restrospective nature of our analysis, our results are in line with previous evidences, confirming the importance of a 2nd-line combination tx, when feasible, as well in an homogeneous population of APC pts treated with 1st-line GemNab. On the basis of our results, ECOG PS may be considered a prognostic factor and the choice of 2nd-line tx should be guided in primis by the baseline general conditions of APC pts.

The role of response as predictor of improved outcome in advanced pancreatic cancer (APC) patients (pts) treated with first-line Gemcitabine plus Nab-paclitaxel (GemNab).

e16758 Background: GemNab is one of the first-line standard treatment (tx) of APC. To date, no predictive factors, both clinical and molecular, of benefit from this regimen exist. Two retrospective studies showed that early tumor shrinkage (ETS) can predict an improved outcome in APC pts receiving a first-line tx with FOLFIRINOX or GemNab. However, data regarding GemNab, limited to a small population of only 57 pts, seem to not confirm the association of ETS with a better outcome. Hence, we retrospectively analysed an homogeneous population of APC treated with first-line GemNab at our Institution, investigating the impact of several clinical factors, including response and ETS. Methods: APC pts receiving a first-line tx with GemNab were included in the analysis. The association of RECIST response and ETS with PFS and OS was evaluated. The following variables were collected: gender; age ( &gt; vs ≤ 55 years and ≥ vs &lt; 70 years ); baseline ECOG PS; Ca 19.9 baseline level (≥ vs &lt; 200); anamnesis of diabetes; site of primary tumor (head/uncinate process vs body/tail); locally A vs metastatic (m) PC; synchronous vs metachronous; number of m sites (1 vs &gt; 1); m sites (liver, peritoneum, lung, nodes); number of tx lines (1 vs &gt; 1). Univariate and multivariate analyses for PFS and OS were performed. Results: A total of 184 APC pts receiving first-line GemNab at our Institution from February 2014 to May 2019 were included in the analysis. RR and ETS were assessed in 174 and 168 pts, respectively. RR was 30%, disease control rate (DCR) 63% and ETS was 24%. Responders had a significant better PFS (12.5 vs 5.7 months, p &lt; 0.0001) and OS (25.1 vs 12.1 months, p &lt; 0.0001). ETS was significantly associated with improved PFS (12.3 vs 6.2 months, p &lt; 0.0001) and OS (24.0 vs 12.8 months, p &lt; 0.0001). At the multivariate analysis a significant association with survival parameters was confirmed for RECIST response, but not for ETS. At the multivariate analysis, also metachronous disease and number of tx lines &gt; 1 were independently associated with better OS. Conclusions: Despite its retrospective nature, this is one of the largest series of APC pts treated with first-line GemNab investigating the role of RECIST response and ETS in predicting outcome. On the basis of our results, RECIST response may be considered a positive prognostic factor, whereas ETS does not. In conclusion, achieving tumor shrinkage, not necessarily early, significantly delays PC progression and prolongs survival in pts treated with first-line GemNab.

Modified FOLFIRINOX in pancreatic cancer patients Age 75 or older

BackgroundAlthough FOLFIRINOX (5-Fluorouracil + leucovorin + irinotecan + oxaliplatin) is now the standard of care for patients (pts) with metastatic pancreatic cancer (PC) based on the 2011 study by Conroy et al. which demonstrated improved median overall survival (mOS), pts > 75 yrs old were excluded from this study. The purpose of this study was to assess the safety and efficacy of modified FOLFIRINOX (mFOLFIRINOX) in this population. MethodsWe retrospectively analyzed unresectable PC pts, age ≥ 75, treated with mFOLFIRINOX at MD Anderson from 2011 to 2017. Primary outcome was rate of grade 3 or 4 hematologic toxicity (HT). Results24 pts were included. Grade 3 or 4 HT occurred in 11 pts 6 pts required hospitalization for any toxicity, and 10 stopped mFOLFIRINOX due to toxicity. The most frequently used starting doses of infusional 5-FU, irinotecan and oxaliplatin were 2400, 150 and 75 mg/m2, respectively. Median PFS was 3.7 months (95% CI: 3.0–5.7) with a median OS of 11.6 months (95% CI: 6.14–15.7). For first line pts, median PFS and OS were 5.1 (95% CI: 2.0–12.8) and 12.2 months (95% CI: 4.8–30.8), respectively. ConclusionsIn this single-center retrospective analysis of unresectable PC pts age 75 or older given mFOLFIRINOX, toxicities and survival outcomes were similar to those reported in the initial study. These data indicate that the use of modified dosing FOLFIRINOX in advanced PC pts older than 75 appears to maintain similar toxicity and efficacy when compared to younger pts.

