BackgroundThe majority of pancreatic ductal adenocarcinomas (PDACs) are driven by mutant (mt) KRAS. How mt KRAS and co-driver mutations affect the immune cell (IC) landscape of PDAC remains uncertain. Herein, we characterize the types of IC in the PDAC tumor microenvironment (TME) and the prevalence of immuno-oncologic (IO) biomarkers by genomic and transcriptomic analysis in the context of KRAS status.Materials and methods4142 PDAC and 3727 colorectal cancer (CRC) cases with KRAS mt were analyzed using next-generation DNA sequencing, immunohistochemistry, and whole-transcriptome RNA sequencing. Microsatellite instability and deficiency in mismatch repair (MSI-H/dMMR) and tumor mutational burden (TMB) were also assessed.ResultsWe found KRAS mt in 81% of PDAC, with the most common variant being G12D in PDAC, and fewer cases of KRAS mt were co-expressed with the predictive IO marker MSI-H/dMMR than KRAS-wild-type (wt). However, KRASG12D, KRASG12V, and KRASQ61 mutations had significantly lower TMB than KRAS wt tumors in PDAC. The IC environment of KRAS mt PDAC showed significant differences in nearly all IC types; a similar pattern was observed in CRC but was less pronounced.ConclusionsTherapeutic IO targets like programmed death-ligand 1 are enriched in pancreatic adenocarcinoma cases harboring specific targetable variants of KRAS mt PDAC. Better understanding of the TME could lead to tailored immunotherapeutic strategies to overcome these barriers in KRAS mt PDAC, possibly in combination with molecularly targeted treatment strategies.

e18688 Background:177Lu-Dotatate is FDA approved for advanced well differentiated (WD) midgut neuroendocrine tumors (NETs). However, questions remain about tolerability and efficacy in patients (pts) with higher grade disease, more than one prior line of treatment, and in non-ileal primaries. Methods: This is a retrospective analysis of pts with histologically proven WD metastatic GEP-NETs who received 177Lu-Dotatate at a single racially diverse urban cancer center. Patients had disease that progressed on systemic therapy that included somatostatin analog (SSA), and radiotracer uptake at disease sites using 68Gallium-Dotate PET/CT. ECOG performance score (PS) was 0 to 2. 177Lu-Dotatate was administered in 200 mCi doses every 8 weeks for a total of 4 cycles and a maximum of 800 mCi. Patients were followed with serial CT scan and/or abdominal MRI with best objective response per RECIST criteria. Results: Fifty-one pts were treated between December 2017 and August 2021. Thirty-eight pts completed a minimum 3-month follow-up imaging. Median age was 64 years, 59% were female, 66% identified as white, 26% as Black, 8% as other. Most frequent primary sites were small intestine (64%) and. All had metastatic disease involving the liver except for one pt. Median time from diagnosis to 177Lu-Dotatate was 51 months (3-201). CTCAE grade 3/4 hematologic toxicity was seen in 6 of 51 pts (12%). Grade 3/4 thrombocytopenia occurred in 3 pts, grade 3/4 leukopenia occurred in 2 pts and grade 3 anemia occurred in 1 pt. A single pt developed myelodysplastic syndrome 1 year after 177Lu-Dotatate. Non-white pts had significantly higher risk of grade 1 elevated creatinine at 38% vs 6% in those who identified as white (p = 0.015). Of the 37 pts who reached 3-month follow-up, 27% had partial response, 43% had a mixed/stable response, and 30% had progressive disease. Only gender demonstrated significant difference; with male gender associated with worse response categories (p = 0.001). Median OS was 3.09 years. Metastatic disease in the liver only was associated with significantly worse OS (p = 0.015) compared to liver and other tissues. The median PFS was 1.36 years. Metastatic disease in the liver only was associated with significantly worse PFS (p = 0.043). Higher tumor grade neared significant association with worse PFS (p = 0.053). There was no difference in PFS by race, primary tumor site (pancreatic vs small bowel), PS, prior treatment history or time to first 177Lu-Dotatate. Conclusions: Diverse patients with WD GEP-NETs treated at this single urban cancer center with 177Lu-Dotatate demonstrated acceptable toxicity. Median PFS and OS were inferior to reported outcomes in NETTER-1 probably because of differences in treatment timing and patient populations. Possible variables associated with difference in outcome include pattern of metastatic disease and tumor grade.

