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TAPUR is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. The results of a cohort of patients with colorectal cancer (CRC) withEligible patients had advanced CRC, no standard treatment options, measurable disease (RECIST), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, tumors withThirty patients were enrolled from August 2016 to August 2018; all had CRC with aThe combination of C + V has antitumor activity in heavily pretreated patients with CRC with

TPS480 Background: Locally advanced and metastatic gastric, esophageal, gastroesophageal junction, and pancreatic adenocarcinomas (GC, EC, GEJC, and PC) have poor overall survival, and more effective therapies are needed. Claudin 18.2 (CLDN18.2), a tight junction protein, is commonly expressed in these cancers. Monoclonal antibody and CAR-T cell therapies targeting CLDN18.2 have shown promising antitumor activity (Türeci O et al, 2019; Qi C et al, 2022). This study aims to assess the safety and preliminary efficacy of a CLDN18.2 targeted CAR-T, LB1908, in subjects with GC, EC, GEJC, and PC. Methods: This is a phase 1, open-label, multicenter, dose-escalation and expansion study of LB1908 that aims to identify the recommended phase 2 dose (NCT05539430; open to enrollment early 2023). During prescreening, that may occur as early as at initial diagnosis, we will screen subjects for tumor expression of CLDN18.2 by IHC of ≥ 1+ in ≥ 50% of tumor cells. Inclusion criteria include: must be ≥18 and ≤75 years old; histologically/cytologically confirmed unresectable, locally advanced, or metastatic adenocarcinoma of the GC, EC, GEJC, and PC; progressed on at least standard 1st line therapy; ECOG PS 0 or 1; life expectancy > 4 months per investigator judgment; and adequate organ function per protocol. The study has 2 parts. In Part A (dose escalation), 12 to 21 subjects with GC, EC, or GEJC will be enrolled in up to 3 planned dose level cohorts (0.5X106, 1.5X106, and 3.0X106 CAR+ viable T cells/kg), to determine the recommended dose for expansion (RDE). In Part B (dose expansion) the RDE will be administered to up to 35 subjects with GC, EC, and GEJC in one expansion cohort and PC in another cohort (n=11-17 for GC/EC/GEJ, to total 23 subjects when pooling with RDE-treated subjects from part A; n=18 for PC). LB1908 will be manufactured from autologous T cells collected via PMBC apheresis. Subjects may receive optional bridging therapy followed by lymphodepleting chemotherapy with fludarabine 30 mg/m2/day and cyclophosphamide 300 mg/m2/day for 3 days. One infusion of LB1908 will then be administered, and subjects will be followed post-infusion for safety, laboratory, and disease assessments. Primary endpoints are incidence, duration, and severity of AEs and laboratory abnormalities (Parts A and B); and frequency of DLTs at each dose level (Part A). Secondary and exploratory endpoints include: objective response rate, disease control rate, duration of response, progression-free survival, characterization of PK by CAR-positive T cell counts, CAR transgene level in blood, effusions, and target tissues, and evaluation of immunogenicity by presence of anti-LB1908 antibodies. Acknowledgments: This study is funded by Legend Biotech USA Inc. Clinical trial information: NCT05539430 .

122 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of pts with CRC with ATM mut treated with O are reported. Methods: Eligible pts had advanced CRC with ATM mut, no standard treatment (tx) options, measurable disease, ECOG Performance Status (PS) 0-2, and adequate organ function. Genomic testing was done in CLIA-certified, CAP-accredited labs. Recommended dosing for O was 300 mg twice daily (tablets) or 400 mg twice daily (capsules) until disease progression. Primary end point was disease control (DC), defined as complete or partial (PR) response per RECIST v. 1.1, or stable disease (SD) at 16+ weeks (wks) (SD16+). Simon 2-stage design tested the null DC rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 has DC, 18 more pts are enrolled; otherwise, cohort is closed for futility. If ≥7 of 28 pts has DC, the null DC rate is rejected. Secondary end points were progression-free survival (PFS), overall survival (OS), duration of response (DOR), duration of SD, and safety. DOR is defined as time from the pt’s first documented objective response (OR) until progressive disease (PD). Duration of SD is defined as time from start of tx to PD. Results: 30 pts with CRC and ATM mut were enrolled from Sept 2016 to Aug 2019. 3 pts were not included in efficacy outcomes: 2 pts had no post-baseline tumor evaluation; 1 pt was found to be ineligible after receiving 1 dose. 1 PR ( ATM P938fs*11 and RAD50 variant of unknown significance (VUS); DOR was 18.6 wks) and 3 SD16+ ( ATM R1875*, splice site 4237-11_4241del16, E522*; duration of SD was 19.7, 25.3 and 27.0 wks, respectively) were observed for DC rate of 23% (95% CI, 6% to 39%) and OR rate of 4% (95% CI, 0.1% to 19%). The null DC rate was not rejected (p=0.38). 6/30 pts had a BRCA2 co-alteration, but none of these pts achieved OR or SD16+; no pts had a BRCA1 co-alteration; aside from the pt with PR and RAD50 VUS, only 1 other pt who achieved OR or SD16+ had a co-alteration among the other homologous recombination-related genes examined ( ATR VUS). 7 pts had ≥1 Grade 3 adverse or serious adverse event (SAE) at least possibly related to O, including urinary tract infection, white blood cell decreased, febrile neutropenia (SAE), anemia (1 SAE), lung infection (SAE), fatigue (SAE), and nausea (SAE). Conclusions: Monotherapy O does not show sufficient antitumor activity in pts with advanced CRC with ATM mut to warrant further study. Clinical trial information: NCT02693535 . [Table: see text]

546 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of pts with BTC with ERBB2/3 amp, oe, or mut treated with P+T are reported. Methods: Eligible pts had advanced BTC, no standard treatment (tx) options, measurable disease, ECOG Performance Status (PS) 0-2, and adequate organ function. Genomic testing was done in CLIA-certified, CAP-accredited labs. Dosing of P was 840 mg IV over 60 minutes (m), then 420 mg IV over 30-60 m Q3 weeks (wks); T was 8 mg/kg IV over 90 m, then 6 mg/kg IV over 30-60 m Q3 wks until disease progression. Primary end point was disease control (DC), defined as complete (CR) or partial (PR) response per RECIST v. 1.1, or stable disease (SD) at 16+ wks (SD16+). Simon 2-stage design tested the null DC rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 has DC, 18 more pts are enrolled; otherwise, cohort is closed for futility. If ≥7 of 28 pts has DC, the null DC rate is rejected. Secondary end points were progression-free survival (PFS), overall survival (OS), duration of response (DOR), duration of SD and safety. DOR is defined as time from pt’s first documented objective response (OR) to progressive disease (PD). Duration of SD is defined as time from start of tx to PD. Results: 29 pts with BTC (15 gallbladder (GB), 11 biliary duct (BD), 3 ampulla of Vater) and ERBB2/3 amp, oe, or mut were enrolled from Feb 2017 to Jan 2022. Median (med) age was 66 years (yrs) (range, 34-83 yrs). 66% of pts were female; 52% were White, 21% were Black/African American, 10% were Asian/Asian American; 83% were not Hispanic or Latino. 83% of pts had ECOG PS 0-1 and 48% had ≥3 prior systemic regimens. 1 pt was not evaluable and excluded from efficacy analysis. The table shows efficacy outcomes. 1 pt had CR (GB; ERBB2 amp; DOR: 71.1 wks), 8 pts had PR (6 GB/2 BD; 5 ERBB2 amp; 2 ERBB2 mut; 1 ERBB3 mut/ ERBB2 amp; med DOR: 30.4 wks (4.4 to 68.9 wks)) and 2 pts had SD16+. 4 pts with a KRAS mut did not achieve OR or SD16+. 4 pts had a Grade 3 drug-related adverse or serious adverse event (SAE): anemia, diarrhea, infusion related reaction (SAE), and fatigue. Conclusions: P+T demonstrated antitumor activity in pts with advanced BTC with ERBB2/3 alterations. These data, along with results previously reported by other studies, support continued study of P+T in pts with ERBB2 amplified BTC tumors. Clinical trial information: NCT02693535 . [Table: see text]