Impact of new chemotherapy regimens on the treatment landscape and survival of advanced pancreatic cancer (PAC) patients (pts).

403 Background: The clinical phase III first-line trials MPACT and PRODIGE4/ACCORD11 in metastatic PAC pts have changed the treatment paradigm. We aimed to analyse the impact of these regimens on the treatment landscape and survival of advanced PAC pts. Methods: In this single institutional retrospective cohort analysis patient characteristics and overall survival (OS) from all pts with advanced PAC treated between 01/2011-12/2017 were analysed. Survival analyses were performed by Kaplan-Meier method. Results: A total of 301 pts started a systemic treatment in the observation period. Concerning the first-line treatment, there was a clear shift from four different main regimens (gemcitabine/nab-paclitaxel (G+nab-P), FOLFIRINOX, gemcitabine/oxaliplatin +/- erlotinib, gemcitabine mono) to only two (G+Nab-P, FOLFIRINOX), that made up more than 80% of the administered first-line treatments in each of the groups (2011-2013 vs. 2014-2017). The rate for first-line FOLFIRINOX treatment was balanced between the two groups (19% and 15%). G+nab-P treated pts had a median age of 66 years, 41.3% had an ECOG 1-2, the FOLFIRINOX treated pts were younger and fitter (57 years and 24.5 % ECOG 1, 0% ECOG 2). 60.7% of pts treated with G+nab-P received a second-line and 30.7% pts received a third-line treatment, while for the FOLFIRINOX pts these rates were 69.8% and 41.5%. Median OS of pts that started first-line treatment between 2011 and 2013 was 8.77 months (95% CI 6.98-10.57) and for those that started first-line treatment between 2014 and 2017 median OS was 11.07 months (95% CI 8.94 13.20) (p = 0.038, Log-Rank-Test). Conclusions: There is a clear impact of new chemotherapy regimens on the treatment landscape. Furthermore, we provide real-world evidence that since the introduction of these new treatment options, the survival of pts with advanced PAC has significantly improved.

FOLFIRINOX in pancreatic cancer patients age 75 years or older.

362 Background: Although FOLFIRINOX (5-Fluorouracil + leucovorin + irinotecan + oxaliplatin) is now the standard of care for patients (pts) with metastatic pancreatic cancer (PC) based on the 2011 study by Conroy et al. which demonstrated improved median overall survival (mOS) (11.1 vs 6.8 months [m] with gemcitabine, P &lt; 0.001), pts &gt; 75 yrs old were excluded from this study. As per SEER 2011-2015 data, 38% of new PC cases are diagnosed in pts age &gt; 75. The purpose of this study was to assess the safety and efficacy of FOLFIRINOX in this group of pts. Methods: We retrospectively analyzed unresectable PC pts, age ≥ 75, treated with FOLFIRINOX at MD Anderson since 2011. Data obtained include demographics, line of treatment (tx), starting dose, progression free survival (PFS), OS and toxicities. Response was determined by chart documentation. Primary outcomes were mOS and rates of grade 3/4 hematologic toxicity (HT). Results: A total of 24 pts (19 male) were included with median age of 76 (range 75 to 84). 18 had metastatic disease, and FOLFIRINOX was the 1st line of tx for 18 of the 24 pts. The median number of cycles administered was 4 (range 1 to 12). The most frequent starting doses of infusional 5-FU, irinotecan and oxaliplatin were 2400, 150 and 75 mg/m2, respectively. Bolus 5-FU and leucovorin were omitted in all but 3 pts. Median PFS was 3.7 m (95% CI: 3.0-5.7) with mOS of 11.6 m (95% CI: 6.14-15.7). 16 pts (67%) experienced disease control (response to tx or stable disease). Grade 3 or 4 HT occurred in 11 pts (46%), and 9 (38%) were supported with granulocyte colony-stimulating factor at some point during tx. 6 pts (25%) required hospital admission for any toxicity, most commonly infection (3 pts), and 10 (42%) stopped FOLFIRINOX due to toxicity, most commonly fatigue (6 pts). Conclusions: In this single-center retrospective analysis of 24 unresectable PC pts age 75 or older given FOLFIRINOX, OS outcomes were similar to those reported by Conroy et al in the original trial which excluded pts older than 75. In our review, toxicities including incidences of grade 3 or 4 HT were similar to those reported in the initial study. These data indicate that the use of modified dosing FOLFIRINOX in advanced PC pts older than 75 appears to maintain similar efficacy and toxicity when compared to younger pts.

