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332 Background: Docetaxel-based therapy is currently the most effective neoadjuvant regimen for locally advanced gastroesophageal adenocarcinoma. However, prior trials were primarily designed to target gastric cancer. As survival associated with taxane-based chemotherapy in esophageal adenocarcinoma (EAC) is less well described, we sought to review our experience with docetaxel based therapy as a neoadjuvant approach for EAC. Methods: A single centre retrospective review of a prospectively maintained upper GI cancer surgical database was performed (2008-2021). Patients with EAC undergoing curative intent neoadjuvant therapy with two similar docetaxel-based regimens (DCF - Docetaxel/Cisplatin/5FU or FLOT - 5FU, Leucovorin, Oxaliplatin, and Docetaxel) followed by en-bloc resection were included. Gastric/EGJ type III tumors were excluded. Clinicopathological data and overall survival (OS) were recorded and stratified by chemotherapy type (DCF vs FLOT). Data are presented as median (+/-SD). Mann-Whitney U tests for continuous or Fischer exact test for categorical variables determined significance. Kaplan-Meier curves compared OS. Results: 225 EAC patients were identified: Age 64.2 (±10.3) and tumor location was Esophageal/EGJ I/EGJ II (106/33/86). Clinical stage was cT3-4 in 201/225 (89.3%) and most were cN+ (200/225: 88.9%). There were 121 (53.7%) treated with neoadjuvant DCF whilst 104 (46.3%) received FLOT. All pre-op cycles were completed in 181 (80.4%) and did not differ between DCF and FLOT (81.8% vs 78.8% - NS). Operative procedure included Ivor Lewis in 188 (83.5%), left thoraco-abdominal esophagectomy in 20 (8.8%), and McKeown in 17 (7.5%) and also did not differ between DCF and FLOT. In terms of pathologic outcomes, the median lymph node yield was 35 (±16) of which 3.6±5.8 were positive). There was no difference when comparing between regimens. There were 134 (59.6%) patients ypN1-3 (DCF=76(62.8%) vs FLOT=58(55.8%)- NS). An R0 resection was achieved in 210 (93%) patients (DCF=92.6% vs FLOT=94.2%- NS). Complete pathological response (no residual cancer) was found in 21 patients (9.3%) (DCF=14(11.6%) vs FLOT=7(6.7%) – NS). At follow up of 41(±36) months (DCF= 52±41 vs FLOT=27±23 - p

183 Background: In response to energetic stress, colorectal cancer cells secrete creatine kinase brain-type (CKB). CKB converts creatine and ATP from the extracellular matrix to PC, which is imported intracellularly to sustain survival and metastatic spread. In addition, PC modulates immune cell functions and may play a role in mediating responses to immune checkpoint inhibition. CO.26 was a phase II trial (NCT02870920) that randomized patients (pts) with refractory mCRC to durvalumab plus tremelimumab (D+T) versus best supportive care (BSC). In an exploratory, post-hoc analysis, we investigated the role of plasma PC as a predictive biomarker for response to D+T. Methods: PC concentrations were determined from pre-treatment blood samples with HPLC-tandem mass spectrometer. A minimum p-value approach was used to select an optimum cut-off value which dichotomized patients into low (< 95.6 ng/ml) versus high (≥ 95.6 ng/ml) groups predictive for benefit. Cox proportional hazard models were used to analyze predictive impacts of PC on progression free survival (PFS) and overall survival (OS). Results: Of 180 pts enrolled, pre-treatment blood samples were available for 162 pts (N =115 for D+T; 47 BSC). Pre-treatment PC was low in 15% (N=24) and high in 85% (N=138). There were no differences in baseline characteristics between pts included in this analysis and the total study pts, or PC low and high pts. D+T improved OS significantly in PC low pts (median OS 4.7 months vs 2.3 months; Hazard Ratio (HR) 0.32, 95% confidence interval (CI): 0.11 – 0.95, p = 0.03). There was no improvement in PC high pts with D+T (median OS 6.8 vs 5.2 months; HR 0.80, 95% CI: 0.55 – 1.17, p = 0.24. Interaction p < 0.0001). Plasma PC values had no impact on PFS and rates of disease control. Conclusions: Pts with low plasma PC derived more benefit from immune checkpoint inhibition with D+T in pts with refractory mCRC. Further prospective validation studies are needed. Predictive analysis for OS with pre-treatment PC levels dichotomized by minimum p approach. [Table: see text]

PURPOSE KEYNOTE-164 (NCT02460198) evaluated the antitumor activity of pembrolizumab in previously treated, metastatic, microsatellite instability–high/mismatch repair–deficient (MSI-H/dMMR) colorectal cancer (CRC). METHODS This phase II open-label study involved 128 centers worldwide. Eligible patients were age ≥ 18 years and had metastatic MSI-H/dMMR CRC treated with ≥ 2 prior lines of standard therapy, including fluoropyrimidine, oxaliplatin, and irinotecan with or without anti–vascular endothelial growth factor/epidermal growth factor receptor monoclonal antibody (cohort A) or ≥ 1 prior line of therapy (cohort B). MSI-H/dMMR status was assessed locally. Patients received pembrolizumab 200 mg every 3 weeks for up to 2 years until progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate by RECIST version 1.1 by independent central review. Secondary end points were duration of response, progression-free survival (PFS), overall survival, safety, and tolerability. RESULTS A total of 124 patients with MSI-H/dMMR CRC (61 in cohort A, 63 in cohort B) enrolled. At data cutoff, median follow-up was 31.3 months (range, 0.2-35.6 months) for cohort A and 24.2 months (range, 0.1-27.1 months) for cohort B. Objective response rate was 33% (95% CI, 21% to 46%) and 33% (95% CI, 22% to 46%), respectively, with median duration of response not reached in either cohort. Median PFS was 2.3 months (95% CI, 2.1 to 8.1 months) and 4.1 months (95% CI, 2.1 to 18.9 months). Median overall survival was 31.4 months (95% CI, 21.4 months to not reached) and not reached (95% CI, 19.2 months to not reached). Treatment-related grade 3-4 adverse events occurred in 10 patients (16%) in cohort A and 8 (13%) in cohort B, with the most common occurring in ≥ 2 patients being pancreatitis, fatigue, increased alanine aminotransferase, and increased lipase (2 patients each; 3%) in cohort A. CONCLUSION Pembrolizumab is effective with a manageable safety profile in patients with MSI-H/dMMR CRC.

3521 Background: Response to antiPD-1 monotherapy is poor in patients (pts) with advanced microsatellite stable (MSS)/mismatch-repair proficient (pMMR) CRC. Combination of chemotherapy with antiPD-1 pembro may potentiate the antitumor immune response and provide greater antitumor activity than either agent alone. Combination of pembro and mFOLFOX7 or FOLFIRI in the ongoing phase 1b multicohort KEYNOTE-651 (NCT03374254) study in metastatic MSS/pMMR CRC showed antitumor activity. We present results with approximately 20 mo of additional follow-up. Methods: Pts had metastatic MSS/pMMR CRC and were previously untreated (cohort B) or received 1 prior line including a fluoropyrimidine + oxaliplatin (cohort D). Pts received pembro 200 mg Q3W + mFOLFOX7 Q2W (cohort B) or pembro 200 mg Q3W + FOLFIRI Q2W (cohort D). Primary end points were safety (DLT) and RP2D. Secondary end point was ORR per RECIST v1.1 by investigator review. DOR, DCR, and PFS per RECIST v1.1, and OS were exploratory end points. Results: Median study follow-up (range) at data cutoff (Oct 15, 2021) was 30.2 mo (25.0-43.6) for cohort B (n = 31) and 33.5 mo (25.2-43.2) for cohort D (n = 32). Treatment was discontinued in 29 pts (94%) in cohort B and 28 pts (88%) in cohort D, mostly because of PD (61% and 66%, respectively). At prior analysis (Feb 10, 2020), RP2D was confirmed as the starting dose in both cohorts; no new DLT had occurred. In cohort B, gr 3/4 TRAEs occurred in 18 pts (58%), most commonly neutropenia and decreased neutrophil count (both n = 5; 16%); 19 pts (61%) discontinued drug because of a TRAE. In cohort D, gr 3/4 TRAEs occurred in 17 pts (53%), most commonly, neutropenia (n = 7; 22%), diarrhea and fatigue (both n = 4; 13%); 3 pts (9%) discontinued drug because of a TRAE. There were no gr 5 TRAEs in either cohort. Efficacy by cohort and KRAS mutation status are below (Table). PD-L1 data and DNA/RNA-based biomarker data including GEP, consensus signatures, TMB, and LoF mutations will be included in the presentation. Conclusions: After 2.5 y of follow-up, the combination of pembro with either mFOLFOX7 or FOLFIRI continued to demonstrate a manageable safety profile with no new safety signals. Efficacy data from these single-arm cohorts appear comparable to historical data for current SOC. Clinical trial information: NCT03374254. [Table: see text]