PURPOSE The Targeted Agent and Profiling Utilization Registry (TAPUR) Study is a phase II pragmatic basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancer with genomic alterations known to be drug targets. Results in a cohort of patients with non–small-cell lung cancer (NSCLC) with CDKN2A alterations treated with palbociclib are reported. METHODS Eligible patients were ≥ 18 years old with advanced NSCLC, no remaining standard treatment options, measurable disease, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function. Patients with NSCLC with CDKN2A alterations and no Rb mutations received palbociclib 125 mg orally once daily for 21 days, followed by 7 days off. Simon’s two-stage design was used with a primary study end point of objective response or stable disease (SD) of at least 16 weeks in duration. Secondary end points are progression-free survival (PFS), overall survival (OS), and safety. RESULTS Twenty-nine patients were enrolled from January 2017 to June 2018; two patients were not evaluable for response but were included in safety analyses. One patient with partial response and six patients with SD were observed, for a disease control rate of 31% (90% CI, 19% to 40%). Median PFS was 8.1 weeks (95% CI, 7.1 to 16.0 weeks), and median OS was 21.6 weeks (95% CI, 14.1 to 41.1 weeks). Eleven patients had at least 1 grade 3 or 4 adverse event (AE) or serious AE (SAE) possibly related to palbociclib (most common, cytopenias). Other AEs or SAEs possibly related to the treatment included anorexia, fatigue, febrile neutropenia, hypophosphatemia, sepsis, and vomiting. CONCLUSION Palbociclib monotherapy demonstrated evidence of modest antitumor activity in heavily pretreated patients with NSCLC with CDKN2A alterations. Additional investigation is necessary to confirm efficacy and utility of palbociclib in this population.

Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. The RAS pathway is activated in more than 55% of CRC and has been targeted for therapeutic intervention with MEK inhibitors. Unfortunately, many patients have de novo resistance, or can develop resistance to this new class of drugs. We have hypothesized that much of this resistance may pass through SRC as a common signal transduction node, and that inhibition of SRC may suppress MEK inhibition resistance mechanisms. CRC tumors of the Consensus Molecular Subtype (CMS) 4, enriched in stem cells, are difficult to successfully treat and have been suggested to evade traditional chemotherapy agents through resistance mechanisms. Here, we evaluate targeting two pathways simultaneously to produce an effective treatment by overcoming resistance. We show that combining Trametinib (MEKi) with Dasatinib (SRCi) provides enhanced cell death in 8 of the 16 tested CRC cell lines compared to treatment with either agent alone. To be able to select sensitive cells, we simultaneously evaluated a validated 18-gene RAS pathway activation signature score along with a 13-gene MEKi resistance signature score, which we hypothesize predict tumor sensitivity to this dual targeted therapy. We found the cell lines that were sensitive to the dual treatment were predominantly CMS4 and had both a high 18-gene and a high 13-gene score, suggesting these cell lines had potential for de novo MEKi sensitivity but were subject to the rapid development of MEKi resistance. The 13-gene score is highly correlated to a score for SRC activation, suggesting resistance is dependent on SRC. Our data show that gene expression signature scores for RAS pathway activation and for MEKi resistance may be useful in determining which CRC tumors will respond to the novel drug combination of MEKi and SRCi.

The Targeted Agent and Profiling Utilization Registry (TAPUR) Study, a phase II basket study, evaluates anti-tumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known as drug targets. With no known genomic targets predictive of sensitivity to cetuximab, cetuximab was evaluated in patients with breast cancer (BC), non-small cell lung cancer (NSCLC), and ovarian cancer (OC), without KRAS, NRAS, or BRAF mutations. Eligible patients with advanced BC, NSCLC, and OC received a cetuximab loading dose, then weekly infusions (250 mg/m2 over 60 min). A Simon two-stage design, requiring ten patients in stage I, was employed per each disease-specific cohort. The primary endpoint was disease control (objective response or stable disease for at least 16 weeks). If two or more patients in stage I achieved disease control, the cohort would enroll 18 more patients in stage II. Power and alpha of the design are 85% and 10%, respectively. Secondary endpoints included progression-free survival, overall survival, and safety. Patients with BC (n = 10), NSCLC (n = 10), and OC (n = 29) were enrolled between June 2016 and September 2018. No objective responses or stable disease for at least 16 weeks were observed in the BC and NSCLC cohorts. No objective responses and four patients with stable disease for at least 16 weeks were observed in the OC cohort. Six of 49 patients reported grade 3 or higher adverse events or serious adverse events at least possibly related to cetuximab. Cetuximab does not have clinical activity in patients with advanced BC, NSCLC, and OC without KRAS, NRAS, or BRAF mutations. NCT02693535 (26 February, 2016).

The Targeted Agent and Profiling Utilization Registry (TAPUR) Study is a phase II pragmatic basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancer with genomic alterations known to be drug targets. Results in a cohort of patients with non-small-cell lung cancer (NSCLC) withEligible patients were ≥ 18 years old with advanced NSCLC, no remaining standard treatment options, measurable disease, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function. Patients with NSCLC withTwenty-nine patients were enrolled from January 2017 to June 2018; two patients were not evaluable for response but were included in safety analyses. One patient with partial response and six patients with SD were observed, for a disease control rate of 31% (90% CI, 19% to 40%). Median PFS was 8.1 weeks (95% CI, 7.1 to 16.0 weeks), and median OS was 21.6 weeks (95% CI, 14.1 to 41.1 weeks). Eleven patients had at least 1 grade 3 or 4 adverse event (AE) or serious AE (SAE) possibly related to palbociclib (most common, cytopenias). Other AEs or SAEs possibly related to the treatment included anorexia, fatigue, febrile neutropenia, hypophosphatemia, sepsis, and vomiting.Palbociclib monotherapy demonstrated evidence of modest antitumor activity in heavily pretreated patients with NSCLC with

Background: Incidence of small-intestine neuroendocrine tumors (SINT) has been increasing in the United States over the past 40 years, with higher incidence in Utah than elsewhere. As information about how these tumors arise is limited, elucidating lifestyle factors associated with SINT in a statewide cohort could potentially identify those at risk to help mitigate their effects. Methods: Cases of SINT with a carcinoid histology (8240 or 8241) diagnosed in Utah from 1996 to 2014 with no prior history of cancer within 5 years (n = 433) were matched to population controls (1:10 ratio). Tobacco and alcohol exposures before case diagnosis were identified from International Classification of Diseases codes in statewide medical records and from self-reported data captured at patient encounters beginning in 1996. Multivariate logistic regression was used to estimate risk of SINT associated with tobacco and alcohol in cases compared with controls. Results: An increased risk of SINT was observed in tobacco-exposed individuals compared with unexposed [OR, 1.44; 95% confidence interval (CI), 1.11–1.86; P = 0.006]. Those who were exposed to alcohol exhibited an increased risk of SINT (OR, 1.62; 95% CI, 1.05–2.49; P = 0.03). Conclusions: This study supports tobacco and alcohol use as risk factors for SINT, independent of family history. However, low rates of smoking and alcohol use in Utah coupled with higher rates of SINT suggest other factors may contribute to development of these tumors. Impact: Although tobacco and alcohol modestly contribute to risk, our study suggests in addition to greater detection of tumors, other as-of-yet undefined exposures may drive rising SINT incidence.