Some studies suggest that older patients have reduced or no benefit from the addition of oxaliplatin to fluoropyrimidines as adjuvant chemotherapy for stage III colon cancer (CC). We studied the prognostic impact of age and treatment adherence/toxicity patterns according to age in patients with stage III CC who participated in 12 clinical trials from the ACCENT and IDEA databases and received 3 or 6 months (mo) of FOLFOX/CAPOX. Associations between age and time to recurrence (TTR), disease-free survival (DFS), overall survival (OS), survival after recurrence (SAR) and cancer-specific survival (CSS) were assessed by Cox model or a competing risk model, stratified by studies and adjusted for gender, performance status, T and N stage, and year of enrollment. 17,608 patients were included. The age of 24% of patients was > 70 (N=4,278). Patients >70 were more often included in newer trials (29% in the period 2010-2015 vs 17% for 1998-2003, p<0.0001) and had higher rates of early treatment discontinuation (ETD). The rates of grade ≥3 adverse events were similar between the 2 groups, except for diarrhea for 6-mo CAPOX (18% vs 14%, p=0.03) and neutropenia for 3-mo FOLFOX (24% vs 18%, p=0.08) for patients < and >70 respectively). Comparing patients <70 and >70, TTR, DFS, OS, SAR and CSS were significantly shorter (except for TTR in patients treated with 6-mo regimens) although absolute differences were small (Table1). In patients >70 with stage III CC enrolled in clinical trials, oxaliplatin-based adjuvant chemotherapy was well tolerated. Outcomes were inferior to those of patients under 70, but still provided clinically relevant benefit. Increased deaths from other causes and less intensive management at relapse may account for some of the differences in OS.Table: 317MOCAPOX/FOLFOX 6 moCAPOX/FOLFOX 3 mo≥ 70y<70y≥ 70y<70yETD29%19%12%8%p<0.001<0.001TTR3-year77%77%76%78%HR1.01.1p0.40.04DFS3-year75%77%76%78%HR1.21.3p<0.001<0.001OS5-year78%83%79%85%HR1.41.5p<0.001<0.001SARmedian (y)1.72.42.02.8HR1.41.3p<0.001<0.001Cancer-specific mortality5-year14%10%15%11%HR1.21.2p0.020.04 Open table in a new tab

LY2880070 (LY) is an oral, selective competitive inhibitor of checkpoint kinase 1 (Chk1). LY and low-dose gemcitabine (LD GEM) was tolerable in advanced cancers. This combination has been assessed in advanced or metastatic high-grade serous ovarian cancer (HGSOC). This two-part, open-label, multi-center study explored the safety, pharmacokinetics (PK), and anti-tumor activity of LY in patients with advanced or metastatic cancers. An expansion cohort was conducted in 27 patients with HGSOC. The primary objective of this Phase 2a cohort was to: 1) Characterize the dose-limiting toxicities (DLTs) and overall safety profile for LY+LD GEM in HGSOC; and 2) Evaluate the anti-tumor activity of LY + LD Gem. Patients received LY (50 mg b.i.d. X 5 days/week) + LD GEM (100 mg/m2) on days 1, 8, and 15 (optional) of a 21-day cycle. The combination of LY with GEM was generally well tolerated. The most common related adverse events included fatigue nausea, vomiting, diarrhea, fever, dyspnea, neutropenia, and thrombocytopenia. Treatment-emergent adverse events in >40% of ovarian patients included vomiting, nausea, anemia, fever, decreased appetite, ALT increased, abdominal pain, and fatigue. DLTs included reduced platelet count (Gr2), fatigue (Gr3), diarrhea (Gr3), and thrombocytopenia (x2, Gr2). Two patients (7.4%) had partial response (PR). Fourteen patients (51.9%) had stable disease, one of whom had an unconfirmed PR. Eleven patients (40.7%) achieved disease control ≥ 12 weeks. This combination was generally tolerated in advanced or metastatic HGSOC. Further investigation is needed to better define biomarkers predictive of response in this patient population.

The CCR5/CCL5 axis plays a key role in CRC. We previously showed that polymorphisms in CCR5/CCL5 are associated with outcome in patients (pts) with metastatic CRC. Here we aimed to characterize the molecular features associated with CCR5/CCL5 expression in CRC and whether CCR5/CCL5 levels could impact treatment outcome.