3573 Background: Response to antiPD-1 monotherapy is poor in microsatellite stable (MSS)/mismatch-repair proficient (pMMR) mCRC; the combination of antiPD-1 pembro + anti-MEK bini, with or without chemo, may improve upon this limited response. KEYNOTE-651 (NCT03374254) is an open-label phase 1b multicenter trial of pembro + bini (cohort A) or pembro + bini + chemo (mFOLFOX7 in cohort C, FOLFIRI in cohort E) in MSS/pMMR mCRC. Preliminary results from the dose-finding phase at 2 dose levels (DL) of bini are presented. Methods: Patients (pts) had MSS/pMMR mCRC and must have been previously treated with fluoropyrimidine, irinotecan, and oxaliplatin in cohort A, or with fluoropyrimidine + oxaliplatin-based regimen in cohort E; pts were previously untreated in cohort C. Pts received pembro 200 mg Q3W + bini 30 mg BID (cohort A, DL1), pembro 200 mg Q3W+ bini 30 mg BID + mFOLFOX7 Q2W (cohort C, DL1) or pembro 200 mg Q3W + bini 30 mg BID + FOLFIRI Q2W (cohort E, DL1). Bini dose escalation to 45 mg BID (DL2) was planned in cohorts A, C, and E, with a target dose-limiting toxicity (DLT) of 30%. Primary end point was safety (DLT). Secondary end point was ORR. DCR, PFS, and OS were exploratory. ORR, DCR, and PFS were assessed by investigator per RECIST v1.1. Results: Median study follow-up at data cutoff (Oct 15, 2021) was 36 mo (range, 32-43) for cohort A, 17 mo (2-24) for cohort C, and 11 mo (2-25) for cohort E. In cohort A, 1/6 pts (17%) had DLT at DL1; no DLT occurred in 14 pts (0%) at DL2. In cohort A, gr 3/4 TRAEs occurred in 3/6 pts (50%) at DL1 and 8/14 pts (57%) at DL2. In cohort C, 3/9 evaluable pts (33%) had DLT at DL1; thus, bini dose was not escalated to DL2. In cohort C, gr 3/4 TRAEs occurred in 9/11 total pts (82%). In cohort E, 1/5 evaluable pts (20%) had DLT at DL1 and 5/10 evaluable pts (50%) had DLT at DL2. Enrollment was stopped in cohort E, DL2 and bini dose was de-escalated to DL1; 2/4 additional pts (50%) had DLT at DL1 (total 3/9 pts [33%] had DLT in cohort E, DL1). In cohort E, gr 3/4 TRAEs occurred in 5/9 pts (56%) at DL1 and 10/11 total pts (91%) at DL2. No gr 5 TRAEs occurred in any cohort. ORR was 0% in cohort A; limited efficacy was seen in cohorts C and E (Table). Conclusions: Bini could be safely combined with pembro in cohort A. However, with bini + pembro + chemo, the 45-mg dose of bini was not well tolerated and required dose reduction to 30 mg. Addition of bini to pembro + chemo did not improve efficacy; therefore, enrollment was prematurely closed in cohorts C and E. Efficacy by KRAS mutation status will be shown. Clinical trial information: NCT03374254. [Table: see text]

3600 Background: Immune checkpoint blockade has limited activity in microsatellite-stable (MSS) or mis-match repair proficient (pMMR) CRC. Recent findings suggest that immunotherapy efficacy may be modulated by the presence of liver metastases. We conducted a retrospective analysis of the Canadian Cancer Trials Group (CCTG) CO.26 study to investigate the relationship between the presence of liver metastases and activity of immune checkpoint blockade. Methods: The CCTG CO.26 study was a randomized phase II study (NCT02870920). Pts with treatment refractory CRC were randomized to durvalumab, tremelimumab and best supportive care (BSC) or BSC alone in a 2:1 fashion. Treatment consisted of durvalumab (1500 mg) q 28 days and tremelimumab (75 mg) q 28 days for the first 4 cycles. The primary endpoint was overall survival (OS) and a two-sided p-value

TPS638 Background: Prospective studies of the benefit of neoadjuvant chemotherapy in resectable pancreatic adenocarcinoma (PDAC) have been reported. The ideal peri-operative regimen is yet to be determined. Adjuvant FOLFIRINOX (mFFX) in resected PDAC has been proven to improve overall survival (OS) relative to adjuvant gemcitabine. An accepted perioperative approach involves delivering the majority of chemotherapy (6-8 cycles) in the pre-operative setting, while the remainder (of 12 cycles) is administered post-operatively. This pre-operative treatment period may allow for chemosensitivity assessment, and better patient selection for surgery, thereby improving R0 resection rates and reducing the frequency of early post-operative recurrence. Data from the COMPASS trial (NCT02750657) has shown that shown that low levels of the transcription factor GATA6 expression is a putative surrogate for the RNA Moffit signature and predictive of a chemoresistant phenotype in advanced PDAC. NeoPancONE will evaluate clinical outcomes and molecular biomarkers including GATA6 and radiomic biomarkers in pts with resectable PDAC treated with perioperative mFFX. Methods: NeoPancONE is a Phase 2, open-label, single arm study in pts with resectable PDAC. Tissue and serum are collected for biomarker testing, including GATA6 by FISH and IHC (1) with expression levels measured by RNAseq, and longitudinal ctDNA analysis. Pts with histologically confirmed, resectable PDAC and ECOG PS 0-1 will be recruited over 2.5 years. Resectability will be determined by central review as per NCCN guidelines. The primary objective is to evaluate disease-free survival in resectable PDAC treated with peri-operative mFFX according to baseline tumor GATA6 expression level. The ratio of GATA6-high to low is expected to be approximately 4:1[1]. Assuming 1-year disease-free survival of 65% in the GATA6-high, compared to 34% in the GATA6-low cohort, this corresponds to a hazard ratio of 2.5. With 80% power and a 5% 2-sided significance level, a total of 84 patients will be enrolled with 67 events expected in the GATA6 high cohort and 17 in GATA6 low. Participants will receive up to 6 cycles of neoadjuvant mFFX. After neoadjuvant chemotherapy, definitive surgical resection will proceed as deemed appropriate by a hepatobiliary surgeon. Post-operatively, pts will receive up to 6 cycles of adjuvant chemotherapy. Secondary objectives include determination of overall response rate, incidence of R0 resection, OS, Moffit gene expression profiling (RNAseq), ctDNA, and radiomic signatures to predict outcomes. Enrolment for NeoPancONE began in October 2020 and is being conducted at 8 sites across Canada. To date, 23 pts have been recruited. The study duration will be five years. Reference: O’Kane G M et al. Clin Can Res Sep 2020. Clinical trial information: NCT04472910.

e15589 Background: Worldwide treatment for 1st line (1LTx) mCRC included doublet or triple chemotherapy with or without bTAs. In Quebec, the anti-EGFR therapy (panitumumab or cetuximab) was only recently approved in this setting for patients RAS WT, Bevacizumab (B) not eligible. In this study we evaluated the rational and outcomes using bTAs. Methods: Retrospective study assessing mCRC pts treated with or without bTAs at any time throughout the course of therapy at the Jewish General Hospital between 2010-2018. Pts were divided in 3 groups according to their 1LTx for analysis: Chemotherapy alone (1LChA), Chemotherapy plus B (1LChB), and anti-EGFR with or without chemotherapy (1LaEGFR). The primary objective was to assess the rational of bTAs prescription based in 1LTx selection. Secondary objectives included safety, PFS and OS. Results: Among a total of 463 pts with mCRC; 196 pts (42.3%) received 1LChA, 246 pts (53.2%) 1LChB, and 21 pts (4.5%) 1LaEGFR respectively. 1LChA group, 51% omitted bTAs for physician-patient preferences, 96 pts (49%) had contraindications for B, and 79 pts (40.3%) were potentially candidates for aEGFR, but did not receive it. 152/196 (77.5%) pts continued to 2LTx and 34.8% received bTAs. As for the 3LTx, 78/196 (40%) received a treatment, 48.7% received bTAs. The most common grade 3-4 adverse events (AEs) were hypertension and bowel perforation in B, gastrointestinal (GI) symptoms and skin reaction (SR) in aEGFR. 1LChB group, 31 pts (12.6%) presented AEs related to B. 191/246 pts (77.6%) continued to 2LTx with 48 pts (25%) receiving ChB despite progression in 1LTx on this bTA and 19 pts (10%) receiving aEGFR. The most common AEs reported in 2LTx were GI symptoms and neuropathy. In 3LTx, 54/91pts (59.3%) received aEGFR therapy and 8 pts (14.8%) had SR AEs. 46 pts (18.6%) continued to 4LTx, 13/46 pts (28.2%) received aEGFR. 1LaEGFR group, the most common AEs were SR and GI symptoms. 11/21 pts (52.3%) continued to 2LTx; 5 pts (45.4%) switching bTA class and receiving ChB. 81% pts started treatment between 2017-2018 and had at least two contraindication criteria for. The median PFS for the 1LChA and 1LChB groups were 10 and 11.5 months, respectively, and were not statistically significant (p=0.22). The OS with 1LChA and 1LChB was 33.26 vs. 27.80 months (p=0.27). The PFS and OS between 1LChA and 1LaEGFR were 10 vs 11 months (p= 0.27) and 33.26 vs. 35.07 months (p=0.13). Conclusions: The outcome and tolerability of bTAs in mCRC appear similar in our institution and randomised trials. We were not able to detect any significant difference among the three groups of comparison. The 1LaEGFR available data in this subset of patients are limited. Our data highlights the importance of optimal therapeutic sequencing to prolong OS. Dedicated studies are needed in order to determine the best bTAs therapeutic strategy in mCRC.

