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Patients with gastrointestinal (GI) cancer frequently experience unplanned hospitalizations, but predictive tools to identify high-risk patients are lacking. We developed a machine learning model to identify high-risk patients.In the study, 1341 consecutive patients undergoing GI (abdominal or pelvic) radiation treatment (RT) from March 2016 to July 2018 (derivation) and July 2018 to January 2019 (validation) were assessed for unplanned hospitalizations within 30 days of finishing RT. In the derivation cohort of 663 abdominal and 427 pelvic RT patients, a machine learning approach derived random forest, gradient boosted decision tree, and logistic regression models to predict 30-day unplanned hospitalizations. Model performance was assessed using area under the receiver operating characteristic curve (AUC) and prospectively validated in 161 abdominal and 90 pelvic RT patients using Mann-Whitney rank-sum test. Highest quintile of risk for hospitalization was defined as "high-risk" and the remainder "low-risk." Hospitalizations for high- versus low-risk patients were compared using Pearson's χOverall, 13% and 11% of patients receiving abdominal and pelvic RT experienced 30-day unplanned hospitalization. In the derivation phase, gradient boosted decision tree cross-validation yielded AUC = 0.823 (abdominal patients) and random forest yielded AUC = 0.776 (pelvic patients). In the validation phase, these models yielded AUC = 0.749 and 0.764, respectively (P.001 and P = .002). Validation models discriminated high- versus low-risk patients: in abdominal RT patients, frequency of hospitalization was 39% versus 9% in high- versus low-risk groups (P.001) and 6-month survival was 67% versus 92% (P = .001). In pelvic RT patients, frequency of hospitalization was 33% versus 8% (P = .002) and survival was 86% versus 92% (P = .15) in high- versus low-risk patients.In patients with GI cancer undergoing RT as part of multimodality treatment, machine learning models for 30-day unplanned hospitalization discriminated high- versus low-risk patients. Future applications will test utility of models to prompt interventions to decrease hospitalizations and adverse outcomes.

Background Preclinical studies suggest that combining vandetanib (VAN), a multi-tyrosine kinase inhibitor of rearranged during transfection (RET) proto-oncogene, vascular endothelial growth factor receptor (VEGFR), and epidermal growth factor receptor (EGFR), with everolimus (EV), a mammalian target of rapamycin (mTOR) inhibitor, may improve antitumor activity. We determined the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), and dose-limiting toxicities (DLTs) of VAN + EV in patients with advanced solid cancers and the effect of combination therapy on cancer cell proliferation and intracellular pathways. Patients and methods Patients with refractory solid tumors were enrolled in a phase I dose-escalation trial testing VAN (100-300 mg orally daily) + EV (2.5-10 mg orally daily). Objective responses were evaluated using RECIST v1.1. RET mutant cancer cell lines were used in cell-based studies. Results Among 80 patients enrolled, 72 (90%) patients were evaluable: 7 achieved partial response (PR) (10%) and 37 had stable disease (SD) (51%; duration range: 1-27 cycles). Clinical benefit (SD or PR ≥ 6 months) was observed in 26 evaluable patients [36%, 95% confidence intervals (CI) (25% to 49%)]. In 80 patients, median overall survival (OS) was 10.5 months [95% CI (8.5-16.1)] and median progression-free survival (PFS) 4.1 months [95% CI (3.4-7.3)]. Six patients (7.5%) experienced DLTs and 20 (25%) required dose modifications. VAN + EV was safe, with fatigue, rash, diarrhea, and mucositis being the most common toxicities. In cell-based studies, combination therapy was superior to monotherapy at inhibiting cancer cell proliferation and intracellular signaling. Conclusions The MTDs and RP2Ds of VAN + EV are 300 mg and 10 mg, respectively. VAN + EV combination is safe and active in refractory solid tumors. Further investigation is warranted in RET pathway aberrant tumors., Highlights • VAN + EV is safe, active and provides clinical benefit in some patients with refractory solid cancers. • Dual therapy is superior to monotherapy at inhibiting proliferation and intracellular signaling of RET mutant cancer cells. • This study highlights the importance of identifying novel combination therapies to overcome therapeutic resistance. • Next-generation sequencing of advanced solid tumors may inform treatment strategies and guide future drug development.