Various metals play role in the survival and pathogenesis of the invasive fungal disease. The objectives of this study were to compare the levels of heavy metals in patients with chronic invasive fungal rhinosinusitis (CIFR) and healthy controls, and to analyze their role in disease outcome.Twenty-three patients (15 with invasive mucormycosis and 8 with invasive aspergillosis, Group 1), and 14 healthy controls (Group 2) were recruited. Blood samples were collected from each group into ion-free tubes and analyzed for serum levels of Nickel (Ni), Copper (Cu), Zinc (Zn), Gallium (Ga), Arsenic (As), Selenium (Se), Rubidium (Rb), Strontium (Sr), Cadmium (Cd), and Lead (Pb). The final outcome of the patients during their hospital stay was categorized clinico-radiologically as improved or worsened, or death.The levels of all metals were higher in Group 1 except for As and Pb. However, the differences in Cu (p=0.0026), Ga (p=0.002), Cd (p=0.0027), and Pb (p=0.0075) levels were significant. Higher levels of Zn (p=0.009), Se (p=0.020), and Rb (p=0.016) were seen in the invasive aspergillosis subgroup. Although Zn (p=0.035), As (p=0.022), and Sr (p=0.002) levels were higher in patients with improved outcome, subgroup analysis showed no differences.The levels of some heavy metals in CIFR significantly differ from those of the general population and also vary with the type of the disease and its outcome. These levels may not have a direct effect on the outcome of the patient, but they do play a role in the pathogenesis of the invading fungus.

Simple Summary Colorectal cancer (CRC) is a major cause of cancer deaths. Cetuximab is an FDA-approved, underutilized therapeutic targeting the epidermal growth factor receptor (EGFR) in metastatic CRC. To date, despite selection of patients with wild-type RAS, it is still difficult to identify patients who may benefit from EGFR inhibitor (e.g., cetuximab) therapy. Our aim is to molecularly classify CRC patients to better identify subpopulations sensitive to EGFR targeted therapy. APC and TP53 are two major tumor suppressor genes in CRC whose mutations contribute to tumor initiation and progression and may identify cetuximab-sensitive tumors. Recently, it has been suggested that the consensus molecular subtype (CMS) classification may be used to help identify cetuximab-sensitive patients. Here, we report an analysis of multiple CRC tumor/PDX/cell line datasets using combined APC and TP53 mutations to refine the CMS classification to better predict responses to cetuximab to improve patient outcomes. Abstract Recently, it was suggested that consensus molecular subtyping (CMS) may aide in predicting response to EGFR inhibitor (cetuximab) therapies. We recently identified that APC and TP53 as two tumor suppressor genes, when mutated, may enhance cetuximab sensitivity and may represent easily measured biomarkers in tumors or blood. Our study aimed to use APC and TP53 mutations (AP) to refine the CMS classification to better predict responses to cetuximab. In total, 433 CRC tumors were classified into CMS1-4 subtypes. The cetuximab sensitivity (CTX-S) signature scores of AP vs. non-AP tumors were determined across each of the CMS classes. Tumors harboring combined AP mutations were predominantly enriched in the CMS2 class, and to a lesser degree, in the CMS4 class. On the other hand, AP mutated CRCs had significantly higher CTX-S scores compared to non-AP CRCs across all CMS classes. Similar results were also obtained in independent TCGA tumor collections (n = 531) and in PDMR PDX/PDO/PDC models (n = 477). In addition, the in vitro cetuximab growth inhibition was preferentially associated with the CMS2 cell lines harboring A/P genotypes. In conclusion, the AP mutation signature represents a convenient biomarker that refines the CMS classification to identify CRC subpopulations predicted to be sensitive to EGFR targeted therapies.

Background Over half of colorectal cancers (CRCs) are hard-wired to RAS/RAF/MEK/ERK pathway oncogenic signaling. However, the promise of targeted therapeutic inhibitors, has been tempered by disappointing clinical activity, likely due to complex resistance mechanisms that are not well understood. This study aims to investigate MEK inhibitor-associated resistance signaling and identify subpopulation(s) of CRC patients who may be sensitive to biomarker-driven drug combination(s). Methods We classified 2250 primary and metastatic human CRC tumors by consensus molecular subtypes (CMS). For each tumor, we generated multiple gene expression signature scores measuring MEK pathway activation, MEKi “bypass” resistance, SRC activation, dasatinib sensitivity, EMT, PC1, Hu-Lgr5-ISC, Hu-EphB2-ISC, Hu-Late TA, Hu-Proliferation, and WNT activity. We carried out correlation, survival and other bioinformatic analyses. Validation analyses were performed in two independent publicly available CRC tumor datasets (n = 585 and n = 677) and a CRC cell line dataset (n = 154). Results Here we report a central role of SRC in mediating “bypass”-resistance to MEK inhibition (MEKi), primarily in cancer stem cells (CSCs). Our integrated and comprehensive gene expression signature analyses in 2250 CRC tumors reveal that MEKi-resistance is strikingly-correlated with SRC activation (Spearman P –320), which is similarly associated with EMT (epithelial to mesenchymal transition), regional metastasis and disease recurrence with poor prognosis. Deeper analysis shows that both MEKi-resistance and SRC activation are preferentially associated with a mesenchymal CSC phenotype. This association is validated in additional independent CRC tumor and cell lines datasets. The CMS classification analysis demonstrates the strikingly-distinct associations of CMS1-4 subtypes with the MEKi-resistance and SRC activation. Importantly, MEKi + SRCi sensitivities are predicted to occur predominantly in the KRAS mutant, mesenchymal CSC-like CMS4 CRCs. Conclusions Large human tumor gene expression datasets representing CRC heterogeneity can provide deep biological insights heretofore not possible with cell line models, suggesting novel repurposed drug combinations. We identified SRC as a common targetable node–-an Achilles’ heel–-in MEKi-targeted therapy-associated resistance in mesenchymal stem-like CRCs, which may help development of a biomarker-driven drug combination (MEKi + SRCi) to treat problematic subpopulations of CRC.

142 Background: We previously reported the safety and feasibility of tele-chemotherapy with remote administration of chemotherapy (chemo) in rural hospitals using experienced chemo nurses with direct supervision from medical oncologist at a tertiary site. Herein we report the detailed overview of types of cancers treated, chemo-regimens administered and associated outcomes within an integrated health system. Methods: We retrospectively analyzed 200 patients who received chemotherapy remotely in 4 rural health hospitals in the state of Utah between 2017- 2022. Data collected included age of administration of chemo, gender, cancer type, insurance, chemotherapy regimen, number of cycles, emergency visits, hospitalizations, and infusion reactions. Results: 200 pts received chemotherapy at 4 rural hospitals including Sevier Valley Hospital, Cassia Regional Hospital, Sanpete Valley Hospital, and Heber Valley Hospital in Utah and Idaho. Median age of administration was 53 yrs (11- 96 yrs). Majority were male (n = 118; 59%). Insurances that covered these services included Medicare, Medicaid, Regence Blue Cross, United Healthcare, Tricare and Select Health. The most common cancer types treated included – Colorectal (n = 31), Breast (n = 24), Lung (n = 15), Lymphoma (n = 21), Multiple Myeloma (n = 11), Melanoma (n = 9), Bladder (n = 7), and other benign conditions (n = 25). 47 unique chemo regimens including 1085 cycles were administered. Chemo regimens and cycles detailed below. Among 69 pts with outcomes data available, ED visits noted in 33% (n = 23), hospitalization rate was 17% (n = 12) and infusion reaction rate was 7% (n = 5). Total mileage saved by pts receiving chemotherapy closer to home was 47,955 miles. Conclusions: Tele-chemotherapy is safe, feasible and provides improved access to cancer care in rural areas. Future design of pragmatic clinical trials where remote administration of standard of care treatments closer to home will allow the rural pts access cutting edge clinical trials closer to home.[Table: see text]

In its most direct interpretation, telemedicine is medical care provided at a distance. Although telemedicine’s use had been steadily increasing, the COVID-19 pandemic prompted an unprecedented interest and urgency among patients, health care professionals, and policymakers to facilitate health care devoid of the need for in-person contact. The growth in personal access to telecommunications technology meant an unprecedented number of people in the United States and around the world had access to the equipment and technology that would make virtual care possible from the home. As the mass implementation of telemedicine unfolded, it became quickly apparent that scaling up the use of telemedicine presented considerable new challenges, some of which worsened disparities. This article describes those challenges by examining the history of telemedicine, its role in both supporting access and creating new barriers to access in trying to get everyone connected, frameworks for thinking about those barriers, and facilitators that may help overcome them, with a particular focus on older adults and patients with cancer in rural communities.