4135 Background: PA.7 evaluated whether combining PD-L1 and CTLA-4 inhibition with GEM and Nab-P increases efficacy. A previous analysis of the PA.7 data demonstrated high plasma based TMB (≥9 mut/Mb) was associated with improved OS in the Gem, Nab-P, D+T arm. DNA repair pathway aberrations beyond mismatch repair have been associated with potential immune sensitivity. We assessed the predictive value of germline ATM mutations in the PA.7 trial. Methods: This randomized phase II study (ClinicalTrials.gov NCT02879318) assessed the efficacy and safety of GEM, Nab-P, D, and T (arm A) vs. GEM and Nab-P (arm B) in patients (pts) with mPDAC (n = 180). The primary endpoint was overall survival (OS). Pre-treatment plasma was sequenced with the Predicine ATLAS next generation assay (600 gene, 2.4 Mb panel). 2-sided alpha set at 0.1. Results: 180 pts were randomized (119 to arm A and 61 to arm B) There was no significant difference in OS (9.8 months in arm A vs. 8.8 months in arm B, p-value 0.72) or PFS (5.5 months and 5.4 months respectively, HR 0.98, p-value 0.91). Plasma analysis was performed on 174/180 pts with available samples. 16/174 (9.2%) pts had germline ATM mutations, 12 in arm A and 4 in arm B. GEM, Nab-P, D+T was associated with improved OS in patients with ATM mutations (HR 0.10, 90% CI 0.03-0.37; median OS 13.9 months vs. 4.9 months) while no activity was seen in pts with ATM Wild Type (HR 0.99, 90% CI 0.73-1.33; median OS 9.79 months vs. 10.2 months); interaction p = 0.014. Germline ATM mutation status was independent of plasma TMB levels (Wilcoxon p = 0.76). Conclusions: Germline ATM mutation appeared predictive of benefit from the addition of dual immune checkpoint inhibitors (D and T) to Gem and Nab-P, with a significant interaction p-value. In addition to previous data from this trial regarding the predictive value of high plasma TMB (≥9 mut/Mb), this data further supports that there may be independent subgroups of PDAC, beyond MSI-H, that may benefit from immunotherapy, and trials evaluating immunotherapy in subgroups of PDAC with these profiles are warranted. Clinical trial information: NCT02879318.

411 Background: PA.7 evaluated whether combining PD-L1 and CTLA-4 inhibition with GEM and Nab-P increases efficacy as first line therapy in mPDAC. High TMB is associated with immunotherapy sensitivity, with a threshold of ≥10 mut/Mb receiving FDA accelerated approved for pembrolizumab in a tissue agnostic setting. We assessed the predictive value of plasma TMB in the PA.7 trial. Methods: This randomized phase II study (ClinicalTrials.gov NCT02879318) assessed the efficacy and safety of GEM, Nab-P, D, and T (arm A) vs. GEM and Nab-P (arm B) in patients (pts) with mPDAC (n = 180). The primary endpoint was overall survival (OS). Pre-treatment plasma was sequenced with the CLIA-certified PredicineATLAS cfDNA next generation assay (600 genes, 2.4 Mb panel). A pre-specified cut point of 5 mut/MB was selected based on distribution of TMB in the trial. 2-sided alpha set at 0.1. Results: 180 pts were randomized (119 to arm A and 61 to arm B). There was no significant difference in OS (9.8 months in arm A vs. 8.8 months in arm B, p-value 0.72) or PFS (5.5 months and 5.4 months respectively, HR 0.98, p-value 0.91). Plasma TMB analysis was performed on 174/180 pts with available samples, and tumor derived variants were detected in 173/174 pts (99.4%). 172 pts were microsatellite stable and 1 pt was microsatellite high (MSI-H) (plasma TMB 52.9 muts/Mb). Using the pre-specified cut-point of 5 mut/Mb there was no significant predictive value from plasma TMB (interaction p = 0.91). Using a minimum p-value approach, a cut-point of 9 mut/MB appeared predictive (p-interaction = 0.064; significant at pre-specified p = 0.1). 8/174 (4.6%) pts had a plasma TMB ≥9 mut/Mb (5/115 (4.4%) in arm A and 3/59 (5%) in arm B). GEM, Nab-P, D+T was associated with improved OS in patients with plasma TMB ≥9 mut/Mb (HR 0.30, 90% CI 0.06-1.37) while no activity was seen in pts with < 9 mut/Mb, (HR 0.97, 90% CI 0.73-1.29). TMB cut-point analysis revealed a clear trend for a decreasing HR favoring the GEM, Nab-P, D and T arm above the selected cut point, with no benefit in the low TMB group. Conclusions: Plasma TMB analysis was successful in over 99% of pts with available samples. Plasma TMB ≥9 mut/Mb was predictive of benefit from the addition of dual immune checkpoint inhibitors (D and T) to Gem and Nab-P, with a significant interaction p-value. While only present in a subgroup of pts (4.6%), this data defines a group beyond MSI-H PDAC that may benefit from immunotherapy. The optimal cut-point for high TMB in this setting requires validation. A clinical trial specifically assessing the role of chemotherapy combined with immune checkpoint inhibition in high TMB mPDAC is warranted. Clinical trial information: NCT02879318.

TPS145 Background: Although most cancers are initially susceptible to existing anticancer therapies, over time cancer cells develop resistance. BOLD-100 is a first-in-class therapy that targets the GRP78 pathway, a major regulator of cellular stress and resistance. This therapy suppresses drug resistance, survival and proliferation by restraining stress-induced upregulation of GRP78 in tumor cells, leading to inhibition of the cell survival response. BOLD-100 successfully completed a Phase 1 monotherapy trial, with a manageable safety profile; it has demonstrated synergy in established preclinical models in combination with a wide variety of anticancer therapies and shown to restore sensitivity of drug-resistant cell lines. Methods: BOLD-100-001 is a multicenter, prospective, two-stage, non-randomized Phase 1b dose escalation and expansion study of BOLD-100 in combination with FOLFOX chemotherapy for selected advanced solid gastrointestinal (GI) tumors: colorectal (CRC), pancreatic (PANC), gastric (GC) and bile duct cancers (BDC). Each patient will receive BOLD-100 along with FOLFOX chemotherapy on Day 1 of each 14-day cycle. In the dose-escalation phase (Part A), patients will be enrolled to determine the combination recommended dose using a standard 3+3 design. In the dose-expansion phase (Part B), up to 80 patients with selected GI tumors will be enrolled in 5 cohorts (comprising the 4 GI cancers referred) and treated with BOLD-100 at the recommended dose and FOLFOX, until progressive disease or unacceptable toxicity. In Part A dose-escalation, the primary objective is to assess the safety, tolerability and maximum tolerated dose. The Part B dose-expansion will assess the efficacy (progression free survival, overall survival and response rate), of FOLFOX chemotherapy plus BOLD-100. Secondary objectives in Part A and B include the assessment of pharmacokinetic and pharmacodynamic parameters and potential biomarkers predictive of efficacy. Eligible patients will have previously treated histologically/cytologically confirmed metastatic/unresectable GI tumor (CRC, PANC, GC or BDC), measurable disease per RECIST criteria, an ECOG performance score of 0 or 1, and adequate organ function. In Part A, no formal statistical hypotheses will be tested; analysis of the data will focus on comparisons of safety and dose-limiting toxicities between cohorts and only descriptive methods will be used. In Part B, Bayesian modelling will be used to continually reassess the efficacy endpoints: progression free survival, overall survival and objective response rates. The study was opened for enrollment in August 2020; approximately 25-30 patients will be screened to achieve up to 20 patients in Part A and up to 80 patients will be enrolled in Part B with a maximum of 25 patients per arm. Clinical trial information: NCT04421820.