BACKGROUND: The use of overall survival (OS) as the gold standard primary endpoint (PEP) in metastatic oncologic randomized controlled trials (RCTs) has declined in favor of progression-free survival (PFS) without a complete understanding of the degree to which PFS reliably predicts for OS. METHODS: Using ClinicalTrials.gov, we identified 1,239 phase 3 oncologic RCTs, 260 of which were metastatic solid tumor trials with a superiority-design investigating a therapeutic intervention using either a PFS or OS PEP. Each individual trial was reviewed to quantify RCT design factors and disease-related outcomes. RESULTS: A total of 172,133 patients were enrolled from 1999–2015 in RCTs that utilized PFS (56.2%, 146/260) or OS (43.8%, 114/260) as the PEP. PFS trials were more likely to restrict patient eligibility using molecular criteria (15.1% vs. 4.4%, p=0.005), utilize targeted therapy (80.1% vs. 67.5%, p=0.048), accrue fewer patients (median 495 vs. 619, p=0.03), and successfully meet the trial PEP (66.9% vs. 33.3%, p

Immunotherapy (IO) has altered the therapeutic landscape for multiple cancers. There are emerging data from retrospective studies on a subset of patients who do not benefit from IO, instead experiencing rapid progression with dramatic acceleration of disease trajectory, termed 'hyperprogressive disease' (HPD). The incidence of HPD ranges from 4% to 29% from the studies reported. Biological basis and mechanisms of HPD are currently being elucidated, with one theory involving the Fc region of antibodies. Another group has shown EGFR and MDM2/MDM4 amplifications in patients with HPD. This phenomenon has polarized oncologists who debate that this could still reflect the natural history of the disease. Thus, prospective studies are urgently needed to confirm the underlying biology, predict patients who are susceptible to HPD, and determine the modality of therapy post progression.

273 Background: To date, studies of machine learning (ML) algorithms within oncology for mortality prediction have focused on structured electronic health record (EHR) data. Given the complex symptom burden of patients with advanced cancers, ML models may be better suited to identify patterns and interactions between symptom burden and outcomes compared to traditional statistical methods. To that end, in this study, we leverage the patient reported outcomes (PRO) data together with clinical EHR-based variables to assess the performance of ML algorithms to predict mortality in patients with advanced cancers. Methods: We randomly selected 689 patients with advanced cancer who had their first Palliative Care encounter between January 2012 and December 2017. 59 patients were lost to follow-up and were excluded from this analysis. The remaining cohort of 630 patients was split 4:1 randomly into a training and validation set to develop and test a supervised ML algorithm (Extreme Gradient Boosting [XGB] tree) to predict the 6-month mortality. Candidate variables for algorithm development included gender, age, ECOG performance status (PS), number of prior systemic therapies, and scores on the Edmonton Symptom Assessment System (ESAS)-FS, a 12-item PRO measure of physical and psychosocial symptom burden include the composite Physical Symptom Score (PHS), a sum of the physical ESAS symptoms (pain, fatigue, nausea, drowsiness, shortness of breath, appetite, wellbeing, sleep). Results: Overall, 630 patients were included in this 6-month mortality prediction; mean age 59 years, 354 (56%) female; 276 (44%) male. Variables with the most significant impact on the XGB tree mortality prediction were the ESAS symptoms of shortness of breath (1-AUC, 0.295), appetite, ESAS PHS, financial distress, age, and appetite as well as ECOG PS and number of prior systemic therapies. The XGB tree algorithm demonstrated the best overall prediction performance of 6-month mortality in the independent testing set, AUC 0.716 (95% CI 0.63 - 0.81), sensitivity 0.75 (95% CI 0.66 - 0.87), and a positive predictive value 0.67 (95% CI 0.57 - 0.79). Conclusions: Our ML model leveraged PRO-based assessment of symptom burden to correctly identify the majority of patients who died within 6 months. These models are uniquely positioned to not only automatically identify patients at high risk for short-term mortality but also the specific symptoms of concern for clinical intervention. Such models can be applied to available clinical and PRO data to facilitate clinical decision-making. Futures studies on improving model performance with the inclusion of interventions to modify symptom burden are in design.