Background: The impact of molecular alterations on programmed death-ligand 1 (PD-L1) combined positive score (CPS) is not well studied in gastroesophageal adenocarcinomas (GEAs). We aimed to characterize genomic features of tumors with different CPSs in GEAs. Patients and methods: Genomic alterations of 2518 GEAs were compared in three groups (PD-11 CPS >= 10, high; CPS 1-9, intermediate; CPS < 1, low) using next-generation sequencing. We assessed the impact of gene mutations on the efficacy of immune checkpoint inhibitors (ICIs) and tumor immune environment based on the Memorial Sloan Kettering Cancer Center and The Cancer Genome Atlas databases. Results: High, intermediate, and low CPSs were seen in 18%, 54% and 28% of GEAs, respectively. PD-L1 positivity was less prevalent in women and in tissues derived from metastatic sites. PD-L1 CPS was positively associated with mismatch repair deficiency/microsatellite instability-high, but independent of tumor mutation burden distribution. Tumors with mutations in KRAS, TP53, and RAS-mitogen-activated protein kinase (MAPK) pathway were associated with higher PD-L1 CPSs in the mismatch repair proficiency and microsatellite stability (pMMR&MSS) subgroup. Patients with RAS-MAPK pathway alterations had longer overall survival (OS) from ICIs compared to wildtype (WT) patients [27 versus 13 months, hazard ratio (HR) = 0.36, 95% confidence interval (a): 0.19-0.7, P = 0.016] and a similar trend was observed in the MSS subgroup (P 0.11). In contrast, patients with TP53 mutations had worse OS from ICIs compared to TP53-WT patients in the MSS subgroup (5 versus 21 months, HR = 2.39, 95% CI: 1.24- 4.61, P 0.016). Conclusions: This is the largest study to investigate the distinct genomic landscapes of GEAs with different PD-L1 CPSs. Our data may provide novel insights for patient selection using mutations in TP53 and RAS-MAPK pathway and for the development of rational combination immunotherapies in GEAs.

MDM2 is a key negative regulator of tumor suppressor p53. MDM2 gene amplification has been reported as a potential marker for hyperprogression under checkpoint inhibitors (ICI). We aimed to characterize the molecular and gene expression profile of MDM2 amplified (a-MDM2) GI cancers. 23632 samples were included: 11692 colorectal, 3830 gastric/esophageal, 3960 pancreatic, 1860 biliary cancers (BC), 2330 other GI. Samples were analyzed using NextGen DNA seq for gene mutation (mut) and amplification (copy number > 6), in situ hybridization, whole transcriptome RNA seq and immunohistochemistry (Caris Life Sciences). EBseq was used to identify differentially expressed genes based on MDM2 expression levels (above vs below median) with control for FDR (Q < 0.2). Pathway and functional enrichment analysis was performed using Reactome. A-MDM2 frequency was highest in small bowel cancers (4.5%, 28/627), gastric/esophageal (3.3%, 125/3830), and BC (3.4%, 64/1860). a-MDM2 was more common in males (P = .01). Compared to MDM2 not amplified (na), a-MDM2 GI tumors showed lower mut rates in TP53 (23 vs 69%), KRAS (15 vs 44%), APC (5 vs 41%), and PIK3CA (4 vs 12%), whereas ATM mut were higher (9.5 vs 4%) (Q < .001). Copy number alterations (CNA) were significantly higher in a-MDM2 vs na, including CDK4, ERBB3, HMGA2, LGR5, NACA and WIF1 (Q < .001). Main results according to tumor type are summarized in the table. MDM2 amplification had an inverse relationship with TMB (Q = .04) and MSI-H/dMMR (Q = .03). No association was found with PDL1 levels and CPS score. A total of 785 genes were significantly differentially expressed based on MDM2 levels, with an increase in FGF signaling related pathways in MDM2 overexpressing tumors (Q < .05).Table: 1952PBCEsophagealGastricSmall Bowela-MDM2 %na %Q-valuea-MDM2 %na %Q-valuea-MDM2 %na %Q-valuea-MDM2 %na %Q-valueNGS TP5316440.0024189< 0.0001957< 0.0001860< 0.0001CNA CDK4190.2< 0.0001210.2< 0.000160.10.02110.30.02CNA ERBB3300.0560.10.01200.440.20.8CNA GNAS60.20.00580.70.0300.31370.5< 0.0001CNA HMGA2420.3< 0.0001350.5< 0.0001270.2< 0.0001520.3< 0.0001CNA LGR5310.10.01250.1< 0.000160.10.01180< 0.0001CNA NACA50.1< 0.0001600.002200.400.21CNA WIF1360.1< 0.0001270.4< 0.0001180.1< 0.0001380.2< 0.0001 Open table in a new tab This is the most extensive profiling study to investigate a-MDM2 GI tumors. Our data show distinct molecular patterns of a-MDM2 GI cancers involving WNT pathway genes, upregulation of FGF signaling and inverse association with TMB and MSI which may explain the resistance mechanisms to ICI.