4032 Background: Pembrolizumab provides effective antitumor immunity and durable responses in patients (pts) with advanced, colorectal cancer (CRC) with microsatellite instability-high (MSI-H) tumors. We present data on antitumor immunity with pembrolizumab in pts from the phase 2, KEYNOTE-164 study who had approximately 3 years of follow-up, and in pts re-treated after disease progression. Methods: KEYNOTE-164 enrolled pts with metastatic MSI-H CRC, MSI-H status confirmed locally by IHC or PCR, and ≥2 (cohort A) or ≥1 (cohort B) prior lines of therapy (fluoropyrimidine, oxaliplatin, irinotecan, or anti VEGF/EGFR). Eligible pts received pembrolizumab 200 mg Q3W for 2y (35 administrations) or until progression, unacceptable toxicity, or withdrawal. Pts who stopped pembro due to a confirmed CR or after completing 2y of treatment and who progressed after stopping were eligible for re-treatment with up to 17 administrations in the second-course phase, at investigator discretion. Tumor response was assessed Q9W per RECIST v1.1 by independent review. The primary endpoint was ORR. Secondary endpoints included DOR, PFS, OS, and safety. The data cutoff date was Sep 9, 2019. Results: At data cutoff, the median follow-up was 31.4 mo (range, 0.2-47.8) for 61 pts in cohort A and 36.1 mo (0.1-39.3) for 63 pts in cohort B. ORR was 32.8% (3CR, 17PR; 95% CI% 21.3-46.0) for cohort A and 34.9% (8CR, 14PR; 95% CI 23.3-48.0) in cohort B. Median DOR was not reached (NR [range, 6.2-41.3+]) and not reached (range, 3.9+ to 37.1+), respectively. Fifteen pts in cohort A and 17 in cohort B had ongoing responses at data cutoff. Median PFS was 2.3 mo (95% CI 2.1-8.1) with 3-yr PFS rate of 31% in cohort A and was 4.1 mo (2.1-18.9) with 3-yr PFS rate of 34% in cohort B. Median OS was 31.4 mo (21.4-NR) with 3-yr OS rate of 49% in cohort A and was not reached (19.2-NR) with 3-yr OS rate of 52% in cohort B. Nine pts (6 in cohort A, 3 in cohort B) had a second course of treatment. The best response in second course was PR in 1 patient each in cohort A and B. Grade 3-4 drug-related adverse events occurred in 10 (16%) pts in cohort A and 8 (13%) pts in cohort B. No grade 5 drug-related events occurred. Conclusions: After approximately 3 y of follow-up, pembrolizumab continues to provide effective long-term antitumor immunity with durable responses, with small numbers of drug-related adverse events and no drug-related deaths in pts with advanced, MSI-H CRC. Clinical trial information: NCT02460198 .

673 Background: Folfirinox (FFX) and Gemcitabine with nab-Paclitaxel (GN) are both proven to be superior to Gemcitabine (G) in the first line treatment (1LTx) for advanced pancreatic cancer (APC). Yet, the optimal 1LTx selection nor sequential Tx (ST) has not been fully established. Therefore, the best choice for 1LTx is a matter of debate often influenced by access to drugs. This analysis was conducted to compare outcomes based on 1Ltx selection and ST in APC. Methods: We assessed patients (pts) with APC who received either FFX or GN as 1LTx during 2010-2019 at three Canadian institutions. As well as the ST used. The main objective was to assess survival. Kaplan method and log-rank test were used for survival curves. Results: This retrospective study included 231 pts; 1LTx included 143 pts on FFX and 88 pts on GN. FFX pts were predominantly male; 89(62.2%) vs 46(52.3%) and slightly younger (median age 62 vs 66) than GN. WHO performance status (PS) of 0 were 38 (28.4%) vs 14 (16.5%) and 1 were 90 (67.2%) vs 65 (76.5%) respectively. There were more grade 3-4 toxicity in FFX vs GN group: GI 55 (38.5%) vs 15 (17%) and hematologic 51 (35.4%) vs 20 (22.7%) respectively. Grade 3-4 neutropenia rates were similar in both regimens. The median PFS of FFX was 5.5 months (95% CI: 5.0-6.7) vs 5.1 (95% CI: 3.8-7.1) with GN (p=0.37). The median OS with FFX was 9.3 months (95% CI: 7.5-11.1) vs 10.2 (95% CI: 6.8-11.3) with GN (p=0.81). There were not statically significant. Table shows Tx frequency across 4LTx. 2LTx and beyond regimens included G, GN, FFX, Capecitabine, Irinotecan liposome plus 5-FU, Irinotecan and clinical trials. Conclusions: Our results revealed that pts who received 1LTx FFX or GN had similar PFS and OS even though 1LTx FFX group was younger with better PS, allowing to continue 2-4LTx more frequently when compare with 1LTx GN group. Therefore, 1LTx selection appear to have more impact in our pts rather than ST, whereas GN is less toxic and seems a preferable 1LTx choice for most pts. FFX could be reserved for young high-performance pts. [Table: see text]

719 Background: Although Folfirinox (FFX) prolonged survival in metastatic and adjuvant setting, the role of preoperative FFX is still controversial. Our aim is to evaluate how surgery after neoadjuvant FFX with or without radiotherapy (RT) affects the clinical outcome in these patients. Methods: This is a single arm, open-label, phase 2 prospective study. Based on resectability criteria (NCCN-V.1.2017), patients prospectively were divided into 3 groups of resectable, borderline resectable (BR), locally advanced (LA). Patients received 6 cycles of preoperative FFX. Patients with adequate response, underwent resection. Continuation of chemotherapy or radiation was given to the patients who were deemed unresectable after 6 cycles. Primary objective is time to progression (TTP), and secondary objectives are safety, R0/R1 resection rate, response rate (RR) and overall survival (OS). Results: 20 consecutive patients with pancreatic adenocarcinoma enrolled. The frequency of each group was 4, 8, 8 patients, respectively. Median age was 64 years old (range, 49-78). 45% of patients had primary tumor in head or uncinate process. 25% of cases presented with normal CA 19-9 value. 85% (17/20) of patients completed the preoperative treatment. Folfirinox was given within median of 11.5 weeks (range, 8-17) and median of 6 cycles (range, 1-7). Median relative dose intensity (RDI) was 85.89%. Grade III-IV (G3+4) adverse event (CTCAE-4.03) observed in 47.4% (9/19). RR (RECIST) was 89% (16/18). Best response was partial response (PR) and stable disease (SD) with 22.2% (4/18) and 66.7% (12/18). Resection rate was 64.3% (9/14, 1 case scheduled for resection). R0 and negative lymph node (LN) achieved in 87.50% (7/8) and 62.50% (5/8) of patients. Complete pathological response (cPR) was seen in one patient 12.5% (1/8) who preoperatively reported as SD. Patients TTP and OS will be reported during the meeting. Conclusions: Preoperative FFX was associated with high clinical and pathological response rate translating in high resection rate in majority of BRPC and LAPC, and appears to be a safe treatment strategy. Patients received higher FFX dose intensity than it was reported in adjuvant setting. However, these results need to be assessed in a randomized trial. Clinical trial information: NCT03167112.

3512 Background: Targeting both PD-L1 and CTLA-4 may be synergistic immunotherapy approaches. CO.26 evaluated if dual inhibition leads to improved pt survival vs BSC alone in rmCRC. Methods: rmCRC pts were randomized 2:1 to D+T vs BSC. Treatment consisted of D (1500 mg) D1 q 28 days and T (75 mg) D1 for first 4 cycles, and supportive measures. Primary endpoint was overall survival (OS). Two-sided p < 0.10 was considered statistically significant. Cell-free (cf)DNA sequencing for MSI and TMB used GuardantOMNI panel and baseline plasma. Results: From 08/2016-06/2017, 180 pts were enrolled. Pt characteristics were balanced between arms. At median follow-up of 15.2 months (mos), median OS was 6.6 mos for D+T and 4.1 mos for BSC (p = 0.07; Hazard ratio (HR): 0.72, 90% confidence interval (CI): 0.54 – 0.97). Progression free survival (PFS) was 1.8 mos vs 1.9 mos, respectively (HR 1.01, 90% CI 0.76 – 1.34). Disease control rate (DCR) was 22.6% for D+T and 6.6% for BSC (p = 0.006). cfDNA analysis was successful in 168/169 pts (99.4%). Two pts were MSI-high. In 166 MSS pts, OS HR was 0.66 (p=0.024; 90% CI 0.49-0.89). Excluding the MSI-H cases (TMB of 74.7 and 247.1 mts/Mb), mean TMB was 20.4 ± 16.3 mts/Mb (range: 0.96 – 114.0). In MSS pts, a pre-specified cutpoint of 20 mts/Mb stratified pts into high and low TMB groups but was not predictive for OS , PFS, or DCR (interaction p-values > 0.7). Using a minimum p-value approach, pts with TMB >28 mts/Mb (21% of MSS pts) had the greatest OS benefit (HR 0.34, 90% CI 0.18-0.63) for D+T (interaction p = 0.07). High TMB was associated with a trend in worse prognosis for OS in the BSC arm using both 20 mts/Mb (HR 1.26, 90% CI 0.76-2.12) and 28 mts/Mb (HR 2.59 90% CI 1.46-4.62) cutpoints. Conclusions: D+T significantly prolonged OS in pts with rmCRC. High TMB may select a group of MSS pts who benefit from D+T. Plasma TMB appeared prognostic in the BSC arm. This is the first study showing combined PD-L1 and CTLA-4 inhibition prolongs survival in pts with MSS rmCRC. Updated results based on deaths in more than 90% of pts will be presented. Clinical trial information: NCT02870920.