210 Background: Research shows that healthcare professionals’ personal hopefulness is associated with burnout and life satisfaction, highlighting the value of hope-enhancement interventions. Feldman and Dreher developed a single-session hope intervention, but this has been used rarely with oncology professionals, and only in in-person format (Shah, Ferguson, Corn et al.). Given SWOG Cancer Research Network’s commitment to assessing hope-enhancement approaches and the need for online interventions given COVID-19, we report a feasibility study of a virtual hope workshop in SWOG members. Methods: The workshop was a single 2-hour session delivered live via Zoom to 6-8 participants at a time. The workshop comprises 3 components: A brief lecture on hope and two exercises—a “hope mapping” exercise (aided by a smartphone app created for the workshop) and a hope visualization exercise—both designed to build hope for a life goal of each participant’s choosing. 29 SWOG members participated. A link to post-workshop measures was sent to participants, which they were given a week to complete. Measures included Thanarajasingamet al’s 5-item Was-it-Worth-it (WIWI) measure; Kirkpatrick’s 4-item Training Evaluation Model (TEM; reaction, learning, behavior, results); and an item assessing the degree to which participants believe concepts from the workshop should be integrated into SWOG studies. Results: In all, 25 participants (86%) completed measures. Participants were physicians (n = 8), nurses (n = 4), patient advocates (n = 3), research staff (n = 3), and others (n = 7); mostly female (n = 17), mostly white (n = 18), with a mean age of 55.5 (SD = 13.95). Results for the WIWI items are as follows: “Was it worthwhile to participate in the Hope Workshop?” (23 Yes, 2 No/Undecided/Missing Answer); “If you had to do over, would you participate in the Hope Workshop again?” (22 Yes, 3 No/Undecided/Missing Answer); “Would you recommend participating in the Hope Workshop to others?” (22 Yes, 3 No/Undecided/Missing Answer). Two additional items on the WIWI asked participants to rate on a 3-point scale the degree to which they believe their quality of life had increased due to the workshop (M = 2.52, SD =.51) and their overall experience in the workshop (M = 2.70, SD =.64). Ratings for Kirkpatrick’s TEM items likewise were high, ranging from 6.91 (SD = 1.31) to 7.70 (SD =.70) on an 8-point scale. Finally, participants gave a mean rating of 4.44 (SD =.59) on a 5-point scale to the item “To what degree do you believe it may be useful to integrate concepts from this workshop into SWOG trials/studies?” Conclusions: It is feasible to implement hope-enhancement workshops in an online platform that includes a smartphone app. Data obtained from two validated tools (WIWI instrument and Kirkpatrick’s TEM) attest to an array of positive outcomes. Participants also overwhelmingly advocated integrating hope concepts into SWOG’s research.