Real-world outcomes among patients (pts) treated with gemcitabine (GEM)-based therapy post-FOLFIRINOX (FFOX) failure in advanced pancreatic cancer (APC).

303 Background: Limited evidence exists for the selection of chemotherapy in APC after first-line (1stL) FFOX. Gemcitabine/nab-paclitaxel (GEMNAB) is publicly funded for second-line (2ndL) use in the provinces of Alberta (AB) and Manitoba (MB), but is not covered in British Columbia (BC). We compared population-based outcomes by region to examine the utility of 2ndL GEMNAB versus GEM alone. Methods: We identified pts treated with 1stL FFOX between 2013-2015 across BC, AB, and MB. Baseline characteristics and treatment regimens were compared between AB/MB and BC. Survival outcomes were assessed by the Kaplan-Meier, and compared with log-rank test. Results: 370 pts treated with 1stL FFOX were identified (145 AB/MB, 225 BC), with a median age of 61y, 42% female, and 68% with metastatic disease (similar in both groups). Receipt of 2ndL therapy was 49% AB/MB vs 44% BC ( p = 0.35), and time from diagnosis to 2ndL therapy measured 7.6 mos AB/MB versus 9.4 mos BC ( p = 0.1). The distribution of 2ndL gemcitabine use was: 72% GEMNAB, 23% GEM in AB/MB versus 27% GEMNAB, 66% GEM in BC ( p &lt; 0.001). Median overall survival (OS) from diagnosis was similar: 12.4 mos in AB/MB versus 10.9 mos in BC ( p = 0.75). On Cox regression analysis, region was not significant. A secondary survival analysis by 2ndL regimen demonstrated a median OS of 18.0 mos with GEMNAB versus 14.3 mos GEM ( p &lt; 0.01). Conclusions: In our population-based comparison of APC pts treated with 1stL FFOX, survival outcomes were comparable regardless of publicly funded access to 2ndL GEMNAB versus GEM. OS by regimen favored 2ndL GEMNAB, but patient selection may be largely responsible for this difference. Randomized trials are needed to demonstrate the benefit of GEMNAB post-FFOX in APC.

Oxaliplatin (OX), chronomodulated capecitabine, and UGT1A1 genotype-directed dosing of irinotecan (IR) triplet chemotherapy (OXIRI) in patients (pts) with advanced pancreatic cancer (APC).