481 Background: D is a human monoclonal antibody (mAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor. T is a mAb against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Targeting both PD-L1 and CTLA-4 may have additive/synergistic activity as the mechanisms of action of CTLA-4 and PD-L1 inhibition are non-redundant. This study evaluated whether combining PD-L1 and CTLA-4 inhibition would lead to improved pt survival vs BSC alone in rCRC. Methods: Pts with rCRC were randomized 2:1 to D+T vs BSC . Pts were eligible if they failed all standard regimens; containing a fluoropyrimidine, irinotecan and oxaliplatin (and an EGFR inhibitor if Ras wild type). Prior treatment (Tx) with anti-VEGF agents or TAS-102 was permitted but not mandatory. Tx consisted of D (1500 mg) D1 q 28 days and T (75 mg) D1 for first 4 cycles, and all appropriate supportive measures. Primary endpoint was overall survival (OS) and a two-sided p-value < 0.10 was considered statistically significant. Results: Between August 2016 and June 2017, 180 pts were enrolled and 179 treated as randomized. Pt baseline characteristics were balanced. 85% of pts received ≥ 90% of planned doses of D and T. No pts with known defective mismatch repair (dMMR) tumors were enrolled. With a median (med) follow-up of 15.2 months (mo), the med OS was 6.6 mo for D+T and 4.1 mo for BSC (p = 0.07; Hazard ratio (HR): 0.72, 90% confidence interval (CI): 0.54–0.97). Med progression free survival was 1.8 mo and 1.9 mo respectively (HR 1.01, 90% CI 0.76–1.34; p=0.97). Disease control rate was 22.7% for D+T and 6.6% for BSC (p = 0.006). Grade 3/4 abdominal pain, fatigue, lymphocytosis and eosinophilia were significantly higher in D+T. At 16 weeks, there was significantly less deterioration on EORTC QLQ-C30 physical function for D+T. Confirmation of MMR status is ongoing. Conclusions: D+T significantly prolonged OS in pts with rCRC and preserved quality of life. Adverse events were more frequent with D+T. This is the first study showing that combined PD-L1 and CTLA-4 inhibition prolongs survival in pts with advanced refractory CRC not selected for dMMR. Clinical trial information: NCT02870920.

400 Background: Since 2011, options for treatment of metastatic pancreatic cancer (mPC) have improved with the use of nab-paclitaxel plus gemcitabine (n-PGEM) or FOLFIRINOX (FFX) as first line treatments (1LTx). In 2016, Nanoliposomal irinotecan plus 5FU (nal-IRI-5FU) demonstrated efficacy in 2LTx. Yet, optimal sequential Tx has not been established. Methods: We evaluated oncologist-selected Tx algorithms and resultant progression free & overall survival (PFS, OS) for pts with mPC from 2010 and 2018 at the Jewish General Hospital, Montreal, QC. This retrospective study included 203 pts with mPC (33 to 89 years, 54% male). Results: 1LTx included 66 pts on FFX, 60 pts on n-PGEM, and 66 pts on single-agent GEM. The remaining pts received Capecitabine (CAP) or another Tx (N = 11). Mean PFS in FFX, n-PGEM, and GEM groups was 5.07, 5.52, and 4.10 months, respectively (progression was 1˚ or 2˚ disease progression or a change of Tx due to adverse events or intolerance). Only the FFX and GEM groups were significant when compared (p = 0.049). Only 43.8% of pts (N = 89/203) advanced to 2LTx most receiving GEM (N = 27), n-PGEM (N = 21), or FFX (N = 11), PFS 3.87, 7.04, and 2.30 months, respectively. FFX and n-PGEM groups were significant when compared (p=0.011). CAP and nal-IRI-5FU were 2LTx options for 25.8% (N=23/89) and 7.9% (N = 7/89) of pts, respectively. For 30 pts in 3LTx, Txs included: nal-IRI-5FU (N = 8), clinical trials (CT) (N = 7), GEM (N = 5), FFX (N = 4), n-PGEM (N = 2), CAP (N = 2) and Irinotecan (IRI) (N = 2). Only 7 pts received 4LTx: GEM (N = 3), CAP (N = 2), CT (N = 1), and IRI (N = 1). Median OS from start of 1LTx for pts in FFX (N = 60), n-PGEM (N = 41), and GEM (N = 60) groups was 11.42, 9.50, and 6.23 months, respectively. (Excluding pts on ongoing tx and other censored data points). GEM tx was a significant prognostic factor for shorter OS, GEM verus FFX, HR 1.673 (1.165 to 2.402, p = 0.0053), GEM versus n-PGEM, HR 1.511 (1.012 to 2.258, p = 0.0437). No difference in survival was seen between FFX and n-PGEM groups, HR 0.903 (95% CI 0.605-1.349, p = 0.6196). Conclusions: Though FFX and n-PGEM are considered mainstays of 1LTx, GEM was chosen by physicians in ~1/3 of cases despite reduced PFS. Pts on FFX or n-PGEM had better OS compared to GEM alone, as expected. Further investigation into Tx sequencing in this and larger cohorts, is needed.

Purpose Ganitumab is a fully human monoclonal antibody against type-1 insulin-like growth factor receptor (IGF1R). An open-label phase II study was conducted to evaluate the efficacy and safety of ganitumab monotherapy in patients with metastatic Ewing family tumors (EFT) or desmoplastic small round cell tumors (DSRCT). Patients and Methods Patients ≥16 years of age with relapsed or refractory EFT or DSRCT received 12 mg/kg of ganitumab every 2 weeks. Objective response rate (ORR) was the primary end point. Secondary end points included clinical benefit rate (CBR = complete + partial responses + stable disease [SD] ≥ 24 weeks) and safety and pharmacokinetic profiles of ganitumab. The relationship between tumor response and EWS gene translocation status and IGF-1 levels was evaluated. Results Thirty-eight patients (22 with EFT; 16 with DSRCT) received one or more doses of ganitumab. Twenty-four patients (63%) experienced ganitumab-related adverse events. Grade 3 related events included hyperglycemia (n = 2), thrombocytopenia (n = 5), neutropenia (n = 2), leukopenia (n = 1), and transient ischemic attack (n = 1). There were no grade 4 or 5 treatment-related events. Of 35 patients assessed for response, two had partial responses (ORR, 6%) and 17 (49%) had SD. Four patients had SD ≥ 24 weeks, contributing to a CBR of 17%. The pharmacokinetic profile of ganitumab was similar to that observed in the first-in-human trial. Elevation of IGF-1 levels was observed postdose. EWS-Fli1 translocations were analyzed by RNA sequencing and fluorescent in situ hybridization, and novel translocations were observed in EFT and DSCRT. No apparent relationship between tumor response and IGF-1 levels or EWS gene translocations was observed. Conclusion Ganitumab was well tolerated and demonstrated antitumor activity in patients with advanced recurrent EFT or DSRCT.

3514Background: Pembrolizumab is approved for the treatment of adult and pediatric patients (pts) with previously treated MSI-H cancer regardless of tumor type or site. This approval was based in p...

e15568Background: Mortality related to colorectal cancer (CRC) is largely due to regional metastasis to portal/mesenteric lymph nodes and peritoneum as well as distant metastasis to vital organs su...

TPS3622Background: According to the IDEA trial (Shi Q et al. ASCO 2017;LBA1), 6-month adjuvant chemotherapy should remain the standard in stage III T4 or N2 colon cancer. The relatively poor surviv...

e16107Background: CALGB 80802 study determined that doxorubicin plus sorafenib did not improve survival (OS) compared to sorafenib. The association between platelet count and outcome of patients wi...

414 Background: The efficacy of FFX and GNP as 1LTx of mPC were established in phase 3 trials against Gemcitabine alone. However, no head‐to‐head trial has been performed. This analysis was conducted to compare the use of the two regimens in the 1LTx of mPC patients (pts). Methods: Retrospective study collected data of pts diagnosed with mPC (ECOG 0‐1) that received FFX or GNP as 1LTx at the Jewish General Hospital between 2010‐2016. Pt selection for 1LTx was based in ASCO Guidelines 2016 Criteria (AGC2016). Progression free survival (PFS) and overall survival (OS) were estimated using a Kaplan Meier method. Rate of 1LTx discontinuation and start of 2LTx was compared using two‐sided Fisher's exact test. Results: Among 75 pts with mPC (median age 69), 44 (59%) received FFX and 31 (41%) received GNP. In the FFX group 57% were male and 24 pts (55%) had primary tumors localized in the pancreatic head (PTPH). The majority of patients [n = 36 (82%)] had ECOG 1 at the start of FFX. The most common grade 3‐4 adverse events (AEs) were gastrointestinal symptoms (GI) [n = 12 (27%)], neutropenia (N) [n = 9 (20%)], fatigue (F) [n = 5 (11%)], and peripheral sensory neuropathy (PSN) [n = 2 (4%)]. In the GNP group 61% were male and 20 pts (65%) had PTPH. The majority of pts [n = 23 (74%)] had ECOG 1 at the start of GNP. The most common grade 3‐4 AEs were F [n = 8 (26%)], N [n = 4 (13%)], GI [n = 3 (10%)], and PSN [n = 2 (7%)]. Similar rates of 1LTx discontinuation due to AEs were seen in both groups: 5 pts (11%) in the FFX group due to GI, 2 pts (6.5%) in the GNP group due to F (p = 0.69). In the FFX cohort, 68.2% (30/44) went on to 2LTx whereas in the GNP cohort, 32% (10/31) received 2LTx (p = 0.0001). Of the FFX cohort receiving 2LTx, 40% (12/30) received GNP. The median PFS for the FFX and GNP groups were 5.75 and 4.63 months, respectively, and were not statistically significant (p = 0.523). The OS with FFX and GNP was 9.23 vs. 6.6 months (p = 0.09). Conclusions: For pts selected as per ASC2016, FFX and GNP cohorts showed similar PFS, OS, AEs, and 1LTx discontinuation rate. Our data highlight the importance of optimal therapeutic sequencing to prolong OS. A randomized trial will be needed to confirm 1LTx in mPC.

