Starr, Jason S.

e19088 Background: Significant disparities in the stage at diagnosis and survival outcomes exist between various groups diagnosed with hepatocellular carcinoma (HCC) based on sex, race, insurance coverage, and marital status. Previously published data shows disparities more in patients who are African-American, Asian and low income. Little data has been published on factors that influence timeliness to treatment initiation in patients diagnosed with HCC. Methods: Retrospective analysis was performed on 96,586 patients diagnosed with HCC from 2004-2014 using data in the National Cancer Database (NCDB). Time to treatment was divided into two categories: ≤40 days (early, n = 66322) and > 40 days (late, n = 30264). We carried out univariate and multivariate analyses to compare demographic, clinical, treatment, and facility-related factors influencing the timeliness of treatment initiation in HCC. Results: Univariate analysis revealed a significant difference in time to treatment initiation based on age, race, income, insurance status, type of area, geographic region, type of facility, and cancer stage (P < 0.001). Multivariate analysis showed that household income < $30,000/year, Pacific region, urban area of residence, black race, age 70-79 years old or ≥80 years old, academic centers, stage II disease and medicaid insurance were all factors with longer time to treatment initiation. Discussion: HCC is the sixth most common cancer and the second leading cause of cancer mortality worldwide. The 5-year relative survival for localized, regional, and distant stages are 32.6%, 10.8% and 2.4% respectively. In our results we noted significant disparities in time to treatment with respect to various socioeconomic factors. These results are comparable to that reported in other cancer types. Further subgroup analysis of our data shows 2581 patients who received their first treatment after 200 days. In a similar study done in Taiwan, those treated more than 181 days and 61–180 days after diagnosis had a 1.68 and a 1.39 increased risk of death respectively, which were statistically significant. Many factors contribute to delayed treatment, some of which are difficult to circumvent, however where possible efforts should be made to overcome these. Conclusions: Various socioeconomic factors were found to affect the time to treatment initiation in HCC patients. The next step would be to strategically implement policies and practices to address these factors.

4541 Background: Anti-VEGFR2 therapy (ramucirumab/paclitaxel [RAM/TAX]) and ICI are approved as 2nd- and 3rd-line therapy (Tx), respectively, for pts with mGEA. We unexpectedly saw durable responses in 2 pts on RAM/TAX after progression on an ICI trial (KN-059; PMID 29674442). We performed a pilot to examine the clinical activity of ICI followed by RAM/TAX. Then we retrospectively compared the outcomes of pts who received this serial Tx to pts who received RAM/TAX without prior ICI. Methods: All pts with mGEA at Mayo Clinic who received RAM/TAX (2014-19) were included (N = 87). Outcomes were best objective response rate (ORR: complete [CR] or partial response) per RECIST1.1, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Chi square and multivariate (MV) logistic and Cox regression were used. Results: 15 consecutive pts with measurable mGEA received ICI immediately followed by RAM/TAX after irRECIST progression. Most pts (95%) did not respond to ICI. Yet on RAM/TAX, 100% (15/15) had tumor reduction (range -8% to -100%) with an ORR of 73% (11/15), including 3 CRs. In these pts (who received ICI followed by RAMTAX), PFS on RAMTAX was longer than on last chemotherapy before ICI (12.3 vs 3.0 m, P < .001). Outcomes on RAM/TAX in these pts were significantly better than in pts who received RAM/TAX alone (see Table). Associations were strengthened after adjusting for total lines of Tx, line of Tx of RAM/TAX, age, and ECOG PS. Exploratory analysis of paired tumor biopsies collected pre-ICI and on RAM/TAX in a small subset revealed that the frequency of intratumoral immunosuppressive FOXP3+ Tregs decreased on RAM/TAX, whereas the frequency of antitumor CD8+ T cells was preserved. Conclusions: RAM/TAX immediately preceded by ICI was associated with significantly higher OS, ORR, and DOR than RAM/TAX alone, suggesting ICI may enhance efficacy of subsequent anti-VEGFR/taxane therapy. This novel sequence of therapy will be tested prospectively in a new randomized phase 2 trial (NCT04069273). [Table: see text]