EGFR inhibitor (EGFRi) therapies (cetuximab and panitumumab) have been approved for metastatic CRC patients who harbor wild-type KRAS/NRAS. Unfortunately, only ~50% of treated patients will respond to therapy. While FDA approved for first-line therapy, these agents are seldom used, significantly limiting their utility. Thus, there is an unmet need to develop additional biomarkers to identify EGFRi sensitive patients. Using an innovative hybrid approach fusing gene expression and DNA sequencing, we recently reported that combined mutations in APC and TP53, two major tumor suppressor genes, were strongly correlated with a validated gene expression signature measuring cetuximab sensitivity (CTX-S) in 468 CRC human tumors (Yang et al. Cancer Epidemiol Biomarkers Prev. 2019). Further analysis reported that APC and TP53 mutations predict cetuximab sensitivity across consensus molecular subtypes (CMS1-4) (Thota et al. Cancers. 2021). While APC truncated mutations are known to mediate WNT pathway activation, one of key features of CMS2 CRCs reported to be associated with cetuximab response, little is known about TP53 mutations with cetuximab sensitivity. To investigate a contributive role of mutant TP53 in vitro, we stably transfected expression plasmids of three hotspot mutations (R175H, R248W, R273H) of TP53 in APC-mutated CRC cells such as SW48 cells harboring WT KRAS/NRAS. Multiple stable clones for each of three TP53 mutations (empty vector as a control) were selected for biochemical and RNASeq analyses. We found that the three oncogenic mutations of TP53 enhanced cetuximab-mediated apoptosis under low serum culture conditions (2% FBS). Interestingly, the enhanced drug effect was associated with altered p53 pathway signatures as assessed by RNASeq. In support of the role of TP53 mutations, siRNA-knockdown of TP53 in SW48 cells also demonstrated an increased sensitivity to cetuximab treatments. Collectively, these in vitro analysis supports TP53 mutations, in combination with APC mutations, as predictive mutation biomarkers of cetuximab sensitivity in CRC. Citation Format: Mingli Yang, Heiman Wang, Thomas B. Davis, Lance Pflieger, Ramya Thota, W. Jack Pledger, Timothy J. Yeatman. Hotspot mutations of TP53 sensitize APC-mutated colorectal cancer cells to cetuximab in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5366.

Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. Results in a cohort of pts with solid tumors with ATM mutation (mut) or deletion (del) treated with O are reported. Methods: Eligible pts had solid tumors, no standard treatment (tx) options, measurable disease, ECOG Performance Status (PS) 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received O tablets (300mg) or capsules (400mg) orally twice daily until disease progression. Low accruing histology-specific cohorts with the same genomic alteration were collapsed into one histology-pooled cohort for this analysis. Primary endpoint was disease control (DC) (complete (CR) or partial (PR) response or stable disease at 16+ wks (SD16+)) (RECIST v1.1). For histology-specific cohorts a Simon 2-stage design with a null DC rate of 15% vs. 35% (power = 0.85; α = 0.10) requires 28 pts with futility stopping after 10 pts. For histology-pooled cohorts with sample size > 28, if the lower limit of a one-sided 90% CI is >15%, the null hypothesis of a DC rate of 15% is rejected. 2-sided 95% CIs were used for other efficacy endpoint estimates. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Results: 39 pts with solid tumors (17 histologies) with ATM mut (n=36) or del (n=3) were enrolled from 6/2016 to 1/2019. 3 pts were unevaluable for efficacy. Table 1 shows demographics and outcomes. 1 CR (prostate), 2 PR (unknown primary) and 6 SD16+ were observed in pts with ATM mut for a DC rate of 25% (90% CI: 16%, 100%) and an OR rate of 8% (95% CI: 2%, 23%). The null DC rate was rejected. 9 pts had ≥1 Grade 3 tx-related adverse or serious adverse event related to O. Conclusions: Monotherapy O showed evidence of anti-tumor activity in pts with various solid tumors with ATM mut. Table 1. Demographics and Baseline Characteristics (N=39); Efficacy Outcomes (N=36); Toxicity Outcomes (N=39) Median (Med) age, years (range) 65 (35, 77) Female, % 46 ECOG PS, % 0 33 1 59 2 8 Prior systemic regimens, % 0 3 1 8 2 15 ≥3 74 DC rate, % (OR or SD 16+) (1-sided 90% CI) 25 (16, 100) OR rate, % (95% CI) 8 (2, 23) Med PFS, wks (95% CI) 8.4 (8.0, 15.9) Med OS, wks (95% CI) 40.4 (30.3, 50.7) Med duration OR (range), wks 18.9 (4.3, 24.4) Med duration SD16+ (range), wks 27.3 (19.4, 31.0) Number of pts1 with treatment-related adverse or serious adverse events (all Grade 3) AE2 9 SAE3 4 1Patients may have experienced one or more events2anemia, anorexia, dehydration, fatigue, hypokalemia, nausea 3colitis, dizziness, lung infection, proteinuria, urinary tract infection/obstruction Citation Format: Kathryn F. Mileham, Michael Rothe, Pam K. Mangat, Elizabeth Garrett-Mayer, Eddy S. Yang, Olatunji B. Alese, Angela Jain, Herbert L. Duvivier, Phillip Palmbos, Eugene R. Ahn, Jeanny B. Aragon-Ching, Kathleen W. Beekman, Deepti Behl, Funda Meric-Bernstam, Rodolfo Gutierrez, Amy Sanford, Ramya Thota, Michael Zakem, Song Zhao, Raegan O'Lone, Gina N. Grantham, Susan Halabi, Richard L. Schilsky. Olaparib (O) in patients (pts) with solid tumors with ATM mutation or deletion: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT110.

Neuroendocrine tumors (NETs) of the small intestine undergo large chromosomal and methylation changes. The objective of this study was to identify methylation differences in NETs and consider how the differentially methylated genes may impact patient survival. Genome-wide methylation and chromosomal copy number variation (CNV) of NETs from the small intestine and appendix were measured. Tumors were divided into three molecular subtypes according to CNV results: chromosome 18 loss (18LOH), Multiple CNV, and No CNV. Comparison of 18LOH tumors with MultiCNV and NoCNV tumors identified 901 differentially methylated genes. Genes from the G-protein coupled receptor (GPCR) pathways are statistically overrepresented in the differentially methylated genes. One of the highlighted genes from the GPCR pathway is somatostatin (SST), a clinical target for NETs. Patient survival based on low versus high methylation in all samples identified four significant genes (p OR2S2, SMILR, RNU6-653P, and AC010543.1. Within the 18LOH molecular subtype tumors, survival differences were identified in high versus low methylation of 24 genes. The most significant is TRHR (p

Despite efforts to enhance enrollment and the merger of national cooperative groups, < 5% of patients with cancer will enroll into a clinical trial. Additionally, clinical trials are affected by a lack of diversity inclusive of minority patients, rural residents, or low-income individuals. COVID-19 further exacerbated known barriers of reduced physician-patient interaction, physician availability, trial activation and enrollment, financial resources, and capacity for conducting research. Based on the cumulative insight of academic and community clinical researchers, we have created a white paper identifying existing challenges in clinical trial conduct and have provided specific recommendations of sustainable modifications to improve efficiency in the activation and conduct of clinical trials with an overarching goal of providing improved access and care to our patients with cancer.