411 Background: The FOLFIRINOX regimen is highly active in APC, but its use is limited by toxicity. Irinotecan (IR) toxicity is correlated with UGT1A1 genotype status and chronomodulated delivery of fluoropyrimidines may reduce toxicity and increase efficacy. We have presented the dose escalation (DES) of OXIRI. In dose expansion (DXP), several pts required dose reduction after cycle 1 and we evaluated a lower starting dose. We now present data of the recommended Phase II dose (RP2D) and DES combined. Methods: Pts with APC and ECOG performance status ≤2, adequate organ function were enrolled. Previous OX or IR exposure was disallowed. During DES, APC pts homozygous for UGT1A1*6/*6 or UGT1A1*28/*28 were excluded. During DXP, only pts progressing on ≥ 1 line prior chemo was allowed and IR was dosed according to UGT1A1 genotype. At RP2D, pts received iv OX 37.5mg/m2 and IR 50mg/m2 on D1, 8 and po capecitabine 2650mg once at midnight on D1-14 every 21D until progression. Results: A total of 25 pts were enrolled, 17 in DES and 8 in DXP, 21 had metastatic and 4 had locally advanced APC. Male:Female 11:14, median (range) age and ECOG PS was 65yrs (50-77) and 0 (0-1) respectively. Pts with 0, 1 or 2 lines of prior chemo were 4 (16%) , 14 (56%) and 7(28%) respectively. Grade 3/4 AEs (≥5%) related to OXIRI were neutropenia (32%), anaemia (12%), diarrhoea (16%). No events of febrile neutropenia were reported. At data cut-off on 31 Aug 2017, 4 pts are on study. Median progression-free and overall survival was 22 and 35 wks respectively. Response rate (RR) was 5/25 (20%, overall); 5/20 (25%, evaluable pts) including 1 complete response and 1 unconfirmed partial response. Disease control rate for ≥ 12wks was 16/25 (64%) with 3 pts &gt; 52wks. CA19-9 decrease of ≥ 20% was seen in 9/25 pts. Conclusions: OXIRI is an active regimen with RR of 20% despite 84% of pts having prior chemo, with disease control for ≥ 12wks in 64% of pts. Predominant toxicity was neutropenia. This study was supported by the National Medical Research Council Singapore. Clinical trial information: NCT02368860.

The influence of biliary drainage in patients with advanced pancreatic cancer receiving FOLFIRINOX.

378 Background: FOLFIRINOX (FFX) is a standard of care for patients (pts) with advanced pancreatic cancer (APC). In the original FFX report by Conroy (NEJM, 2011), pts with a biliary drainage were limited and the occurrence of cholangitis was not reported. In practice, however, we experience that a certain fraction of APC pts needs a biliary drainage and some of them have an elevated risk of cholangitis or febrile neutropenia (FN) during the course of FFX. We evaluated the influence of biliary drainage on the efficacy and safety of FFX. Methods: We used individual data from nationwide survey of FFX (JASPAC06). The JASPAC06 was a prospective registry of pts with FFX treated in clinical practice and enrolled 399 pts between December 2013 and November 2014 from 27 centers in Japan. We evaluated the associations of OS and PFS, as well as the frequencies of cholangitis and FN, with the use of biliary drainage. We excluded resected cases because an operative method with choledochojejunostomy was unknown. Results: Of 399 pts in the JASPAC06, 319 were eligible for this analysis and 80 resected cases were excluded. The use of biliary drainage was seen in 28% of pts (mainly bile duct stent inserted); primary dose reduction (modified FFX), 67%; previously untreated tumor, 77%; distant metastases, 76%; pancreas head, 47%. The main results are shown in the table. In summary, cholangitis was more frequent in pts with biliary drainage. Grade 3 or higher FN as well as CRP elevation was observed more frequently in pts with biliary drainage. There was no difference in PFS (median PFS, 7.3 vs. 6.5 mo; logrank, p=0.24) and OS (median OS, 12.3 vs. 12.2 mo; p=0.86) between the two groups. Conclusions: Our observation that the frequency of FN and CRP elevation was significantly higher in pts with biliary drainage indicates a higher risk of infection during the FFX treatment by using biliary drainage.[Table: see text]

TAS-118 (S-1 plus leucovorin) versus S-1 in gemcitabine-refractory advanced pancreatic cancer: A randomized, open-label, phase III trial (GRAPE trial).