Background Although rare, the incidence of BM is increasing due to the improvement in metastatic CRC treatment and longer survival. Genomic analyses of small series revealed that BM can harbor potentially unique driver mutations. We aimed to comprehensively characterize the molecular profile of BM and explore the differences between BM vs other distant metastases (OM) and primary tumors (PT) in CRC. Methods Tumor samples from BM (n = 81), PT (n = 6898) and OM (n = 5918) were analyzed using NGS (TruSEQ on 45 genes or NextSEQ on 592 genes), in situ hybridization and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. Results The most frequently mutated genes in BM were TP53 (80%), APC (73%), KRAS (68%), ARID1A (18%), PIK3CA (13%) and FBXW7 (9%). The most prevalent copy number increase was seen in CDX2 (20%), CCND2 (7%), FLT1 (7%), FLT3 (7%) and FOXO1 (7%). When compared to OM and PT, mutations in KRAS (BM: 68%, OM: 49%, PT: 48%), CDKN2A (5%, 1%, 1%), ERCC2 (2%, 0, 0) and HRAS (1%, 0, 0) were significantly higher in BM (P 17mut/MB) and MSI-high were seen in BM vs PT (2 vs 9% and 1 vs 8%, P=.049 and .031, respectively) but not compared to OM. No RSPO3 nor NTRK1 fusions were seen in BM (n = 5). Female gender was associated with younger age in BM (53.5 vs 62 yr, P=.0014) and OM (58.8 vs 60.2 yr, P Conclusions This is the largest and most extensive profiling study to investigate the molecular makeup of BM and the differences with PT and OM in CRC. Our data show distinct mutations and CNA characterizing BM and lower expression of immune related markers, supporting the rationale to develop tailored approaches to the treatment of this metastatic site. Legal entity responsible for the study The authors. Funding National Cancer Institute grant number P30CA014089, Gloria Borges WunderGlo Foundation-The Wunder Project, Dhont Family Foundation, San Pedro Peninsula Cancer Guild, Daniel Butler Research Fund, Call to Cure Research Fund and Fong Research Project. Disclosure J. Xiu: Full / Part-time employment: Caris Life Sciences. Y. Baca: Full / Part-time employment: Caris Life Sciences. R.M. Goldberg: Research grant / Funding (self), Travel / Accommodation / Expenses: Caris Life Sciences. A. Grothey: Travel / Accommodation / Expenses: Caris Life Sciences. A.F. Shields: Research grant / Funding (self), Travel / Accommodation / Expenses: Caris Life Sciences. A. Seeber: Advisory / Consultancy: Caris Life Sciences. M.E. Salem: Travel / Accommodation / Expenses: Caris Life Sciences. P.A. Philip: Travel / Accommodation / Expenses: Caris Life Sciences. J.L. Marshall: Advisory / Consultancy: Caris Life Sciences. W..M. Korn: Full / Part-time employment: Caris Life Sciences. H.J. Lenz: Travel / Accommodation / Expenses: Caris Life Sciences. All other authors have declared no conflicts of interest.