4108 Background: Circulating tumor DNA (ctDNA) testing can be used for the assessment of molecular residual disease (MRD) in patients with early-stage or advanced colorectal cancer (CRC). Prospective evaluation of this methodology in clinical practice has been limited to-date. Methods: A personalized and tumor-informed multiplex PCR assay (Signatera 16-plex bespoke mPCR NGS assay) was used for the detection and quantification of ctDNA for MRD assessment. We analyze and present results from an ongoing early adopter program of ctDNA testing across the spectrum of CRC management. Results: Here we present a total of 250 patients with colon (n=200), rectal (n=40), and other lower gastrointestinal cancers (n =10; anal, appendiceal, small bowel). MRD positivity rates and ctDNA quantification (mean tumor molecules/mL) are shown in Table. ctDNA detection was significantly associated with stage of disease (p<0.0001 Chi-square: 70.33). Additionally, in patients with radiologically measurable active metastatic disease, ctDNA detection rate was 100%. On the contrary, patients with advanced/metastatic disease who had partial response to treatment or no evidence of disease (NED) showed 28.5% and 19.2% of ctDNA-positivity, respectively. Conclusions: This is the first large, real-world study reporting on the results from a clinically validated MRD assay. For the first time we delineate MRD rates and quantify ctDNA concentration in patients with early-stage and advanced CRC. Furthermore, we provide an initial readout that effective ongoing treatment in patients with CRC may be correlated with ctDNA clearance. Ongoing analysis expanded to a cohort of 1200 clinical cases including correlation with genomic and serial testing will be presented. [Table: see text]

629 Background: Pancreatic neuroendocrine tumors (pNETs) are rare neoplasms with outcome varying by stage, grade, and clinical presentation. We present an analysis of the epidemiology and prognosis of patients (pts) with PNETs over the last two decades using a large population-based database. Methods: Using 2000-2016 data from the SEER 18 registry, we identified pts with PNETs using a combination of ICD-O-3 and histology codes. Age-adjusted incidence rates were calculated using SEER*Stat 8.3.5. Using SAS 9.4, overall survival (OS) was analyzed using the Kaplan–Meier method, and prognostic factors were investigated using a multivariate Cox proportional hazards model. Results: We identified 8,944 pts with PNETs. Annual incidence rates increased over the study period from 0.27 to 1.00 per 100,000. This was largely explained by a significant increase in number of pts diagnosed with localized disease in recent years (2012-2016). Median OS (mOS) for the entire cohort was 68 months (95% CI 64-73) and 5-year OS rates in localized, regional, and metastatic disease were 83%, 67%, and 28%, respectively. There was a significant improvement in OS for pts diagnosed between 2009-2016 (mOS 85 months) compared to those diagnosed between 2000-2008 (mOS 46 months) (HR 0.66; p < .001). In addition, pts with grade I/II metastatic disease who underwent surgery experienced significantly longer OS (mOS 84 months) compared to those who did not undergo surgery (mOS 18 months) (HR 0.31; p < .001). In the multivariate analysis, more recent diagnosis, younger age, female sex, surgery, early stage, and lower grade favorably predicted OS. On the other hand, functional status and race did not predict OS. Conclusions: There has been a steady increase in the incidence of PNETs with notable stage migration as most patients are diagnosed in early stages of disease in recent years. Additionally, this increase in incidence is accompanied by a significant improvement in survival across different disease stages.

617 Background: Currently, there is no published data on the efficacy of SSAs for well-differentiated G3 NETs. Randomized trials have demonstrated a progression-free survival (PFS) benefit and limited tumor response for lower grade 1-2 NETs, but the optimal systemic therapy for metastatic/unresectable G3 NETs is unknown. We sought to evaluate the efficacy of SSAs in G3 NETs. Methods: We performed a retrospective analysis of Mayo Clinic patients treated with SSAs for metastatic/unresectable G3 NETs, querying data from 1992 - present. Inclusion criteria were: centrally reviewed pathology confirming well-differentiated morphology, G3 based on WHO classification, SSA monotherapy, and radiological data available to assess response. Patients who had prior lines of treatment were included as long they subsequently were treated with single-agent SSA. Poorly-differentiated tumors were excluded. The primary endpoint was PFS. Best overall response was determined by radiographic regression, stabilization, or progression of tumor size. Results: Ninety patient records were reviewed, with 14 meeting inclusion criteria (diagnosed 2014 – 2018). Median Ki-67 proliferative index was 25%. Two patients (14%) had a partial response to SSA therapy, five (36%) had stable disease, and seven (50%) had progressive disease. The estimated median PFS was 4.4 months (95% CI 2.9 – 24). Of the 7 patients with stable disease or partial response, the median time to progression was 8.7 months. Three patients had stable disease for greater than 9 months (24, 29 and 42 months, respectively). Overall survival was not estimable. There was no association of Ki-67 index with PFS based on a proportional hazards model. Conclusions: This is the first report on the efficacy of SSAs for G3 NETs. Although half of the patients in our series had at least stable disease, the PFS was modest at only 4.4 months. Given their favorable side-effect profile compared to cytotoxic chemotherapy, SSAs may present an attractive option to be further explored in a prospective fashion. We are presently updating this data by reassessing response using RECIST criteria.