4099 Background: Addition of oral leucovorin (LV) to S-1 significantly improved progression-free survival (PFS) in a previous randomized phase II trial in Japanese patients (pts) with gemcitabine (GEM)-refractory advanced pancreatic cancer (PC). TAS-118 is an oral drug containing S-1 and LV. This phase III trial conducted in Japan and Korea compared overall survival (OS) between GEM-refractory advanced PC pts treated with TAS-118 and S-1. Methods: GEM-refractory PC pts were randomized in a 1:1 ratio to receive TAS-118 (S-1; 40-60 mg and LV; 25 mg bid for 1w, q2w) or S-1 (S-1; 40-60 mg bid for 4w, q6w). The primary endpoint was OS. The secondary endpoints included PFS, overall response rate, disease control rate, duration of response, and safety. Results: Five hundred and eighty-six pts were eligible for efficacy assessment (TAS-118: n=296 and S-1: n=290). Baseline characteristics were well balanced between the treatment arms. TAS-118 did not result in a statistically significant improvement in OS compared with that achieved with S-1 (median OS, 7.6 months vs. 7.9 months; hazard ratio [HR], 0.98; 95% CI, 0.82 to 1.16; P=0.756). However, it significantly improved PFS compared to that achieved with S-1 (median PFS, 3.9 months vs. 2.8 months; HR, 0.80; 95% CI, 0.67 to 0.95; P=0.009). Pre-planned subgroup analysis of OS showed significant interactions between the treatment effects and pancreatic resection (P=0.025), and between the treatment effects and country (P=0.004). Grade 3/4 drug-related adverse events (≥5% incidences) in TAS-118 and S-1 arms included diarrhea (7.0% vs. 7.3%), anorexia (6.7% vs. 5.0%), stomatitis (6.7% vs. 0.7%), and anemia (3.3% vs. 5.0%). Conclusions: The primary endpoint was not met. Further, the interactions between the treatment effects and pancreatic resection, and between the treatment effects and country, might affect the results. Clinical trial information: 132172. [Table: see text]

Early tumor shrinkage as a predictor of favorable outcomes in patients (pts) with advanced pancreatic cancer treated with FOLFIRINOX.

237 Background: Results from the phase III PRODIGE 4/ACCORD 11 trial provided one of current standard regimens for advanced pancreatic cancer (PC), consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX), which has superior response rate (RR) and survival benefit even with severe toxicity (Thierry C, et al. N Engl J Med 2011;364:1817-1825). There are several reports on the correlation between early tumor shrinkage (ETS) or depth of response (DpR) and survival in chemotherapies for colorectal cancer; however, few studies have investigated it in PC. We therefore analyzed retrospectively whether the ETS will predict outcomes in pts with PC treated with FOLFIRINOX therapy. Methods: Advanced PC pts with ECOG PS of 0 or 1, who received FOLFIRINOX as 1st- or 2nd-line treatment between November 2012 and July 2015 in 3 institutes of Showa University were included in this analysis. ETS was defined as a reduction ≥ 20% of target lesions’ diameters measured at 8 weeks from treatment start. We evaluated the association of ETS with progression-free survival (PFS) and overall survival (OS) but also addressed the correlation between outcomes and DpR, which was percentage of maximal tumor shrinkage observed at the nadir diameter compared with baseline. Results: Fifty-nine PC pts with median age of 63 (range 34-76) years and males of 68% were enrolled: 80% of pts had metastatic disease. In the population, RR, median PFS, and OS were 28%, 5.4 months, and 10.7 months, respectively. Among 46 (78%) evaluable pts for the ETS, 12 (26%) pts experienced ETS. The PFS was significantly longer in pts with ETS compared to pts with no ETS (9.0 vs. 4.2 months, HR 0.43, 95%CI 0.17-0.96, log-rank P= 0.045). Moreover, pts with ETS had a better OS although no statistical significance (HR 0.53, log-rank P= 0.25). Median DpR was 11.1% (from -75.7 to 100), and the correlation of DpR with clinical outcome was observed (P= 0.024 for PFS, P= 0.22 for OS). Conclusions: This retrospective analysis suggests that the early response to FOLFIRINOX treatment may predict better outcomes in pts with advanced PC. The ETS may serve as a novel predictor of prolonged survival time in PC pts treated with FOLFIRINOX.