Background Werner syndrome gene (WRN) encodes a DNA helicase with an exonuclease activity that contributes to DNA repair. In cancer, WRN mutations lead to genomic instability. It is known that WRN is necessary to sustain in-vivo growth of cancers cells with microsatellite instability (MSI), including CRC. WRN is a very promising new target especially in cancers with MSI. There is still a lack of knowledge about the frequency of WRN alterations and their association with immunological and molecular phenotypes. Methods Tumour samples from 6854 CRC patients were analyzed using NGS (NextSEQ on 592 genes), in-situ hybridization and immunohistochemistry (Caris Life Sciences, Phoenix, AZ, USA). Tumour mutational burden (TMB) was calculated based on somatic non-synonymous missense mutations, and MSI was evaluated by NGS of known MSI loci. Results WRN mutations (WRN-mut) were observed in 80 of 6854 samples (1.2%). A higher prevalence of WRN-mut was detected in right- compared to left-sided CRC (2.4% vs 0.7%, p<.0001). In WRN-mut (MT) CRC, TMB (43 vs. 8.6 mutations/megabase [mut/MB], p<.0001) and PD-L1 expression (13% vs 4%, p<.0001) were higher compared to WRN wild-type (WT). A higher frequency of MSI-H was seen in cancers harboring WRN-mut (56% vs 7%, p<.0001). Also, WRN-mut was associated with a higher TMB in both MSI-H subgroup of tumors (54 vs 40 mut/MB, p=.03) and MSS subgroup (43 vs 8.6 mut/MB, p<.0001). Several differences between WRN-mut and WRN-WT CRC was observed, including TP53 (47% vs 73%), KRAS (34% vs 49%), APC (56% vs 73%), BRAF (26% vs 9%), ASXL1 (25% vs 4%), ERBB2 (9% vs 2%), BRCA1 (8% vs 1%), BRCA2 (15% vs 2%), CDK12 (10% vs 1%), (p<.01 for all). Copy number alterations (CNA) of CDX2 were seen only in WRN-WT tumours (6.4% vs 1%, p=.026) and CNAs seen more frequently in WRN-mut tumours included CD274, CALR, CRTC1, ELL, JAK3, KEAP1, LYL1, MEF2B (p<.01). Conclusions This is the largest profiling study to investigate the molecular and immunological landscape of WRN-mut CRCs. We show the high prevalence of MSI in WRN-mut tumours and their association with higher TMB and PD-L1 expression. Furthermore, it revealed that WRN-mut CRC is characterized by a distinct genetic profile. Our data might serve to tailor treatment in WRN-mut CRC. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background Several studies in BRAFV600E colorectal cancers (CRC) have failed to replicate the efficacy of BRAF inhibitors in treatment of BRAFV600E melanomas (Mel), suggesting the existence of different resistance mechanisms as well as molecular and biological differences between the 2 tumor types. Herein, we examine these differences. Methods Tumor samples submitted to Caris Life Sciences for NGS DNA sequencing (592 gene panel) and RNA sequencing (54 gene panel) between the years 2015 and 2019 were retrospectively studied. Only microsatellite stable (MSS) tumors with either BRAFV600E mutation or wild type (WT) BRAF status were included in this initial analysis. Chi-square tests determined differences. Results A total of 8409 tumor samples were analyzed: CRC (N = 7453: BRAFV600E=373; WT = 7080) and Mel samples (N = 956: BRAFV600E=274; WT = 682). The most frequently mutated genes in BRAFV600E CRC were TP53 (81%), APC (26%), and SMAD4 (22.4%), compared to CDKN2A (22%), PTEN (13%), and TP53 (13%) in BRAFV600E Mel. Molecular alterations that are significantly more frequent in BRAFV600E CRC vs BRAFV600E Mel but not significantly different between BRAF WT CRC vs BRAF WT Mel included RSPO3 fusions (CRC=22.6% vs Mel=0%, P = 0.027); RNF43 deletions (2.0% vs 0%, p = 0.019); and mutations in RNF43 (18.8% vs 0%, P Conclusions BRAFV600E CRC carry molecular alterations that are distinct from BRAFV600E Mel. RSPO3 fusions and RNF43 alterations are prevalent in BRAFV600E CRC tumors in a mutually exclusive manner, suggesting that Wnt pathway activation via genetic alterations in upstream Wnt pathway regulators may play an important role in BRAFV600E CRC tumorigenesis and resistance to BRAF inhibitors. Drug combinations that target both the MAPK and Wnt pathways may warrant further investigation. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure M.E. Salem: Travel / Accommodation / Expenses: Caris Life Sciences. J. Xiu: Full / Part-time employment: Caris Life Sciences. A. Grothey: Travel / Accommodation / Expenses: Caris Life Sciences. R.M. Goldberg: Research grant / Funding (self), Travel / Accommodation / Expenses: Caris Life Sciences. Z. Gatalica: Full / Part-time employment: Caris Life Sciences. R. Feldman: Full / Part-time employment: Caris Life Sciences. M. Saul: Full / Part-time employment: Caris Life Sciences. W..M. Korn: Full / Part-time employment: Caris Life Sciences. A.F. Shields: Research grant / Funding (institution), Travel / Accommodation / Expenses: Caris Life Sciences. J.L. Marshall: Advisory / Consultancy: Caris Life Sciences. H.J. Lenz: Travel / Accommodation / Expenses: Caris Life Sciences. All other authors have declared no conflicts of interest.