362 Background: Most pts with mGEA do not respond to ICI or ramucirumab/paclitaxel (RAM/TAX). Emerging data suggest that ICI may potentiate subsequent therapy (Tx). In KN059 we unexpectedly observed durable responses in 2 pts on RAM/TAX after ICI (PMID 29674442). We examined if ICI impacts efficacy of subsequent RAM/TAX in a larger cohort and explored alterations in the tumor microenvironment. Methods: All pts with mGEA at Mayo Clinic (MN, AZ, FL) who received RAM/TAX (2014-19) were included. We compared best objective response rate (ORR: complete [CR] or partial response [PR]) per RECIST1.1 and overall survival (OS) in pts who received RAM/TAX with (Group A) vs without (Group B) immediately preceding PD-1 blockade. Chi square and multivariate logistic and Cox regression were used. We adjusted for total lines of Tx received and the line of Tx in which RAM/TAX was given, to control for potential differences in the biology of heavily treated pts or those receiving RAM/TAX as 2nd vs 3rd line Tx. We also adjusted for age and ECOG PS. Results: In total 87 pts met inclusion criteria. In the 19 pts (Group A) who received RAM/TAX (usually as 3rd line Tx) after progression on ICI, there was a 77% relative risk reduction of death after initiation of RAM/TAX compared to the 68 pts (Group B) who received RAM/TAX (usually as 2nd line) without preceding ICI (median OS 15.0 vs 7.6 mo; HR 0.23; P < .001). The ORR was also significantly higher (58% vs 18%; P < .001) including the CR rate (16% vs 1%; P = .006). Two CRs in Group A are ongoing (10 - 34 mo). Of note, 95% of Group A pts did not respond to ICI, and all had irRECIST progression on ICI. Immunofluorescent analysis from a responder showed 65-fold reduction (post vs pre-Tx) in intratumoral density of immunosuppressive FOXP3+ Tregs, with preserved density of antitumor CD8+ T cells. Conclusions: Higher than expected efficacy was observed on RAM/TAX when immediately preceded by ICI, suggesting ICI may enhance efficacy of subsequent anti-VEGFR/taxane therapy. This serial immunotherapy combination may be a novel option for pts with primary resistance to ICI and will be tested prospectively in a new randomized phase 2 trial (NCT04069273).

e15698 Background: Neuroendocrine tumors (NETs) and carcinomas (NECs) are a diverse group of tumors with an equally diverse biology and clinical behavior. Data on tissue-based genomic profiling of NETs exists, however, there is limited data using circulating tumor DNA (ctDNA) technology. We sought out to characterize NETs via ctDNA to identify genomic alterations. Methods: 27 patients with metastatic NET/NEC with 32 total plasma samples were analyzed using Guardant360 ctDNA assay. Breakdown of NET/NEC by location: 14 pancreatic NET (pNET), 11 NEC, 1 small bowel NET, 1 lung NET. The ctDNA test detects single nucleotide variants in 54-73 genes, copy number amplifications, fusions, and indels in selected genes. Results: Of the 27 patients, 19 (70%) had a detectable genomic alteration. The detectable (non-synonymous) alterations are as follows: TP53 (n = 14, 70%), NF1 (n = 8, 40%), EGFR (n = 5, 25%), BRCA2 (n = 4, 20%), KRAS (n = 4, 20%), ARID1A (n = 3, 15%), CDK6 (n = 3, 15%), ALK (n = 3, 15%), MET (n = 2, 10%), PTEN (n = 2, 10%), BRAF (n = 2, 10%), MTOR (n = 2, 10%) AKT1 (n = 1), BRCA1 (n = 1), CCND2 (n = 1), CCNE1 (n = 1), CTNNB1 (n = 1), ESR1 (n = 1), FGFR2 (n = 1), HRAS (n = 1), IDH1 (n = 1), KIT (n = 1), MYC (n = 1), NOTCH1 (n = 1), NRAS (n = 1), PDGFRA (n = 1), RAF1 (n = 1), RB1 (n = 1), SMAD4 (n = 1), STK11 (n = 1), TSC1 (n = 1), ERBB2 (n = 1), PIK3CA (n = 1). Conclusions: This experience highlights the feasibility of ctDNA to help identify genomic alterations in this patient population. Further studies incorporating ctDNA testing in this patient population are warranted.