This report presents the American Society of Clinical Oncology’s (ASCO’s) evaluation of the adaptations in care delivery, research operations, and regulatory oversight made in response to the coronavirus pandemic and presents recommendations for moving forward as the pandemic recedes. ASCO organized its recommendations for clinical research around five goals to ensure lessons learned from the COVID-19 experience are used to craft a more equitable, accessible, and efficient clinical research system that protects patient safety, ensures scientific integrity, and maintains data quality. The specific goals are: (1) ensure that clinical research is accessible, affordable, and equitable; (2) design more pragmatic and efficient clinical trials; (3) minimize administrative and regulatory burdens on research sites; (4) recruit, retain, and support a well-trained clinical research workforce; and (5) promote appropriate oversight and review of clinical trial conduct and results. Similarly, ASCO also organized its recommendations regarding cancer care delivery around five goals: (1) promote and protect equitable access to high-quality cancer care; (2) support safe delivery of high-quality cancer care; (3) advance policies to ensure oncology providers have sufficient resources to provide high-quality patient care; (4) recognize and address threats to clinician, provider, and patient well-being; and (5) improve patient access to high-quality cancer care via telemedicine. ASCO will work at all levels to advance the recommendations made in this report.

The Targeted Agent and Profiling Utilization Registry (TAPUR) Study, a phase II basket study, evaluates anti-tumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known as drug targets.With no known genomic targets predictive of sensitivity to cetuximab, cetuximab was evaluated in patients with breast cancer (BC), non-small cell lung cancer (NSCLC), and ovarian cancer (OC), without KRAS, NRAS, or BRAF mutations.Eligible patients with advanced BC, NSCLC, and OC received a cetuximab loading dose, then weekly infusions (250 mg/mPatients with BC (n = 10), NSCLC (n = 10), and OC (n = 29) were enrolled between June 2016 and September 2018. No objective responses or stable disease for at least 16 weeks were observed in the BC and NSCLC cohorts. No objective responses and four patients with stable disease for at least 16 weeks were observed in the OC cohort. Six of 49 patients reported grade 3 or higher adverse events or serious adverse events at least possibly related to cetuximab.Cetuximab does not have clinical activity in patients with advanced BC, NSCLC, and OC without KRAS, NRAS, or BRAF mutations.NCT02693535 (26 February, 2016).

Survivin, an inhibitor of apoptosis protein is a biomarker of significance in prognostication of many malignancies. In the current study we investigated the serum survivin levels in patients with oral submucosal fibrosis (OSMF) and squamous cell carcinoma (OSCC). Serum was isolated from, peripheral blood collected of clinically and histopathologically confirmed OSMF and OSCC patients. Circulating level of survivin was measured in patients and control subjects by ELISA and analyzed further using Kruskal–Wallis test and two-sample Wilcoxon rank-sum (Mann–Whitney) test. Serum Survivin levels were significantly reduced in the OSCC group as compared to the control group. No significant correlation was noted between the serum survivin level and various clinicopathological characteristics of OSCC and OSMF patients. Our study suggests that free, wild form of circulating survivin probably has no role in predicting the prognosis of oral cancer or the malignant transformation potential of oral submucosal fibrosis.

PURPOSE: A telehealth oncology practice was created to care for patients in rural communities to improve access to health care, decrease financial burdens, and save time. PATIENTS AND METHODS: Patients with cancer at Sevier Valley Hospital in Richfield, Utah, were treated with a real-time video-based telehealth program under the care of an oncologist at a tertiary medical center. Data on financial savings, travel hours, mileage avoided, carbon emissions reduced, and revenue retained by Sevier Valley Hospital were collected from 2015 to 2018. RESULTS: From 2015 to 2018, 119 patients with cancer in Richfield, Utah, were treated with telehealth for oncology visits, accounting for 1,025 patient encounters. On average, patients saved 4 hours and 40 minutes and 332 miles roundtrip per encounter. In total, patients’ savings were estimated to be $333,074. Carbon emissions were reduced by approximately 150,000 kg. Of new patient referrals, 59% were for solid tumors (70 of 119 referrals; 42 metastatic and 28 nonmetastatic cancers), and 41% were hematology consultations (49 of 119 referrals; 28 classical and 21 malignant hematologic conditions). We estimate that Sevier Valley Hospital retained $3,605,500 in revenue over this 4-year period. CONCLUSION: Using a telehealth program in rural Utah, patients with cancer benefited from substantial time and monetary savings. The local medical center was able to retain revenue it would have otherwise lost to outsourcing cancer care. Recent regulatory changes to address the COVID-19 pandemic should increase the number of patients with cancer treated via telehealth nationwide.

Objectives Heat shock protein 90 regulates multiple signaling proteins involved in key pathways of pancreatic cancer pathogenesis. Ganetespib binds to heat shock protein 90 and interferes with its binding to client proteins thus leading to inactivation and degradation of the signaling proteins that promote cancer progression. This phase II study was designed to evaluate the efficacy of ganetespib in patients with refractory metastatic pancreatic cancer (rMPC). Methods Patients with rMPC received 175 mg/m ganetespib intravenously once weekly for 3 weeks in 4-week cycles. Primary endpoint was disease control rate at 8 weeks, with a goal of 70%. Secondary endpoints were progression-free survival, overall survival, and safety. Simon's 2-stage design was used to assess futility and efficacy. Ganetespib was considered inactive if ≤8 patients among the first 15 treated had disease control after 8 weeks of treatment. Results Fourteen patients were treated on study. Grade 3 treatment-related toxicities were diarrhea, abdominal pain, fatigue, nausea, vomiting, and hyponatremia. Disease control rate at 8 weeks was 28.6%, and median progression-free survival and overall survival were 1.58 months and 4.57 months, respectively. Early stopping rules for lack of clinical efficacy led to study closure. Conclusions Single-agent ganetespib was tolerable with only modest disease control in rMPC. This disease is resistant to chemotherapy, and given the emerging data in lung and rectal cancers, as well as in pancreatic cancer cell lines, suggesting improved activity of ganetespib in combination with cytotoxic agents, studies combining this agent with chemotherapy in rMPC are more likely to yield success.

112 Background: Telehealth improves access to cancer care for patients with cancer in rural communities. It allows qualified infusion nurses to administer chemotherapy in smaller rural towns under supervision by health professionals from larger tertiary sites. Here we would like to share our institutional experience in tele-chemotherapy administration to patients in rural Utah. Methods: We collected patient data including treatment regimens administered at our tele health sites from March 2019 to February 2021. Results: A total of 133 unique patients received 1073 cycles of low to intermediate risk treatment regimens. 42 unique regimens including intravenous and oral chemotherapy drugs, immune therapy and targeted drugs were administered at four rural facilities including Cassia Regional Center, Sanpete Valley Hospital, Severe Valley Hospital and Heber Valley Hospital in Utah. 52 physicians located at tertiary sites were involved in tele-chemotherapy administration. In addition to Medicare, Medicaid, the tele chemotherapy was covered by four commercial payers including Blue Cross Blue Shield, Select Health, Tricare and United Healthcare. Conclusions: Tele chemotherapy administration is feasible and allows improved access to cancer patients in rural communities. We aim to expand current project to capture the patient satisfaction and clinical outcomes including treatment delays, dose modifications, infusion reactions, hospitalizations or emergency visits.