Background: Disruption of epigenetic regulation in CRC, particularly aberrant histone methylation, has been shown to correlate with poorer survival rates in mCRC. We aimed to highlight the molecular differences between CRC harboring pathological mutations in genes involved in histone modification (KMT family). Methods: Tumors were examined by NextGen sequencing, protein expression, and gene amplification. Tumor mutational burden (TMB) was calculated based on somatic missense mutations (TMB-high ≥ 17 mt/MB) and microsatellite instability (MSI) was evaluated on known MSI loci in the target regions. Chi-square and t-tests were used for comparative analyses. Results: In total, 3621 CRC were examined, and 224 (6.2%) showed a pathological mutation in KMT2A, KMT2C, or KMT2D. Demographics were as follow: F/M 47%/53%, median age 60. KMT mutations were strongly associated with MSI-H (66.5% vs 2.5%, P<.0001), TMB-high (72% vs 3%, P<.0001), BRAF mutation (24.7% vs 7.5%, P<.0001), PD-L1 overexpression (14.2% vs 2.7%, P<.0001), right-sided (11.7% vs 3.4% in left-sided tumors, P = 0.001) and POLE mutations (6.7% vs 0.1%, P<.0001). Furthermore, the rate of mutations among several genes such as ATM, ATRX, BRCA1/2, MLH1, MSH2/6, PMS2 (all P < 0.001) were more frequently seen in the KMT mutated tumors. All remained significant after multiple test correction. When we analyzed MSS tumors and POLE non-mutant tumors excluding MSI-H or POLE mutation, TMB-H remains more frequent in tumors with KMT mutations (8.3% vs 0.9%, P = 0.004), as well as several genes were more frequently mutated in KMT mutated tumors compared to WT tumors (CDC73, 1.7% vs 0.0%, P=.003; KDR, 1.7% vs 0.03%, P=.011; SDHB, 1.7% vs 0.1%, P=.023; PRKDC, 1.7% vs. 0.1%, P=.046; CHEK2, 5.6% vs 1.4%, P=.049). Conclusions: Our findings provide the first exploratory data on KMT genes mutations and their association with clinical and molecular features in CRC, in a large population of patients. Further investigations are warranted to elucidate the association between TMB-H and histone modifications, potentially leading to a better understanding of epigenetic alterations in CRC and to identify novel targets for therapeutic options for CRC patients. Legal entity responsible for the study: Heinz-Josef Lenz. Funding: Has not received any funding. Disclosure: K. Poorman, M. Winerip, W.M. Korn: Employee: Caris Life Sciences. J.L. Marshall: Consultant: Caris Life Sciences. All other authors have declared no conflicts of interest.

Background:Six months of adjuvant oxaliplatin-based chemotherapy is standard for patients with stage III colon cancer following surgery. However, oxaliplatin is associated with peripheral neurotoxicity which worsens over treatment duration. Consequently, a shorter treatment duration, if equally effective, would be extremely beneficial. A pooled analysis of data for 12 834 stage III colon cancer patients, from six randomised phase III trials of adjuvant therapy, the International Duration Evaluation of Adjuvant chemotherapy study, was carried out and the results presented at the ASCO Annual Meeting 2017. To clarify the potential impact of these results on clinical practice, ESMO decided to sponsor a special session at their 2017 Annual Meeting dedicated to achieving a more meaningful interpretation of the results.Methods:Medical oncologists from Europe, the United States and Asia selected for their involvement in the trials, together with an independent statistician and an independent clinician, were invited to provide their independent interpretations of the results and contribute to a moderated panel discussion. The pooled analysis evaluated the non-inferiority of 3 versus 6 months of adjuvant FOLFOX/CAPOX therapy but not the non-inferiority of 3 months CAPOX versus 6 months FOLFOX therapy.Results:There was strong evidence of an interaction between the choice of regimen (CAPOX or FOLFOX) and duration of treatment. Patients were classified as either 'fighters' or 'fatalists', and 3-month CAPOX was considered standard for patients classified as fatalists even if they had high-risk disease. However, patients classified as 'fighters' would only receive 3 months of CAPOX if they had low-risk disease but would always receive 6 months of CAPOX/FOLFOX if they had T4 disease. The panel was split on whether they would advocate 3 or 6 months CAPOX therapy based on high-risk N2 disease.Conclusions:The main drivers of the duration of treatment were choice of regimen and patient attitude, with risk, based mainly on T4 stage, having less influence.