618PD - A Phase 2 Randomized, Double-Blind, Placebo Controlled Study of Simtuzumab or Placebo in Combination with Gemcitabine for the First Line Treatment of Pancreatic Adenocarcinoma

ABSTRACT Aim: Simtuzumab (SIM) is a humanized antibody that inhibits lysyl oxidase-like molecule 2 (LOXL2), an extracellular matrix enzyme that catalyzes the covalent cross-linking of collagen and is widely expressed across desmoplastic tumors. Inhibiting LOXL2 is expected to block formation of desmoplasia, which is thought to play an important role in tumor progression and metastasis. In the Phase 1 study, SIM was safe and well-tolerated in patients (pts) with advanced solid tumors and showed early evidence of efficacy. Based on these results, a randomized, double-blind, placebo-controlled phase 2 study of SIM + gemcitabine (Gem) vs. placebo (pbo) + Gem in pts with metastatic pancreatic adenocarcinoma was initiated. Methods: Eligible pts had no prior systemic therapy for advanced disease and Eastern Cooperative Oncology Group performance status of 0 or 1. The primary endpoint was progression free survival (PFS). Pts were randomized to 200 mg SIM, 700 mg SIM, or pbo at a 1:1:1 ratio in combination with Gem in cycles of 28 days. In each cycle, pts received IV SIM or pbo infused on Days 1 and 15, and IV Gem (1000 mg/m2) on Days 1, 8, and 15. Results: Between 3/28/12 and 5/15/13, 236 pts were randomized and treated; 76 pts (200 mg SIM/Gem), 79 pts (700 mg SIM/Gem), and 81 pts (pbo/Gem). Median PFS was 3.5 (HR 1.12; p = 0.63 vs pbo), 3.7 (HR 1.08; p = 0.75 vs pbo), and 3.7 months for 200 mg SIM/Gem, 700 mg SIM/Gem, and pbo/Gem arms, respectively. Median overall survival (OS) was 5.9 (HR 1.05; p = 0.76 vs pbo), 7.6 (HR 0.83; p = 0.26 vs pbo), and 5.7 months, respectively. Gemcitabine-related expected toxicities included anemia, thrombocytopenia, neutropenia, and nausea. There were no differences in the safety profile of the SIM plus Gem groups versus pbo plus Gem group. Conclusions: The addition of SIM to Gem does not improve PFS or OS in advanced pancreatic cancer pts. Disclosure: H. Dong: is an employee of Gilead Sciences, the sponsor of the clinical study, and holds shares of Gilead stock; D. Thai: is an employee of Gilead Sciences, the sponsor of the clinical study, and holds shares of Gilead stock. All other authors have declared no conflicts of interest.

Second-line gemcitabine plus nab-paclitaxel (G+A) for advanced pancreatic cancer (APC) after first-line FOLFIRINOX: Single institution retrospective review of efficacy and toxicity.