349 Background: GEM and Nab-P is a standard first line therapy for mPDAC based on the MPACT Trial. D is a human monoclonal antibody (mAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor. T is a mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). PA.7 is designed to evaluate whether combining PD-L1 and CTLA-4 inhibition with GEM and Nab-P increases treatment efficacy. Methods: This randomized phase II study (ClinicalTrials.gov NCT02879318) is assessing the efficacy and safety of GEM and Nab-P vs. GEM, Nab-P, D, and T in patients (pts) with mPDAC (n = 190). Pts with untreated mPDAC and good performance status (ECOG PS 0-1) are eligible. A safety run in was planned for 10 pts receiving GEM, Nab-P, D and T. The study is then planned to randomize pts in a 2:1 ratio to receive GEM (1000mg/m2 D1, 8, 15); Nab-P (125mg/m2 D1, 8, 15); D (1500 mg) D1 q 28 days and T (75 mg) D1 for first 4 cycles vs. GEM and Nab-P alone. The primary endpoint is overall survival (OS); secondary endpoints include progression free survival (PFS), safety, overall response rate and quality of life. Results: 11 pts were enrolled in the safety run in (2 final pts enrolled on the same day). Median (Med) age = 59; 9 male/ 2 female; 2 ECOG 0/ 9 ECOG 1; no pts had prior adjuvant therapy. Med follow-up was 8.3 months at the time of data lock. Med number of treatment cycles was 6 (3-10). The most common Grade 3 or greater adverse events included fatigue (27%), anemia (36%), abnormal WBC (27%), hyponatremia (27%), hypoalbuminemia (45%), and abnormal lipase (45%). 1 pt (9.1%) experienced grade 3 colitis. 8/11 pts (73%) had a partial response, with the med duration of 7.4 months. Disease control rate was 100%. Med PFS was 7.9 months (95% C.I. 3.5-9.2 months). 6-month survival rate was 80% (95% C.I 40.9%-94.6%). Med OS has not been reached. Conclusions: The combination of GEM, Nab-P, D and T was well tolerated and promising efficacy signals were noted. The originally designed randomized phase II study is ongoing, and an international randomized phase III trial is planned. Clinical trial information: NCT02879318.

TPS4149 Background: Gemcitabine (GEM) and Nab-Paclitaxel (Nab-P) has become a standard 1st line therapy for advanced PDAC based on the MPACT Trial.Durvalumab (D) is a human monoclonal antibody (mAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor (PD-1). Tremelimumab (T) is a mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Monotherapy with immune checkpoint inhibitors has thus far demonstrated limited activity in PDAC. This may be partly related to the activity of cancer associated fibroblasts (CAF) in promoting an immunosuppressive tumoural microenvironment in PDAC. GEM and Nab-P treatment may deplete stroma and CAFs, release neo-antigens and increase the immunogenicity of PDAC. This study is designed to evaluate whether the addition of PD-L1 and CTLA-4 inhibition to GEM/Nab-P increases treatment efficacy. Methods: This randomized phase II study (ClinicalTrials.gov NCT02879318) will assess the efficacy and safety of GEM/Nab-P vs. GEM/Nab-P/D/T in patients (pts) with metastatic PDAC (n = 190). Good performance status pts (ECOG < 2) with untreated metastatic PDAC will be eligible. Prior adjuvant therapy is allowed provided recurrence is > 6 months post-completion. There is a safety lead in of 10 pts receiving GEM/Nab-P/D/T. Assuming no safety concerns the study will go on to randomize pts in a 2:1 ratio to receive GEM (1000mg/m2 D1, 8, 15)/Nab-P (125mg/m2 D1, 8, 15) with/without D (1500 mg) D1 q 28 days and T (75 mg) D1 for first 4 cycles. Treatment will continue until disease progression, death, intolerable toxicity, or patient/investigator decision to stop. Primary endpoint is overall survival; secondary endpoints include progression free survival, safety, overall response rate and quality of life. Analysis will be according to randomized group stratified by ECOG PS and receipt of prior adjuvant chemotherapy. Blood, plasma, and archival tissue will be collected and assessed for potential prognostic and predictive biomarkers. As of February 1 2017, 11 pts have been enrolled and the initial safety analysis is ongoing. Clinical trial information: NCT02879318.

10064 Background: Non-CNS cancer and treatments are associated with neurocognitive sequelae in older adults; whether YAC (age 18-39 yrs) are protected from these effects is unknown. In YAC, cancer interferes with education and occupational attainment and is associated with psychological distress. This prospective, inception-cohort study characterizes neurocognitive functions and psychological distress in YAC. Methods: YAC completed a 2-hr battery of standardized neurocognitive tests and questionnaires 1.7 ± 1 months after diagnosis prior to chemotherapy (mean ± SD, T1) and 8.2 ± 1.2 (T2) and 14.2 ± 1.6 (T3) months later. Healthy YA with no cancer history (HYA) were tested at similar time points. Tests were scored using published norms, transformed to T-scores, and grouped into neurocognitive domains. Results: YAC (n = 108; lymphoma, breast, gyne, GI, GU, sarcoma) were grouped according to whether they required chemotherapy (n = 70) or not (n = 38), and compared to 63 HYA. At baseline, there were no group differences in neurocognitive performance, number of impaired tests, or neurocognitive complaints (Kruskal Wallis, all p-values > .4). About 70% of each group completed assessments at T2 and T3. Mean performance improved over time (random effects models, all p-values < .01), but there were no group differences or interactions between group and time. There were also no differences in proportions of participants in each group whose test scores improved ( > 10 points) or declined ( < 10 points) from T1 to T2 or T3. Adjusting for psychological distress, fatigue, or neurocognitive complaints did not change these results, despite higher symptoms of somatic distress, anxiety and fatigue in YAC compared to healthy YA over time (all p-values < .03). Conclusions: Before chemotherapy and up to about 14 months later, YAC have elevated distress and fatigue, but do not demonstrate the cognitive decline reported in older cancer patients. Our findings are consistent with research suggesting that aging brains are more vulnerable to neurotoxic insult. Whether the effects of cancer treatment emerge later in YAC, placing them at risk for accelerated aging as reported in older patients, remains to be examined.

498 Background: Metastatic pancreatic adenocarcinoma (mPDAC) carries a dismal prognosis, with often a poor response to treatment (Tx). Although gemcitabine with nab-paclitaxel (GnP) is now a standard 1st-line (1L) Tx in mPDAC, provincial policies limit its use. To understand the implications of the restriction, this real-life study was conducted. Methods: A historical prospective data was compiled using the local electronic medical record (Endovault Oncology v3.0, NY) at the Jewish General Hospital-McGill. All patients (pts) diagnosed with mPDAC that received GnP from 2013-2016 were identified. Demographics and Tx data was obtained. Primary objective was to evaluate tolerability in all lines of Tx [grade >2 CTCAE v4.03, mean Tx delay (mTxd)]. Secondary objectives were Tx attrition and outcomes [RECIST 1.1, complete response (CR), stable disease (SD) and progression disease (PD)]. Results: Of the 40 pts (female 60%, median age 64.3), 25 (62.5%) had primary at the head of the pancreas and 30 (75%) liver metastasis. 1L Tx: GnP 24 (60%), FOLFIRINOX 10 (FFX, 25%), Gemcitabine 5 (Gc, 12.5%) and FOLFOX 1 (2.5%). 70% of both FFX and Gc pts had grade 2 peripheral neuropathy (PN), neutropenia (NEUT) and fatigue. Half GnP pts had grade 2 NEUT and fatigue. mTxd in GnP, FFX and Gc were 7, 14 and 7 days. All FFX and Gc pts had PD. GnP cohort had 1 CR and 7 SD. 2L Tx was in 22 (55%): GnP 13 (59.5%), FFX 3 (13.5%), Capecitabine 2 (9%), FOLFOX 2 (9%) and Gc (9%). FFX pts 66.6% had grade 3 fatigue. GnP pts had grade 2 NEUT, PN and fatigue in 53.8%, 15.3% and 46.2%. mTxd were GnP 14 days and FFX 14 days. Except 1 SD, all FFX pts had PD. GnP pts had 1 CR, 6 SD, and 6 PD. All pts on Capecitabine, FOLFOX and Gc had PD. 3L Tx was in 6 (15%): 3 GnP (50%) and 3 on clinical trials (50%). All pts had PD and < 3 cycles. In 1L FFX pts, 7/10 and 3/6 went on to receive GnP in 2L and 3L. All 1L Gc pts had 2L GnP. Only 3 pts and 1 pt from 1L GnP pts went on to receive 2L and 3L Tx. Conclusions: Due to access limitations to GnP, its use was likely reserved for poor performance status pts. Instead, 1L FFX was used when possible. 1L FFX pts received more Tx lines due to initial pt selection. Further studies are needed in broader populations to evaluate optimal 1L Tx selection accounting for expected attrition and overall survival.

e15154Background: Phase III trials CORRECT and CONCUR have shown that Regorafenib confers survival advantage in metastatic colorectal (mCRC) patients. Unfortunately, toxicity often limits its full ...

e15030Background: More than ever, patients with metastatic colorectal cancer (mCRC) are exposed to multiple sequential chemotherapeutic and biological treatment lines (CLs) / agents (CAs). Yet rece...