36 Background: ASCO published a position statement regarding home infusion of anticancer therapy in June 2020. This statement recommends independent research to evaluate the safety and effectiveness of home infusions. Intermountain Healthcare (IM) incorporated this statement into its oncology care with an IRB-approved, prospective single-arm pilot study to determine the safety and feasibility of home administration of checkpoint inhibitor (CPI) immunotherapy with synchronous telemedicine visits. Methods: Patients with cancer receiving treatment at Intermountain Medical Center and Intermountain Cancer Center St. George were screened for enrollment into an IRB-approved, non-randomized pilot study of 20 patients. Eligibility criteria required patients to receive a CPI for an FDA-approved indication, live in Washington County or Salt Lake County, Utah, and have commercial payer coverage of CPI home infusion. Eligible patients were required to receive 2 doses of CPI at an infusion center, and patients who experienced an infusion reaction were excluded from receiving home infusion. Home infusion nurses are trained in oncology, CPIs, and home infusion reaction protocol. During synchronous video visits, infusion nurses are trained to perform the hands-on portions of the physical exam. A financial analysis estimated cost to IM and commercial payers for routine and home CPI infusions. Results: 622 patients were screened, of which 104 were receiving a CPI. 64 patients lived in an eligible county and 19 patients had commercial payer coverage. Of patients on CPIs, 8.7% (9/104) met all eligibility criteria accounting for 1.4% (9/622) of all patients with cancer screened (Table). Financial analysis estimated $829 cost (excluding drug cost) to IM for standard infusion reimbursement compared to $599 for in-home CPI infusions, accounting for savings of $230 per infusion. Majority of cost savings are from elimination of infusion center facilities fee ($495). Analysis includes $269 for home infusion nurse wages. Subsequent analysis for commercial payer SelectHealth estimates $270 reimbursement savings for the payer. Conclusions: Home immunotherapy infusions are estimated to be cost effective for both IM and commercial payers. However, lack of drug coverage and the rural demographics of Utahns with cancer are barriers to home CPI infusions. The pilot study was discontinued per infeasibility stopping criteria.[Table: see text]

Colorectal cancers (CRCs) are hard-wired to RAS/RAF/MEK/ERK pathway oncogenic signaling. However, the promise of targeted therapeutic inhibitors (KRASi/BRAFi/MEKi/ERKi), has been tempered by disappointing clinical activity, likely due to complex resistance mechanisms including intrinsic and adaptive resistance. Here we report a central role of SRC in mediating intrinsic and adaptive “bypass”-resistance to MEK inhibition in cancer stem cells (CSCs). The SRC oncogene is a well-studied non-receptor tyrosine kinase that can regulate multiple signaling pathways involved in the control of cell proliferation, survival, differentiation, adhesion, invasion and motility. Previously, our laboratory was the first to document that human CRC truncating mutations in the negative regulatory domain of SRC result in SRC activation (Nat Genet 1999). Now our integrated and expansive gene expression signature analyses in >2000 human CRCs reveal that MEKi bypass-resistance is strikingly-correlated with SRC activation, which is associated clinically with regional metastasis, disease recurrence and poor overall survival, and associated biologically with EMT and “stemness”. In support of this, SRC-associated MEKi resistance is strongly related to the CMS4 subtype that has a mesenchymal CSC phenotype. The finding is further supported by in vitro analyses demonstrating that CSCs vs. non-CSCs display greater levels of MEKi-resistance, which is attenuated by a SRC inhibitor. These results support a novel notion that SRC may serve as a common targetable node in MEKi resistance mechanisms, permitting effective cancer stem cell targeting. These pre-clinical data, based on strikingly-correlated pathway analyses of thousands of human tumors, support the “fast-track” development of a biomarker-driven (MEKi + SRCi) drug combination targeting problematic SRC-mediated, mesenchymal CSCs. Citation Format: Mingli Yang, Thomas B. Davis B. Davis, Michael V. Nebozhyn, Andrey Loboda, Heiman Wang, Michael J. Schell, Lance Pflieger, Ramya Thota, W. Jack Pledger, Timothy J. Yeatman. A novel role of SRC in mediating bypass resistance to MEK inhibition in colorectal cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1083.

Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. S is an oral multi-kinase inhibitor that inhibits Fibroblast Growth Factor Receptor family members 1-4 (FGFR1-4) in biochemical and cellular assays and is FDA approved in several tumor types. Results in a cohort of mBC pts with FGFR1 mutations (mut) or amplifications (amp) treated with S are reported. Methods: Eligible pts had mBC, no standard treatment (tx) options, measurable disease, ECOG Performance Status (PS) 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received S 50 mg orally daily for four weeks followed by two weeks off, until tumor progression. Simon 2-stage design tested the null disease control (DC) - defined as partial (PR), complete response (CR) or stable disease at 16+ weeks (SD 16+) - rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled. If ≥7 of 28 pts have DC, the null DC rate is rejected. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Thirty pts with mBC with FGFR1 mut (1 pt), amp (28 pts), or both (1 pt) were enrolled from Oct 2016 to June 2019. 3 were not evaluable and excluded from efficacy analyses. Demographics and outcomes are summarized in Table 1. Two partial responses (PR) and 5 SD16+ (FGFR1 amp only) were observed for DC and OR rates of 29% (95% CI: 13%, 42%) and 7% (95% CI: 1%, 24%), respectively, and the null DC rate of 15% was rejected (p=0.09). S related grade 3-5 TAEs (Table 1) were consistent with the product label for S except encephalopathy. Conclusions: Monotherapy S showed modest anti-tumor activity and clinically significant TAEs in heavily pre-treated pts with mBC with FGFR1 amplification. Table 1.Demographics, Efficacy (N=27) and Toxicity Outcomes (N=30)Median age, yrs (range)61 (28, 81)Female, %97ECOG PS, %047137217Prior systemic regimens, %1-210≥390Hormone Receptor (HR) & HER2 Status, %HR (+) HER2 (-)77HR (-) HER2(-)13HR (+) HER2 (+)7Not reported3DC rate, % (OR or SD16+) (95% CI)29 (13, 42)OR rate, % (95% CI)7 (1, 24)Median PFS, wks (95% CI)8.7 (8.1, 15.7)Median OS, wks (95% CI)33.9 (23.0, 49.0)Number of Pts with Treatment-related AEs/SAEs (TAEs, maximum grade reported)Grade 211Grade 329Grade 4321Skin infection (SAE)2Cytopenia, encephalopathy (SAE), febrile neutropenia (SAE), increased alkaline phosphatase, Palmar-plantar erythrodysesthesia syndrome, vomiting3Cytopenia, hypertension Citation Format: Carmen Calfa, Michael Rothe, Pam K. Mangat, Elizabeth Garrett-Mayer, Eugene Ahn, Keerthi Gogineni, Nitin Rohatgi, Monika L. Burness, Anu Gaba, Omid Hamid, Tareq Albaghdadi, Alison Conlin, Philip Gold, Jordi Rodon, Ramya Thota, Richard L. Schilsky. Sunitinib (S) in patients (pts) with metastatic breast cancer (mBC) with FGFR1 mutations or amplifications: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT173.