Background: Mps1 is a serine threonine kinase and a core component of the spindle assembly checkpoint. Two potent, selective, and orally active Mps1 inhibitors -- BAY 1161909 (BAY; lead compound) and BAY 1217389 -- have shown improved efficacy in combination with paclitaxel (Pac) in xenograft models, including Pac-insensitive and acquired resistance models. We report here on the safety, tolerability, and maximum tolerated dose (MTD) of the lead compound BAY in combination with Pac. Methods: Subjects with advanced malignancies (solid tumors) and refractory to standard therapy were eligible. BAY was administered twice daily (BID) in a 2-days on/5-days off dosing schedule in combination with weekly IV Pac starting at 75 mg/m2 (Pac-75), and then at 90 mg/m2 (Pac-90). The dose of BAY was doubled in sequential cohorts until the MTD was reached. Pharmacokinetic analyses were done to determine exposure of BAY and Pac. Results: A total of 37 patients were enrolled and treated in the Pac-75 cohort and 32 in the Pac-90 cohort, with median age 60 in both groups. Breast, NSCLC, and ovarian adenocarcinomas were the most common cancers. The majority of patients (53.6%) had >3 prior lines of anticancer therapy. BAY exposure generally increased in a dose proportional manner and did not affect Pac exposure. In BAY plus Pac-75 cohorts, 16% of patients had grade (G) 3 BAY-related adverse events (AEs), with no G4/G5 events. In the Pac-90 cohorts, 28% of patients had G3 events, one G4 and no G5 BAY-related events. The most common treatment emergent AEs were fatigue (44.9%), anemia (39.1%), alopecia (37.7%), diarrhea (34.8%) and nausea (33.3%). In 35 evaluable patients from the BAY plus Pac-75 group, there were 5 (14%) PRs, 11 SD,17 PD, and 2 patients not determined. In 28 evaluable patients in the BAY plus Pac-90 group, there were 4 (14%) PRs, 13 SD, and 11 PD. Six of 9 patients with a PR had prior Pac. One dose limiting toxicity (ALT increased) was reported in the BAY 180 mg BID plus Pac-90 dose cohort. The MTD was determined as BAY 90 mg BID plus Pac-90. Conclusions: BAY in combination with Pac demonstrated good tolerability with manageable AEs and preliminary evidence of efficacy. Study with the follow-up compound BAY 1217389 is ongoing. Clinical trial identification: NCT02138812. Legal entity responsible for the study: Bayer AG. Funding: Bayer AG. Disclosure: P. Rajagopalan, C. Cyris, I. Bruns, J. Mei, F. Souza: Employment: Bayer. All other authors have declared no conflicts of interest.

Previous studies have depicted a correlation between 18FDG PET maximum standardized uptake value (SUVmax) and pathologic complete response (pCR) in patients treated with preoperative chemoradiation therapy (CRT) for esophageal cancer. However, it is unclear whether or not this correlation differs based on tumor histology. Our objective is to determine how SUVmax before and after neoadjuvant CRT for esophageal carcinoma relates to the rate of pCR at surgical resection, and to examine whether or not the relationship varies based on histology. After IRB approval, patients at two NCI-designated cancer centers from 2000-2013 who were treated with neoadjuvant CRT followed by surgical resection for esophageal cancer were identified. Medical records were reviewed to gather clinical, radiographic, and pathologic data. PET scans were performed prior to and 3-6 weeks after the completion of preoperative CRT. SUVmax was measured at each scan, and the percent decrease in SUVmax was calculated. A least squares regression analysis was performed to investigate an association between pCR and important clinical factors. One hundred and thirty-two patients were identified. Median age was 62 (36-80), 79% male and 21% female. Adenocarcinoma was identified in 83% and squamous cell carcinoma in 16%; one patient had a neuroendocrine tumor. One hundred and four (79%) patients had a PET scan both prior to and after the completion of preoperative CRT. Thirty percent of patients achieved a pCR, 20% had residual microscopic disease, and 50% had gross residual disease. The pCR rates for adenocarcinoma and squamous cell carcinoma were 28% and 36% respectively. The percent decrease in SUVmax was significantly associated with pCR (p = 0.04). The median pre- and post-treatment SUVmax were 9.5 (2.3 - 44.4) and 4.1 (0 - 24.4) respectively, and did not differ significantly based on histology. The mean reduction in SUVmax was 60%. For patients achieving a pCR, the mean reduction was 69% compared to 56% for patients with residual disease. When controlling for histology, SUVmax remained associated with pCR (p = 0.04). The median post-treatment SUVmax was 4.1. Patients who had a post-treatment SUV of 4.1 or less were more likely to have a pCR (p = 0.02). In this cohort of patients, we confirm that SUV response after neoadjuvant CRT is significantly associated with pCR. Additionally, this association holds true when controlling for histologic type. These data should be considered as new approaches are modeled based on response-adapted therapy.