2020Background: BEV + radiotherapy/temozolomide (RT/TMZ) improves progression-free survival (PFS) (vs placebo [PBO] + RT/TMZ) in newly diagnosedGBM, but this does not translate into an OS benefit (...

665 Background: Selection and sequencing of treatment regimens for individual metastatic colorectal cancer (mCRC) patients is governed by the goals of maintaining reasonable quality of life while extending survival. The timing of KRAS testing and its effect on EGFRi therapy is poorly described. The goals of this analysis wereto describe rates and timing of KRAS testing relative to EGFRi therapy for Canadian patients diagnosed with mCRC. Methods: A retrospective chart review conducted at 6 Canadian centres included patients diagnosed with mCRC from Jan 1, 2009 onwards, who commenced 1st-line systemic treatment for mCRC between Jan 1–Dec 31, 2009. Information on the proportion of patients who received 2nd, 3rd, or subsequent lines of systemic therapy for mCRC was determined and the rates and timing of KRAS testing was ascertained. Results: 200 patients commenced 1st-line therapy and the median age was 62 yr; 78% had mCRC at the time of diagnosis. The proportions of patients who started 2nd, 3rd, and 4th lines of systemic therapy were 70%, 30%, and 15%, respectively. 103 (52%) patients had KRAS testing; 6%, 18%, 57%, 16%, 2%, and 1% of patients were tested at diagnosis or before the 2nd, 3rd, 4th, 5th and 6th lines of therapy, respectively. Median time from testing to EGFRi treatment was 105 (range, 7–1192) days, and varied by site. The frequency of KRAS testing for patients ranged from 30%–70% across study sites; across provinces, the frequency of testing ranged from 46%–60%. 38/68 (56%) of patients with wt KRAS tumors received EGFRi; 31 (46%) patients received EGFRi therapy as next therapy following KRAS testing. 19 (28%) died and 4 were lost to follow-up within 120 days of KRAS testing with no other therapy. 2 additional patients with unknown KRAS status received EGFRi (1 without KRAS testing; 1 undetermined). Conclusions: KRAS testing occurred after starting 2nd line in 76% of cases and varied by site and province. About half of patients underwent KRAS testing and 56% of those patients with wt KRAS tumors received an EGFRi. The short time interval between (K)RAS testing and EGFRi therapy may point to the need for earlier testing if EGFRi therapy is to be used in earlier lines of therapy.

192 Background: An exploratory analysis of a randomized phase II study in HCC comparing doxorubicin (D) alone to doxorubicin plus sorafenib (D+S) showed a significant improvement in overall survival favoring D+S (JAMA, 2011). The results appeared promising compared to the historic outcomes seen in the pivotal sorafenib (S) trials. CALGB 80802 was designed to determine if D+S improved survival compared to S alone. Methods: Patients with histologically proven advanced HCC, no prior systemic therapy and Child-Pugh A were randomized to receive D 60 mg/m2 every 21 days plus S 400 mg PO twice daily (D+S) or S alone. For bilirubin ≥ 1.3x normal, D and S doses were halved. D was maxed out at 360 mg/m2. The study was stratified by extent of disease (locally advanced; metastatic), the primary endpoint was overall survival (OS); and secondary endpoint progression-free survival (PFS). The final analysis was to occur when 364 events were observed among 480 total patients, with 90% power to detect a 37% increase in median OS (10.7 to 14.7 months; 1-sided α = 0.05). Results: The Alliance DSMB halted the study after accrual of 346 patients (173 on each of D+S and S) when a futility boundary was crossed at a planned interim analysis. With 107 events in each arm, median OS was 9.3 months (95%CI 7.1-12.9) for D+S, and 10.5 months (95% CI 7.4-14.3) for S with a hazard ratio (HR) 1.06 (95% CI 0.8-1.4) for D+S vs. S. Median PFS was 3.6 (95% CI 2.8-4.6) and 3.2 months (95% CI 2.3-4.1), respectively (HR = 0.90, 95% CI 0.72-1.2). There were 38 deaths on treatment: 18 on D+S and 20 on S. Among these 8 [sepsis (1), dysphagia (1), pneumonia (1), cardiac (2), hepatic failure (2), and not otherwise specified (1)] on D+S, and 3 [fatigue (1), hepatic failure (1), and a secondary malignancy (1)] on S, were at least possibly related to treatment. A maximum grade 3 or 4 only hematologic adverse events (AE) occurred in 37.8% of patients on D+S and 8.1% of patients on S. Non-hematologic AEs were comparable, in 63.6% and 61.5% of patients, respectively. Conclusions: The addition of D to S resulted in higher toxicity and did not improve OS or PFS. The S median OS of about 10 months is consistent with previous reports. NCI Grant U10CA180821 Clinical trial information: NCT01015833.

199 Background: Cancer treatment is associated with neurocognitive sequelae and changes in structural and functional brain imaging in older adults, even if they do not receive central nervous system directed therapy. Because the brain continues to develop into the 3rd decade of life, YA (age 18-39 yrs) may also be vulnerable to neurocognitive dysfunction. In YA, cancer disrupts acquisition of developmental milestones and is associated with psychological distress. This study aims to characterize neurocognitive functions and its relation to psychological distress in YA. Here we present baseline results of our longitudinal study. Methods: In this prospective, inception-cohort study, we recruited 3 groups of YA from ambulatory oncology clinics: YA with cancers (YAC; lymphoma, breast, gynecology, gastrointestinal, genitourinary, sarcoma) who required chemotherapy (YAC+, n = 55), YAC who do not require it (YAC-, n = 31), and healthy YA (HYA, n = 54). Participants completed a 2-hr battery of standardized neurocognitive tests and validated self-report questionnaires. YAC were assessed within 3 months of diagnosis, and YAC+prior to chemotherapy. Test scores were converted to age-corrected scaled scores and transformed to z-scores (mean 0, SD 1). A global neurocognitive function score and 6 domain scores were evaluated. Results: There were no group differences in neurocognitive domains (ANOVA, all p-values > .1), or in the number of impaired test scores (defined as z < -1). YAC+ reported greater symptoms of somatic distress (p = .001) and anxiety (p = .004) than both HYA and YAC-. Symptoms were unrelated to neurocognitive performance (ρ < .16 for all). However, each group had poorer memory compared to population norms (1-sample t-tests: YAC+ p = .007; YAC- p = .047; HYA p = .023). Conclusions: Prior to treatment, neurocognitive functions of YAC were not different from HYA, suggesting that cancer itself is not a neurocognitive risk factor in YA. It is important to use appropriate control groups, rather than relying on normative data for comparison. We continue to follow this cohort to document neurocognitive function and distress over time, and to identify risk factors that contribute to outcomes in YA.

e14692 Background: Contrary to the general population, incidence of CRC in AYA is on the rise. However, their clinical outcomes and treatment (tx) efficacy remains somewhat abstruse. A MIRR was per...

e14664 Background: Standard of care in the treatment of stage III colorectal cancer (CRC) involves 6 months of adjuvant combination chemotherapy with 5-FU and oxaliplatin. Despite lack of true comparative study, 2 regimens FOLFOX (MOSAIC trial) and CAPOX (XELOXA trial) are believed to be similar in their efficacy and tolerability. However, the latter has been disputed as real-life data presented from Canada has shown CAPOX to be more toxic, leading to more frequent rate of reduction in its dose intensity. Consequently, its impact on clinical outcomes has been brought to question. Methods: A retrospective data review was conducted by Segal Cancer Centre (SCC) Quebec, and Tom Baker Cancer Centre (TBCC) Alberta, on patients with stage III CRC between 2006-2013. Patients were treated with either CAPOX or mFOLFOX6 as per Canadian treatment guidelines. Primary endpoints were dose intensity and toxicity with secondary endpoints disease free survival (DFS) and overall survival (OS). Results: 180 patients (80 SCC,...

e15215 Background: Epidemiology and clinical outcomes for pancreatic adenocarcinoma (PDAC) are not well described in adolescent and young adult (AYA) population. Furthermore, treatments’ efficacy f...

TPS9636 Background: Chemotherapy is associated with long-lasting neurocognitive sequelae and structural and functional brain imaging changes in about 25% of older adults who do not receive central ...