153 Background: The long-term symptoms from COVID-19 (C19) infection in pts with cancer is not fully known. To monitor the evolution of this symptom burden over time, we designed and implemented a C19-specific patient-reported outcome (PRO) measure that integrated with a known measure of cancer symptom burden. Methods: Within the institutional initiative on C19 and cancer named Data-Driven Determinants for C19 Oncology Discovery Effort (D3CODE), pts with cancer & PCR-pos C19 are invited to participate in this longitudinal study. Pts complete the EQ-5D-5L, the 13 symptom severity & 6 interference items of the core MD Anderson Symptom Inventory (MDASI)+14 COVID-specific items, all scored on a 0-10 scale, 0 = none, 10 = worst imaginable. Pts complete the survey daily x 14 days from positive test date, then weekly x 3months, then monthly x 2yrs. Demographic and disease information was collected. Psychometric procedures determined validity and reliability of the MDASI-COVID. Results: Between 5/15/20 – 02/14/21, 2154 pts w PCR-confirmed C19 were invited to participate in the longitudinal study. 1282 (60%) pts provided consent and began the longitudinal completion of PRO surveys. Pts were 54.5% Female and 45.5% Male, median age 59 years (range 15 – 92). 1021 (80%) are White/Caucasian, 206 (16%) Hispanic, 113 (9%) African American, and 39 (3%) Asian. The validation analysis of MDASI-COVID instrument included the 1st 600 pts where the mean overall health rating on EQ-5D-5L was 78.3 (SD 19.6), best being 100. Highest mean (M) severity symptoms on the MDASI-COVID were fatigue (M 3.45, SD 2.17), drowsiness (M 2.50, SD 2.89), sleep disturbance (M 2.44, SD 2.99), malaise (M 2.37, SD 3.05), and distress (M 2.27, SD 2.90). Most severe (≥ 7) symptoms) reported were fatigue (21.3% of pts), change in taste (14.8%), change in smell (14.4%), malaise (14.3%), sleep disturbance (14.3%), and drowsiness (14%). showed internal consistency (Cronbach α) of the 27 symptom items was 0.957, of the 6 interference items was 0.937. Mean severity of the 27 symptom items was significantly correlated with overall EQ-5D-5L health rating (correlation = -0.45, P < 0.0005), demonstrating concurrent validity. Mean symptom severity and interference showed known-group validity between pts who required hospitalization (symptom M 2.32, SD 2.09; interference M 3.29, SD 3.02) and those who did not (symptom M 1.69, SD 1.85; interference M 2.20, SD 2.64) (symptom P 0.007; interference P 0.004). Conclusions: We successfully deployed a PRO-based long-term symptom monitoring platform for pts with C19 and cancer. The validation analysis of this novel C19 specific PRO, the MDASI-COVID, aids in the quantification of the global symptom burden in pts with both cancer and COVID-19 infection. Deployment of this measure in the ongoing longitudinal observational cohort allows for in-depth understanding of the long-term symptoms related to C19 and cancer.

322 Background: Natural language processing (NLP) algorithms can be leveraged to better understand prevailing themes in healthcare conversations. Sentiment analysis, an NLP technique to analyze and interpret sentiments from text, has been validated on Twitter in tracking natural disasters and disease outbreaks. To establish its role in healthcare discourse, we sought to explore the feasibility and accuracy of sentiment analysis on Twitter posts (‘’tweets’’) related to prior authorizations (PAs), a common occurrence in oncology built to curb payer-concerns about costs of cancer care, but which can obstruct timely and appropriate care and increase administrative burden and clinician frustration. Methods: We identified tweets related to PAs between 03/09/2021-04/29/2021 using pre-specified keywords [e.g., #priorauth etc.] and used Twarc, a command-line tool and Python library for archiving Twitter JavaScript Object Notation data. We performed sentiment analysis using two NLP models: (1) TextBlob (trained on movie reviews); and (2) VADER (trained on social media). These models provide results as polarity, a score between 0-1, and a sentiment as ‘’positive’’ (>0), ‘’neutral’’ (exactly 0), or ‘’negative’’ (

55 Background: To date, drugs used for CACS have limited efficacy and may have unwanted side effects. Despite this, clinicians commonly prescribe certain drugs for CACS, adding financial burden to patients through out-of-pocket costs near or at the end of life. We sought to describe the range of costs of the multiple drugs commonly used to manage CACS. Methods: We reviewed oncology, nutrition, and supportive care guidelines (ASCO, ESMO, ESPEN, MASCC) and compiled a list of drugs recommended for CACS. We also included drugs commonly used off-label in clinical practice as identified by study authors. Using GoodRx.com, we extracted available formulations (e.g., tablet [tab] vs capsule [cap] vs oral disintegrating tablet [ODT] vs solution [sol]), and brand name vs generic products for each drug. We identified the average retail price, and the lowest price with coupons, for each formulation using the most commonly used dosage for a 2-week period (typical fill). The average retail price is the cash price for consumers without prescription drug coverage. The lowest price represents a discounted, ‘’best case’’ scenario of out-of-pocket costs for patients without prescription drug coverage. We collected data using the zip code 10065 in May 2021 to describe the range of costs of these drug formulations. Results: We included 7 drugs available in 20 formulations (Table). For a 2-week fill, the least expensive options included generic olanzapine 5 mg tab (once daily) and generic mirtazapine 15 mg tab (once daily), costing $4.50 per fill. Brand-name solutions were costly, ranging from $605.50 (megestrol acetate, Megace ES) to $1,156.30 (dronabinol, Syndros). Costs between formulations of the same drug/dosage varied widely: for olanzapine 5 mg, the lowest price varied from $4.50 [generic, tab] to $238.40 [Zyprexa zydis, brand-name, ODT]. Conclusions: We found that the costs of drugs used for CACS are highly variable, ranging from < $5 to > $1000 per fill. Overall there is limited data supporting use of drugs for managing CACS. Thus, our findings can help guide patient-clinician discussions about the risk/benefit ratio of a prescription for managing CACS, while highlighting the importance of seeking less expensive formulations when possible.[Table: see text]