4110 Background: Neuroendocrine tumors (NET) comprise around 2% of all malignant tumors of the gastrointestinal system. The genomic landscape of NET has not been well studied. The aim of this study was to confirm the feasibility of next generation sequencing (NGS) using ctDNA in NET and characterize common alterations in the genomic profile. Methods: Molecular alterations in 114 plasma samples from 114 patients with NET using clinical-grade NGS of ctDNA (Guardant360Ò) across multiple institutions were evaluated. The test detects single nucleotide variants in 54-73 genes, copy number amplifications, fusions, and indels in selected genes. Results: A total of 114 NET patients were evaluated, of which 64 (56.1%) were female. Mean age was 59.7 years with a range between 23-89 years. ctDNA NGS testing was performed on 114 plasma samples; 1 patient had testing performed twice. Genomic alterations were defined in 94 (n = 94/114, 82.5%) samples with a total of 289 alterations identified after excluding variants of uncertain significance (VUSs) and synonymous mutations. Alterations were identified in at least one sample from 83 patients; TP53 associated genes were most commonly altered (n = 83/289, 28.7%), followed by KRAS (n = 22, 7.6%), PI3CA (n = 15, 5.2%), CCNE1 (n = 15, 5.2%), BRAF (n = 13, 4.5%), MYC (n = 12, 4.1%), ERBB2 (n = 11, 3.8%), APC (n = 10, 3.5%), EGFR (n = 10, 3.5%), MET (n = 10, 3.5%), PTEN (n = 9, 3.1%), RB1 (n = 9, 3.1%), CDK6 (n = 7, 2.4%), AR (n = 5, 1.7%), ARID1A (n = 5, 1.7%), FGFR1 (n = 5, 1.7%), and PDGFRA (n = 5, 1.7%). Other genomic alterations of low frequency, but clinical relevance included: CDK4 (n = 4, 1.3%), NF1 (n = 4, 1.3%), RAF1 (n = 4, 1.3%), GNAS (n = 3, 1.0%), KIT (n = 3, 1.3%), BRCA2 (n = 2, 0.7%), CCND2 (n = 2, 0.7%), CTNNB1 (n = 2, 0.7%), JAK2 (n = 2, 0.7%), NRAS (n = 2, 0.7%), SMAD4 (n = 2, 0.7%), and TERT (n = 2, 0.7%). Alterations in AKT1, ALK, ATM, BRCA1, CCND1, CDKN2A, FGFR2, MTOR, RHOA, SMO and STK11 were all reported once (n = 1, 0.3%). Conclusions: Evaluation of ctDNA is feasible among individuals with NET. Liquid biopsies are not invasive and can provide personalized options for targeted therapies in NET patients.

e15066 Background: Circulating cell-free tumor-DNA (ctDNA) testing (‘liquid biopsy’) is increasingly being employed both in clinical trials as well as clinical practice. We aimed to contrast and compare the differences in the number of somatic mutations observed on ctDNA testing between mismatch repair deficient/microsatellite instability-high (dMMR/MSI-High) versus mismatch repair proficient/microsatellite stable (pMMR/MSS) colorectal cancers (CRC). Methods: We had 20 patients at Mayo Clinic Florida that were dMMR/MSI-High with testing through the commercially available platform (Guardant360) that uses a 73-gene panel. Median numbers of somatic mutations were compared between the 2 subset of CRC. Results: Patients with dMMR/MSI-High CRC had a median of 8 mutations (range: 2-15) versus a median of 4 mutations (range: 1-22) in pMMR/MSS patients, p-value of 0.001. Similarly, the mean number of somatic mutations were 7.47 (S.D. ± 4.15) versus 5.02 mutations (S.D. ± 3.83) in patients with dMMR/MSI-H and pMMR/MSS, tumors respectively. Though it is simplistic, we could still potentially identify patients who may be candidates for immunotherapy by gauging the mutational burden reported (Table). Furthermore, on serial testing, decline in mutational burden as early as few weeks into therapy was predictive of response later on imaging. Conclusions: Analysis of number of somatic mutations on ctDNA testing can be complementary to MMR/MSI-testing, especially in situations when tissue is not available or safe to obtain. This can also be of value in predicting and/or following response to immunotherapy. The utility of this may go beyond CRC in identifying patients who may benefit from immunotherapy. [Table: see text]