Background: The IDEA collaboration was established to prospectively pool and analyse data from 6 randomized trials to answer whether 3-months of oxaliplatin-based adjuvant therapy (FOLFOX4/modified FOLFOX6 or XELOX) is non-inferior to the current standard 6-month treatment in pts with stage III colon cancer, with a primary endpoint of 3 years disease-free survival. A 3 month duration of oxaliplatin-based adjuvant therapy would provide substantial advantages in toxicity, cost, and patient convenience.Design: Members of the IDEA have agreed to pool data from their individual trials (SCOT-UK led with accrual from Australia, Denmark, Spain, Sweden & New Zealand, final accrual 4027 pts; TOSCA-Italy, final 2436 pts; GERCOR/PRODIGE-France, final 2000 pts; CALGB/SWOG-US/Canada, current accrual 1600 pts; ACHIEVE-Japan, final 1200 pts; HORG-Greece, current 600 pts) to allow a definitive analysis. IDEA members prospectively agreed on eligibility criteria, treatment administration, primary endpoints, and statistical analysis plan. May 1, 2014 total IDEA accrual exceeds 11,500 pts. This sample size will provide 3390 DFS events to provide 90% power to declare non-inferiority, based on an expected 3 year DFS rate in the control group of 72%, with a one-sided alpha of 0.025 if the true DFS HR is 1.12. A single pooled interim analysis, conducted by an external Data Monitoring Board (DMB), is prospectively specified when 50% of planned DFS events have been observed; this analysis occurred in May 2014 and the DMB recommended the trial continue per protocol with no modifications.Disclosure: T. Yoshino: Research funding provided by Yakult Honsha. All other authors have declared no conflicts of interest.

Aim: Exportin 1 (XPO1) is a nuclear export protein whose inhibition leads to the nuclear accumulation of tumor suppressor proteins (TSPs). XPO1 is overexpressed in many tumors including PrCa. Selinexor is an oral SINE that activates ≥10 TSPs with potent activity against various cancers including CRPC.

The aging process is accompanied by physiological changes including reduced glomerular filtration and hepatic function, as well as changes in gastric secretions. To investigate what effect would aging have on the disposition of capecitabine and its metabolites, the pharmacokinetics between patients ⩾70 years and <60 years were compared in SWOG0030. Twenty-nine unresectable colorectal cancer patients were stratified to either ⩾70 or <60 years of age, where the disposition of capecitabine and its metabolites were compared. Notable increase in capecitabine area under the curve (AUC) was accompanied by reduction in capecitabine clearance in ⩾70 years patients (P<0.05). No difference in 5’-deoxy-5-fluorocytidine, 5’-deoxy-5-fluorouridine (DFUR), and 5-fluorouracil (5FU) AUCs between the two age groups, suggesting that carboxylesterase and cytidine deaminase (CDA) activity was similar between the two age groups. These results suggest that metabolic enzymes involved in converting capecitabine metabolites are not altered by age. An elevation in capecitabine Cmax and reduction in clearance was seen in females, where capecitabine AUC was 40.3% higher in women. Elevation of DFUR Cmax (45%) and AUC (46%) (P<0.05) was also noted, suggesting that CDA activity may be higher in females. Increases in capecitabine Cmax and AUC was observed in patients ⩾70 years when compared with younger patients who were >60 years.