3112 Background: The advent of tyrosine kinase inhibitors (TKIs) has altered the therapeutic landscape of multiple hematological and solid malignancies. FDA approved starting doses of TKIs are based on the recommended phase 2 dose (RP2D) in clinical trials. Since many of these drugs are continuously dosed, ongoing toxicities may lead to drug reductions and drug discontinuations. Hence in practice, many patients are started on lower doses due to tolerability concerns or are dose-reduced subsequently for toxicity. Herein, we assessed the dosing, drug reduction rates, and drug discontinuation rates among FDA approved TKIs. Methods: We established a database of all FDA approved TKIs from the FDA online label repository. We extracted descriptive data for indications and usage, type of approval, approval dosage, dose reduction recommendation, median age, dose reduction rates, drug discontinuation rates, dose modification, warnings, adverse reactions, clinical trial experience, and geriatric use above 65 yrs and 75 yrs. Results: TKIs were approved for 143 different indications, ranging from 1 indication to 11 indications (eg. Imatinib) from data arising from 7 patients to 2816 patients for a specific indication. Among all TKIs, median dose was 150 mg and average dose was 237 mg; 34 (23.8%) were approved bid vs 71 (49.7%) qd. Specifically for oncology, 54 indications were biomarker based (eg. EGFR mutant NSCLC) and 52 were non-biomarker based for specific diseases (eg. metastatic RCC). Among approved indications range of dose reduction rate (DRR), drug interruption rates (DIR), drug discontinuations rates (DDR) were 0.80-89%, 3%-89%, and 1-39% respectively. Most common reasons for DRR, DIR, and DDR were diarrhea, fatigue, nausea, vomiting, hepatotoxicity, rash, and hypertension. Geriatric use was listed in 99 indications ( > 65 yrs, 6-68%; > 75 yrs, 0.50-24%). Patient reported outcomes were not available. Conclusions: TKIs have a variable dose reduction and drug discontinuation rate. Clinical trials should evaluate multiple dosing regimens and schedules to lessen the toxicity burden and improve QOL in patients. Future studies are warranted to look into flat dosing vs alternative dosing, like weight-based dosing for TKIs, and to report patient reported outcomes.

e13555 Background: Contra to national guidelines, women with ovarian cancer often receive aggressive treatment until the end-of-life. We trained machine learning algorithms to predict mortality within 180 days for women with ovarian cancer. Methods: Data were collected data from a single academic cancer institution in the United States. Women with recurrent ovarian cancer completed biopsychosocial patient-reported outcome measures (PROMs) every 90 days. We randomly partitioned our dataset into training and testing samples with a 2:1 ratio. We used synthetic minority oversampling to reduce class imbalance in the training dataset. We fitted training data to six machine learning algorithms and combined their classifications on the testing dataset into a voting ensemble. We assessed the accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC) for each algorithm. Results: We recruited 245 patients who completed 1319 assessments. The final voting ensemble performed well across all performance metrics (Accuracy = .79, Sensitivity = .71, Specificity = .80, AUROC = .76). The algorithm correctly identified 25 of the 35 women in the testing dataset who died within 180 days of assessment Conclusions: Machine learning algorithms trained using PROM data offer state-of-the-art performance in predicting whether a woman with ovarian cancer will reach the end-of-life within 180 days. We highlight the importance of PROM data in ML models of mortality. Our model exhibits substantial improvements in prediction sensitivity compared to other similar models trained using electronic health record data alone. This model could inform clinical decision making and improve the uptake of appropriate end-of-life care. Further research is warranted to expand on these findings in a larger, more diverse sample.