11565 Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of STS pts with CDK4 amplification treated with P are reported. Methods: Eligible pts had advanced STS, no standard treatment options, measurable disease, ECOG PS 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received P at 125 mg orally once daily for 21 days, followed by 7 days off until disease progression. Pts matched to P had CDK4 amplification and no RB mutations. Simon 2-stage design tested the null disease control (DC) - defined as partial (PR), complete response (CR) or stable disease at 16+ weeks (SD 16+) - rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled. If ≥7 of 28 pts have DC, the null DC rate is rejected. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: 29 pts (66% male) with STS with CDK4 amplification were enrolled from July 2016 to Nov 2019. 1 pt was not evaluable and excluded from efficacy analyses. Demographics and outcomes are summarized in Table. One pt with partial response (PR) and 12 pts with SD16+ were observed for DC and objective response (OR) rates of 48% (95% CI: 31%, 62%) and 3.7% (95% CI: 0.1%, 19%), respectively, and the null DC rate of 15% was rejected (p32 weeks. 14 pts had at least one grade 3-4 AE at least possibly related to P with the most common being low WBC/platelets. Other grade 3 AEs included increased alanine aminotransferase, anemia, and fatigue. Conclusions: Monotherapy P demonstrated anti-tumor activity in heavily pre-treated pts with STS with CDK4 amplification. Additional study is warranted to confirm the efficacy of P in pts with STS with CDK4 amplification. Clinical trial information: NCT02693535. [Table: see text]

6043 Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of HNC pts with CDKN2A loss or mutation treated with P are reported. Methods: Eligible pts had advanced HNC, no standard treatment options, measurable disease, ECOG PS 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received P at 125 mg orally once daily for 21 days, followed by 7 days off until disease progression. Pts matched to P had CDKN2A loss or mutation and no RB mutations. Simon 2-stage design tested the null disease control (DC) - defined as partial (PR), complete response (CR) or stable disease at 16+ weeks (SD 16+) - rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled. If ≥7 of 28 pts have DC, the null DC rate is rejected. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: 28 pts (64% male) with HNC with CDKN2A loss (20 pts) or mutation (8 pts) were enrolled from June 2016 to Sept 2019. All were eligible for efficacy and toxicity. Demographics and outcomes are summarized in Table. No objective response (OR) and 10 pts with SD16+ (9 with CDKN2A loss, 1 with mutation) were observed for a DC rate of 37% (95% CI: 21%, 50%); the null DC rate of 15% was rejected (p=0.005). 14 pts had at least one grade 3-5 adverse or serious adverse event (AE/SAE) at least possibly related to P with the most common being low WBC/platelets. Other grade 3-4 AEs included anemia, fatigue, hypocalcemia, and syncope. There was one pt with grade 5 respiratory failure likely due to extensive lung metastases and aspiration but P-related pneumonitis could not be ruled out. Conclusions: Monotherapy P demonstrated modest anti-tumor activity and clinically significant AEs in heavily pre-treated pts with HNC with CDKN2A loss or mutation. Additional study is warranted to confirm the efficacy of P in pts with HNC with CDKN2A loss or mutation. Clinical trial information: NCT02693535. [Table: see text]

e16191 Background: Biliary tract cancers are aggressive tumors with limited treatment options. Several ongoing clinical trials are currently exploring role of immune therapy in advanced BTC. Programmed death-ligand 1 (PD-L1), tumor mutational burden (TMB), and microsatellite instability (MSI) are commonly used immune related-biomarkers. Herein, we analyzed the TMB, MSI and PD-L1 expression in advanced BTC. Methods: We retrospectively evaluated the association of TMB, MSI and PD-L1 expression with survival and related treatment outcomes. Results: The immune mediated biomarkers were reported in a total of 62 BTC patients (pts). The mean age of the pts is 73 (range 32-83) years, with predominant females (59%) and Caucasians (82%). The most common histology noted was intrahepatic cholangiocarcinoma (67%) followed by extrahepatic cholangiocarcinoma (18%) and gallbladder carcinoma (15%). Approximately, 40% received 2 or more lines of therapy while 20% of patients didn’t receive any treatment and over. The treatment regimen included gemcitabine-based regimen (35%), 5FU based regimen (18%), immune therapy (15%) and targeted therapy (6%). The TMB was low in 52 pts (83%), intermediate 7 pts (11%) and high in 2 pts (3%). MSI is stable in 55 pts (89%) and PD-L1 expression is negative in 29 pts (47%) and positive in 23 pts (37%). Conclusions: Our data suggests the BTC’s have in general low TMB, are microsatellite stable and have low PD-L1 expression. The potential prognostic and predictive value of these immune related- biomarkers need to be validated in larger studies.

Objectives The programmed death 1 (PD-1) pathway is upregulated in the immune microenvironment of many cancers. In this study, we examined the PD-1 pathway and the immune microenvironment of small intestinal adenocarcinomas by immunohistochemistry. Methods From our department pathology archives we identified 42 small intestinal adenocarcinomas from between 2000 and 2015, with blocks available for IHC studies. Tumors were immunohistochemically stained for CD3, CD4, CD8, CD20, PD-1, and programmed death ligand 1 (PD-L1) expression. Results PD-1 was expressed by intratumoral and peritumoral lymphocytes in 35 of 42 (83%) cases. PD-L1 expression on tumor cells and immune cells was observed in seven of 42 (17%), and 18 of 42 (43%) cases, respectively. PD-L1 was mainly expressed by histiocytes capping cancerous glands/nests at the invasive front or by most tumor cells in medullary carcinomas. All the PD-L1+ tumors also expressed PD-1. The tumors expressing PD-L1 contained more CD3+, CD4+, and CD8+ T cells, but showed a lower CD4+/CD8+ ratio than those without expression of PD-L1. Conclusions PD-1 and PD-L1 are highly expressed by most small intestinal adenocarcinomas. Blockage of the PD-1 pathway should be evaluated in the treatment of small intestinal adenocarcinomas.

Prior phase III trials in advanced pancreatic cancer have been predominantly unsuccessful. In this review, we attempt to understand how past preclinical data were translated into phase III clinical trials in metastatic pancreatic cancer as described in the article. A systematic literature review conducted through the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases, from January 1997 to June 2015 using key words-phase III clinical trials, metastatic/advanced pancreatic adenocarcinoma or pancreatic cancer identified 30 randomized controlled trials (RCTs) that met criteria. The trials were limited to RCTs in the first-line treatment of patients with metastatic pancreatic cancer. The success rate of first-line phase III studies in advanced pancreatic cancer was only 13%. In 60% of the RCTs, no preclinical experiments were referenced in biologically cognate pancreatic models. Nine (30%) of the RCTs were designed based on preclinical evidence from in vitro cell lines alone without additional in vivo validation in xenograft models. It remains uncertain how strongly the preclinical data influence the development of clinical regimens but so far the studies developed based on more solid preclinical evidence have been successful.

Nasal dermoid sinus cysts are uncommon congenital anomalies, presenting either as cysts or sinuses with varied presentation at birth, childhood, or even adulthood. A midline nasal pit, fistula, or infected mass may be located anywhere from the glabella to the nasal columella. Preoperative radiological investigation with CT (computed tomography) and MRI (magnetic resonance imaging) scans is mandatory to rule out intracranial extension. Complete excision of the cyst along with its tract is the only definitive therapeutic modality. We present a case of nasal dermoid sinus cyst in a 3-year-old male child who underwent excision by open rhinoplasty approach.

Low-grade fibromyxoid sarcoma (LGFMS) is an enigmatic soft tissue tumor. It frequently presents as a deeply seated mass in the proximal extremities and trunk. Superficial LGFMSs of the head and neck are exceedingly rare. Hyalinizing spindle cell tumor with giant rosettes (HSTGR) is an entity considered to be on the histologic spectrum of LGFMS. We present a case of a 44-year-old female who presented with a superficial, polypoid mass of the external auditory meatus. Microscopic examination revealed the classic histologic features of HSTGR. To our knowledge, this case is the first described at this extremely unusual location. Identification and reporting of such unusual cases is important to understand and compare the behavior of superficial LGFMS to that of the more common deeply seated tumors.