344 Background: Gemcitabine (G) plus paclitaxel protein-bound particles for injectable suspension (Abraxane, A) is an active first line regimen for APC based on improved efficacy compared to G (Van Hoff, DD et al. J Clin Oncol 31, 2013 [suppl;abstr 4005]). However, there is a paucity of data regarding efficacy of G+A in pts who received prior FOLFIRINOX. To assess efficacy and tolerability of 2nd line G+A, we reviewed our single institution experience with G+A in APC pts who received 1st line FOLFIRINOX. Methods: We conducted a retrospective review of dose, toxicity, efficacy of second line G+A in FOLFIRINOX-treated APC pts treated at Yale Cancer Center between 12/2011 and 08/2013. Pts were treated until progression, unacceptable toxicity, or pt preference. Doses were at treating physician’sdiscretion. Dose densities were compared to full doses (A 125 mg/m2 + G 1000 mg/m2 days 1, 8,15 q 4 wks). Response rate, med time to treatment failure (TTF), med overall survival (OS) were calculated. Results: 23 pts were treated with G+A after 1st line FOLFIRINOX. Pts characteristics: metastatic, 18; locally advanced, 5; med age, 61 (range 50-74);male, 9; ECOG PS ≤1, 22; med # FOLFIRINOX cycles, 12 (range 5-46). Med interval from FOLFIRINOX to G+A was 5 wks (range 1.7-40.3). Responses by RECIST were: PR, 2 (8.7%); SD for ≥7 wks, 8 (34.8%); PD, 10 (43.4%); ineval, 3 (13.1%). 9 (39%) and 8 (34%) pts had &gt;30% decrease in CA 19-9 and CEA, respectively. 13 pts died, 6 pts stopped G+A, 4 pts are still receiving G+A. Med TTF was 11 wks (range 1-35). Med OS was &gt;17.9 wks (range 2.1-69.6). All pts had initial dose reductions of G or A; 7 and 12 pts required further dose reductions with A and G, respectively. Dose densities were 56.9% and 63.5% for A and G, respectively. Grade ≥3 hematologic toxicities included neutropenia 17%, anemia 26%, thrombopenia 26%. Conclusions: In this single institution pt population, G+A has limited activity after FOLFIRINOX. Most of our pts received FOLFIRINOX for &gt;6 months and were still able to receive a 2nd line doublet. Most required dose reductions for cytopenias, but this sequence was tolerable. In this setting, an additional 11 wks med TTF is about half of the TTF in 1st line G+A and may be clinically valuable.

Phosphorylated ERK (pERK) as biomarker in patients with advanced pancreatic cancer treated with erlotinib within a randomized phase III trial (AIO-PK0104).

189 Background: Validated biomarkers for patients (pts) with advanced pancreatic cancer (APC) treated with anti-EGFR drugs have not yet been defined. pERK represents the downstream target of the RAS-RAF-MEK cascade. Methods: Within AIO-PK0104 281 pts with APC were randomized between gemcitabine/erlotinib followed by capecitabine and capecitabine/erlotinib followed by gemcitabine. Archival formalin fixed paraffin embedded (FFPE) tumor tissue for central pERK analysis by immunohistochemistry (IHC) was available from 153 pts. Within a retrospective subgroup analysis, pERK data (either as dichotomous or continuous variable) were correlated with AIO-PK0104 biomarker results on KRAS mutation status and EGFR expression and with efficacy study endpoints using a Cox regression model. Results: A semi-quantitative immunohistochemistry scoring system considering cytoplasmic and nuclear pERK expression (staining intensity &amp; % of positive cells) was developed (score 0-12). FFPE samples with a score of 6-12 were defined a pERKhigh. 98/153 pts were classified as pERKhigh and 55/153 pts as pERKlow, respectively. The median pERK score was 7 (range 0-12). No significant correlation of pERK with baseline characteristics like stage of disease, gender, age, KPS or CA 19-9 was detected. Median OS in pERKhigh pts was estimated with 5.7 months and with 6.2 months in pERKlow pts (HR 1.29, 95% CI 0.90-1.83, p=0.16). However, when analysing pERK as continuous variable, a significant association between the pERK score and OS was found (HR 1.06, 95% CI 1.0-1.12, p [log rank]=0.050, p [likelihood ratio]=0.047), indicating an increase in the hazard for death by a factor of 1.06 for each score level of pERK expression. There was no correlation of pERK expression with the objective disease control rate (OR 0.99, p=0.91) or the occurrence of skin rash (OR 0.93, p=0.41). Pts with a KRAS mutation had a similar rate of pERKhigh expression compared to patients with KRAS wildtype (61% vs 71%, p=0.32). Conclusions: pERK expression may have an impact on OS of APC pts treated with the anti-EGFR agent erlotinib. Prospective validation of these results is recommended. Clinical trial information: NCT00440167.