12124 Background: Most studies of clinician-patient communication use scales created ad hoc with unknown validity. To provide a standard measure for future studies, we developed and validated a new scale of clinician-reported skills in communicating difficult news: the Self-Efficacy for Medical Communication (SEMC) scale. Methods: Using evidence-based scale development guidelines, we created 16 items sampling a range of communication skills, including “Disclose difficult news in manageable chunks, so the patient is not overwhelmed,” and “Determine how to present information based on the patient’s emotional state.” Items are rated on Likert scales from 1 ( cannot do at all) to 10 ( highly certain can do). We constructed two forms—one assessing communication with patients and one with family—using identical items but replacing “patient” with “family/caregiver.” We examined the convergent and discriminant validity of the SEMC (correlations with similar and dissimilar measures) as well as its reliability and factor structure. A total of 221 clinicians working in oncology settings (physicians, nurses, medical students) completed measures online. Convergent measures included medical communication items from past studies; the Self-Perceived Communication Competence Scale to measure communication ability outside the medical realm; and the General Self-Efficacy and Occupational Self-Efficacy scales to measure overall self-efficacy/confidence. Discriminant measures included the Ten Item Personality Inventory to measure personality factors; the Maslach Burnout Inventory to measure job burnout; and the Satisfaction with Life Scale to measure well-being. Finally, the Marlowe-Crowne Social Desirability (MCSD) scale measured motivation to “look good” in responding to survey questions. Results: Mean scores were similar for the patient (126.36) and family (127.09) forms (max score 160), both with excellent reliability ( alphas =.94,.96, respectively). Because these forms were almost perfectly correlated ( r =.95, p

TPS3143 Background: Many rare cancers are understudied, and affected patients often have few if any standard treatment options and limited access to clinical trials. Comprehensive genomic profiling (CGP) is a robust tool to efficiently identify the genomic alterations of cancer and can be applied to study rare tumors. The promise of this technology is to simultaneously enhance our understanding of diverse rare tumors and find matched therapies to benefit the individual patient in real-time. The COVID19 pandemic has challenged the “trial-centric” clinical trial infrastructure. Novel “patient-centric” trials are needed, especially for rare cancers. TRACK is a decentralized, patient advocacy-initiated trial that aims to establish whether patients with rare tumors and cancer of unknown primary can benefit from matched molecular therapy as dictated by their CGP results. Methods: This is a national open label, non-randomized, multi-center (includes community and academic centers) pragmatic study in rare tumors ( 6 months; PR; CR), and high-grade toxicities (as available) of matched targeted therapy. Exploratory endpoints include matching rates; understanding genomic correlates of response; concordance rates between CGP from tissue and blood, time-to-treatment failure, and the impact of the cancer treatment from the patient perspective (via ESAS-FS, a validated patient-reported outcomes (PRO) instrument). All eligible and enrolled patients, regardless of whether receiving matched treatment or not, will be followed for a minimum of one year in a uniform way such that the treatment efficacy and outcomes can be assessed in standard formats. The study is open with six patients enrolled at time of submission. Clinical trial information: NCT04504604.