345 Background: Liver metastasis is evident in many oncological patients at the time of initial presentation. Recently, platelet-albumin-bilirubin (PALBI) score was reported to be superior to Child-Pugh classification and albumin-bilirubin (ALBI) score in terms of mortality prediction, while Model for End-Stage Liver Disease (MELD) score is the most frequent used. Trans-arterial radioembolization (TARE) is a minimally invasive therapy used to treat liver tumors. The aim of this study is to assess prognostic performance of pre-TARE liver function scores. Methods: We retrospectively assessed all patients with liver metastasis that underwent TARE between February 2008 and January 2020 at a single institution. Demographic characteristics; and laboratory values were collected to calculate MELD, ALBI, PALBI, within six months before TARE administration. Results are presented as proportions and median (IQR). Multivariate Cox regression analysis was performed to identify risk factors for overall survival. Results: A total of 90 patients were included, 46.7% were females with a median age was 61 (50-69). Colorectal (CR) metastasis was found in 45.6% of cases, neuroendocrine tumors (NET) in 27.8% and the remainder a heterogenous group of metastatic disease. In 90% of cases, TARE was used as destination therapy. The median tumor size was 5.1 (3.3-7.1) cm with 81% having multifocal lesions. The median scores were: MELD 8 (7-10), ALBI -2.77 (-3.01 to -2.56), PALBI -2.58 (-2.77 to -2.32). Other metastatic disease (OR=2.3: 95%CI 1.3-4.3; p=0.02), MELD (OR=1.1: 95%CI 1.002-1.2; p=0.04), ALBI (OR=2: 95%CI 1.2-3.3; p=0.005) and PALBI (OR=2.4: 95%CI 1.2-4.7; p=0.01) were significant in univariate Cox regression. In the multivariate Cox regression, MELD score was not statistically significant when adjusted with diagnosis and PALBI or ALBI score. As expected due to similar variables to calculate score, ALBI and PALBI score were not statistically significance when these are used in the same model (Table). Conclusions: To our knowledge, this is the first report of PALBI as prognostic factor in patients undergoing TARE for metastatic liver disease. Interestingly, the multivariate cox regression showed us that MELD score is not a significant score for these patients. Further non-inferiority assessment of PALBI and ALBI over MELD score should be developed. [Table: see text]

Background Epistaxis is a commonly managed emergency by the ENT specialty. Although successfully managed in most of the times, internal carotid artery (ICA) aneurysms are among the rare causes that require prompt diagnosis, management and interdisciplinary intervention for saving the patient’s life. Case presentation We report the presentation and management of four cases of ICA pseudoaneurysm bleeds, out of which three of them were successfully managed with endovascular coiling by interventional neuroradiology. Conclusion Endovascular coiling of the PA (pseudonaurysm) with preservation of patency of ICA is the preferred treatment option when possible. Being a new technique, studies are required to assess the long term complications and failure rate.

Hematopoietic stem cell transplantation (HSCT) has an integral role in the treatment of malignant and nonmalignant diseases. Long-term complications after HSCT have been well established and include graft-versus-host disease (GVHD), conditioning regimen-related toxicities, disease relapse, and infections. Immune-mediated phenomena are increasingly described after HSCT with clinically significant sequelae. Diagnosis is challenging because of features that overlap with other commonly reported post-transplantation complications. Patients who experience immune-mediated disease after HSCT tend to have poor outcomes. Early recognition of immune-mediated complications is imperative to reduce preventable morbidity and mortality. This review looks at the currently available literature on pathogenesis, incidence, risk factors, treatment, and outcomes of immune-mediated disease (other than GVHD) after HSCT.

Background Precision oncology increasingly utilizes molecular profiling of tumors to determine treatment decisions with targeted therapeutics. The molecular profiling data is valuable in the treatment of individual patients as well as for multiple secondary uses. Objective To automatically parse, categorize, and aggregate clinical molecular profile data generated during cancer care as well as use this data to address multiple secondary use cases. Methods A system to parse, categorize and aggregate molecular profile data was created. A naÿve Bayesian classifier categorized results according to clinical groups. The accuracy of these systems were validated against a published expertly-curated subset of molecular profiling data. Results Following one year of operation, 819 samples have been accurately parsed and categorized to generate a data repository of 10,620 genetic variants. The database has been used for operational, clinical trial, and discovery science research. Conclusions A real-time database of molecular profiling data is a pragmatic solution to several knowledge management problems in the practice and science of precision oncology.

4094 Background: The Consensus Molecular Subtypes (CMS) of colorectal cancer (CRC) have prognostic and predictive value in identifying patients that derive benefit from EGFR targeted therapies. The CMS2 cohort was specifically noted to predict response to cetuximab. Besides CMS classification, we recently reported a two-gene mutation signature of APC and TP53 (AP) that predicts potential response to cetuximab. In this study, we hypothesize AP mutations, in addition to CMS cohorts, predict cetuximab sensitivity. Methods: A prespecified and validated 203 gene expression signature score measuring cetuximab sensitivity (CTX S-score) was used as a surrogate for response to cetuximab sensitivity. A cohort of 458 patients with colorectal cancer was accrued between October 2006 and September 2011. The population classified into CMS cohorts, and CTX-S scores were determined across each of the cohorts based on AP mutation status. Results: Among 458 tumor samples sequenced, AP mutations were identified as significantly associated with higher CTX-S scores. Among the CMS 1-4 cohorts identified, AP mutations were noted in 13 of 77 (17%) patients in CMS1 cohort, 87 of 116 (75%) patients in CMS2 cohort, 15 of 64 (23%) patients in CMS3 cohort, 46 of 112 (41%) patients in CMS4 cohort, indicating that AP mutations are dominant in CMS2 cohort. Further CTX-S score comparisons across CMS cohorts based on AP status show that AP mutated tumors have higher CTX-S scores than non-AP mutated tumors—irrespective of the CMS cohorts (p

566 Background: Hepatobiliary (HB) tumors are aggressive tumors with emerging evidence for increasing sensitivity to immune checkpoint inhibitors (ICI). Tumor mutation burden (TMB) was found to be a quantitative biomarker associated with production of neoantigens within the tumor and predict the sensitivity to immune therapy. Herein, we explore the TMB, microsatellite instability (MSI) and PD-L1 expression as a potential biomarker of response to immune therapy in HB tumors. Methods: We retrospectively assessed all patients with hepatobiliary malignancies who have undergone next generation sequencing (NGS) between October 2009 and June 2019. We then analysed the tumor mutation burden and PD-L1 of these tumors and also identified frequency of patients with no clinically actionable mutations. Results: In our total 61 patients with HB tumors predominantly were male (62.3%) with mean age of 63 years. Thirty-four patients had hepatocellular carcinoma, 22 patients had cholangiocarcinoma and 5 patients had gallbladder carcinoma. The most common risk factors were smoking status, cirrhosis, alcohol consumption and hepatitis C virus. The mean TMB reported was 3.2 (1.16 – 7.35). MSI was identified in 13 patients and one was indeterminate. Only 17 patients had PD-L1 positive. At least, 37 patients had one clinically actionable mutation while 24 patients had no clinically actionable mutations. Mean overall survival was 16.6 months, but no statistically significant difference was found by high PD-L1 (3 vs 3.7 months, p=0.3) expression. Conclusions: Our data suggests the TMB in HB tumors is low in general irrespective of their underlying risk factors. We also noted more than half had microsatellite stable tumors and PD-L1 expression. Future larger studies are needed to evaluate TMB, MSI and PD-L1 as a potential biomarker in hepatobiliary tumors to help select patients that will benefit from immune therapy.