3514 Background: In contrast to BRAFV600 mutated (BRAFm) advanced melanoma, BRAFm colorectal carcinoma (CRC) does not respond to BRAF inhibitors due to strong feedback activation of the epidermal g...

TPS3656 Background: Biopsy-driven trials offer unique opportunities for discovery and validation of molecular signatures. We began a Phase II investigator-initiated study (IIS) to identify biomarke...

e14627 Background: Pts with mCRC receiving a first-line (1L) OX-t exhibit a PFS that extends beyond their treatment duration. However, the perception is that neurotoxicity limits OX-t treatment dur...

e14584 Background: XELOX for colorectal cancer (CRC) reportedly causes more grade III/IV toxicity in clinical practice, leading to a greater reduction in dose intensity than mFOLFOX6. We reported t...

2005^ Background: GBM has a high disease burden and poor prognosis, and impacts negatively on HRQoL. Symptomatic therapies for GBM, such as corticosteroids (CS), may impact patient status negatively Methods: AVAglio, a randomized, double-blind, placebo (P)-controlled trial in patients (pts) ≥18 yrs with newly diagnosed GBM, evaluated the addition of Bv or P (10mg/kg, q2w) to 6 wks of T (75mg/m2/d) + RT (2Gy, 5d/wk) followed by 28 treatment-free days, then 6 cycles of T (150–200 mg/m2/d, 5d q4w) with Bv or P (10 mg/kg, q2w), and then single-agent Bv or P (15 mg/kg, q3w) until disease progression (PD)/unacceptable toxicity. Co-primary endpoints were investigator-assessed PFS and overall survival. Secondary endpoints included HRQoL (EORTC QLQ-C30 and BN20, with 5 prespecified domains based on relevance in GBM). HRQoL time to definitive deterioration (TDD) was defined as time from randomization to ≥10 point deterioration from baseline with no subsequent improvement, PD, or death. Exploratory endpoints included KPS and CS use. Results: Baseline characteristics were well balanced. Bv significantly prolonged PFS (HR 0.64, 95% CI 0.55–0.74, p

e14556 Background: Xelox and Folfox regimens have been shown to be equivalent in clinical trials for colorectal cancers. However, concerns about toxicity induced by Xelox in clinical practice have been reported, resulting in reduced dose intensity. In this retrospective analysis, we compared the dose intensity of Xelox to Folfox in relation to toxicity. Methods: 208 patients were treated in adjuvant (Xelox: n=56, median age 65 years; Folfox: n=40, median age 66 years) or metastatic (Xelox: n=65, median age 66 years; Folfox: n=47 median age 62 years) settings. 90% of patients had ECOG 0-1. Results: In the adjuvant setting, 86% of patients treated with Xelox received a lower dose of the drug up front, compared to only 10% of Folfox-treated patients. Additional dose reductions occurred in subsequent cycles in 23% of Xelox-treated patients (mean relative dose intensity (RDI) Oxaliplatin: 72%; Capecitabine: 74%) but not Folfox-treated patients (mean RDI Oxaliplatin: 85%, 5-FU: 86%). A higher percentage of Folfox-treated patients had toxicities compared to Xelox-treated patients: nausea (30% vs 18%), diarrhea (47% vs 24%), and peripheral sensory neuropathy (32% vs 3%). Treatment delays were more frequent in Folfox (40%); mean cumulative delay, 9.4 (range 2.1-52.4) weeks, compared to Xelox (20%); mean cumulative delay, 10.2 (3.1-48.1) weeks. Mean treatment duration was equal (Xelox: 22.8 (3.0-78.1); Folfox: 22.6 (2.3-64.4) weeks). In the metastatic setting, results followed a similar pattern. 75% of Xelox-treated patients received a lower dose up front compared to 33% of Folfox-treated patients. Further dose reductions occurred in 31% of Xelox-treated patients (mean RDI Oxaliplatin: 70%; Capecitabine: 67%) compared to 20% of Folfox-treated patients (mean RDI oxaliplatin: 75%; 5-FU: 69%). Treatment delays occurred in 60% of Folfox-treated patients and 43% of Xelox-treated patients becauseof toxicities. Mean treatment duration was 24.9 (3.0-65.0) and 26.1 (4.0-60.1) weeks respectively. Conclusions: The higher dose reduction of Xelox compared to Folfox appeared to enable treatment completion with less toxicities. The impact on survival and cost of treatments will be presented.

9557 Background: Adolescent and young adult (AYA) cancer patients are faced with obstacles and challenges related to their diagnosis and treatment compared to children and older adults. The aim of this study was to explore the patient and health care system-related delays in the interval from cancer symptom onset to diagnosis and treatment as well as to identify the possible contributing factors to these delays in the AYA group. Methods: This study was based on a questionnaire conducted in 2010-2011 completed by patients diagnosed with a malignancy between the ages of 16 and 39 in addition to older patients diagnosed with a pediatric type malignancy. Four categories of delays: patient delay (time from patient symptom onset until first health care contact date), health care system delay (time from first health care contact until diagnosis date), treatment delay (time from diagnosis date until first treatment) and oncologist delay (time from first health care contact until first medical oncologist meeting) were calculated. Median delay (in days) with interquartile interval (IQI) was the main outcome measure. Median time for each category of delay was further analysed to explore how they vary with different patient characteristics. Results: We identified a median patient delay of 30 days (IQI 1-131), a median health care system delay of 53 days (IQI 1-213), a median treatment delay of 36 days (IQI 5-92) and a median oncologist delay of 77 days (IQI 30-281). Patient delay was affected by patient gender, age at diagnosis and type of first health care contact. Health care system delay was associated with patient marital status, financial situation and attitude of first health care professional. Treatment delay was related to type of cancer. Conclusions: The health care system delay (including oncologist delay) accounts for much of the delay from symptom onset to first treatment. Professional characteristics of frontline medical personnel as well as socioeconomic and biological characteristics of the patients may contribute to delay. Healthcare professionals and the general community as a whole need to be aware of the factors contributing to delay in diagnosis and treatment in the underserved patient population.

448 Background: EZN-2208 is a water-soluble, parenterally-delivered PEGylated conjugate of SN38 that increases solubility, exposure, and apparent half-life of SN-38. Methods: Patients with metastatic or locally recurrent CRC previously treated with fluoropyrimidines, oxaliplatin and irinotecan, and no more than 2 distinct progressions, were screened for K-Ras mutation and stratified accordingly. Patients with K-Ras tumor mutation (Mut) were treated with EZN-2208 (9mg/m2 SN-38 equivalents) over 1-h IV on days 1, 8, 15 in 4-wk cycles (Arm A). Patients with K-Ras wild type (WT) tumors were randomized (2:1) to EZN-2208 (as above) and cetuximab (250mg/m2 weekly following 400mg/m2 on D1) (Arm B) or to irinotecan (125mg/m2) over 90min IV days 1, 8 in 3 week cycles and cetuximab (as above) (Arm C). The primary objectives of the study were to determine the overall response rates (ORR) and progression free survival (PFS) (Arm A) and compare PFS (Arms B and C). A comparison of safety and toxicity of EZN-2208 and irinotecan was planned as well. Results: Demographic and efficacy parameters are summarized in the table . Common adverse events (Arms A%, B%, C%), observed in > 25% of patients in at least one arm of the study, were diarrhea (45%, 64%, 55%), fatigue (56%, 56%, 39%), nausea (43%, 59%, 47%), vomiting (31%, 46%, 39%), constipation (27%, 26%, 37%), abdominal pain (25%, 28%, 32%), anemia (33%, 21%, 21%), dermatitis acneiform (0%, 28%, 26%), hypokalemia (17%, 28%, 26%), and alopecia (12%, 28%, 3%). Conclusions: EZN-2208 in combination with cetuximab is active in patients in the 3rd line setting of CRC and comparable to irinotecan in combination with cetuximab. EZN-2208 monotherapy did not result in responses in patients with CRC following progression on irinotecan. EZN-2208 has an acceptable safety and tolerability profile as monotherapy, and in combination with cetuximab. [Table: see text]

2010 Background: Epidermal growth factor receptor (EGFR) is over-expressed in ~50% of glioblastoma (GBM); approximately half express the constitutively active mutant receptor EGFRvIII. Afatinib (A)...

e14158 Background: Bev prolongs overall survival (OS) and time to progression (TTP) when added to standard chemotherapy for mCRC and was approved for use in this setting in Feb 04. Bev was not appr...

10001 Background: IGF1 signaling is implicated in the pathobiology of EFT and DSRCT. AMG 479 is a fully human monoclonal antibody antagonist of IGF1R that induced a complete response (CR) in 1 EFT ...

e19555 Background: Young adult (YA) patients with cancer have aggressive disease and treatment. They struggle to maintain quality of life and would greatly benefit from exercise interventions. The ...

2094 Background: TLN-4601 is a structurally novel farnesylated dibenzodiazepinone that has demonstrated broad in vitro cytotoxicity and in vivo tumor growth inhibition. TLN-4601 exerts its antiprol...