12113 Background: The symptom burden experienced by patients with cancer who contract the COVID-19 (C19) infection remains to be fully understood. To accurately assess this symptom burden, we developed a valid, reliable patient-reported outcome (PRO) measure of C19 symptoms combined with a known measure of cancer symptom burden. Methods: Within the institutional initiative on COVID-19 and cancer named Data-Driven Determinants for COVID-19 Oncology Discovery Effort (D3CODE), patients with cancer and PCR-positive C19 tests were invited to participate in this longitudinal study after providing consent. Pts completed the EQ-5D-5L and the 13 symptom severity and 6 interference items of the core MD Anderson Symptom Inventory (MDASI) plus 14 COVID-specific symptom items generated from literature and expert review. Items were measured on a 0-10 scale, 0 = none to 10 = worst imaginable symptom or interference. Demographic and disease information was collected. Psychometric procedures determined validity and reliability of the MDASI-COVID. Results: 600 pts enrolled, mean age 56.5y (range 20 to 91y). 59% female, 80% white. 78% solid tumors, 19% heme cancers. 12.5% required hospitalization for C19. Median number of days between positive C19 test and PRO completion was 17 days. Mean overall health rating on EQ-5D-5L was 78.3 (SD 19.6), best being 100. Highest mean (M) severity symptoms on the MDASI-COVID were fatigue (M 3.45, SD 2.17), drowsiness (M 2.50, SD 2.89), sleep disturbance (M 2.44, SD 2.99), malaise (M 2.37, SD 3.05), and distress (M 2.27, SD 2.90). Most severe (≥ 7) symptoms) reported were fatigue (21.3% of pts), change in taste (14.8%), change in smell (14.4%), malaise (14.3%), sleep disturbance (14.3%), and drowsiness (14%). Internal consistency (Cronbach α) of the 27 symptom items was 0.957, of the 6 interference items was 0.937. Mean severity of the 27 symptom items was significantly correlated with overall EQ-5D-5L health rating (correlation = -0.45, P < 0.0005), demonstrating concurrent validity. Mean symptom severity and interference showed known-group validity between patients who required C19 hospitalization (symptom M 2.32, SD 2.09; interference M 3.29, SD 3.02) and those who did not (symptom M 1.69, SD 1.85; interference M 2.20, SD 2.64) (symptom P 0.007; interference P 0.004). Conclusions: We have validated a novel PRO, the MDASI-COVID, to quantify the combined symptom burden in patients with cancer and COVID-19. This measure allows longitudinal evaluation of COVID-19 on cancer symptom burden and provide clinicians with an accurate tool for ongoing symptom assessment and management. Longitudinal analysis on long-term symptoms related to COVID-19 and cancer are ongoing.

6510 Background: Most COVID-19 (C19) vaccine trials excluded patients with active cancer. Here, we report our real-world patient-reported and clinical outcomes of BNT162b2 mRNA C19 vaccine in patients with cancer. Methods: Our institutional Data-Driven Determinants for COVID-19 Oncology Discovery Effort (D3CODE) follows a longitudinal observational cohort of pts w cancer getting C19 vaccine. Pts complete a validated PRO tool, MD Anderson Symptom Inventory (MDASI, 13 core, 6 interference plus 17 items of symptoms from prior vaccine trials) pre-dose 1, then daily x 6d, then weekly, then on day of dose 2, then daily x 6d, then weekly x 3w. Demographics, cancer variables, prior immune checkpoint inhibitors (ICI), C19 status pre- & post-vaccine are aggregated via Syntropy platform: Palantir Foundry. Primary outcome is incidence of PRO symptoms bw dose 1 & 2 across AYA 15-39y, mid-age 40-64y & senior 65y+ cohorts. Secondary outcomes include PRO symptom incidence post-dose 2, post-vaccine change in cancer symptoms, post-vaccine symptom severity based on prior ICI, and confirmed C19 > 7 days post-dose 2. First planned 8-wk interim analysis is reported here. Results: 6388 pts w cancer (4973 w mets) received a BNT162b2 vaccine dose (4811 both doses, 1577 received one & await dose 2). Overall, median age 64y (range 16-95y); 382 AYAs, 2927 mid-age, 3079 seniors (65-70y n = 1158, 70-79y n = 1521, 80-89y n = 378, 90y+ n = 22). 4099 (64%) are White, 823 (13%) AA, 791 (12%) Hispanic, 441 (7%) Asians. Primary cancers: breast (1397), GU (821), heme (775), thoracic/HN (745), and CRC (385). Prior to dose 1, 1862 had no prior systemic tx while 4526 pts did including 3243 who had only non-IO tx (chemo, targeted tx), 1,283 had immunotherapy including 857 who had ICIs prior to dose 1. Patient-reported symptoms after C19 Vaccine: Of 6388 pts, 4714 (74% response rate, median age 67y, range 16-95y) completed 16485 PRO surveys. After 2 doses, seniors reported lower mean scores vs mid-age or AYAs on 22 of 36 symptoms including injection site pain, palpitations, itch, rash, malaise, fevers/chills, arthralgia, myalgia, headache, pain, fatigue, nausea, disturbed sleep, distress (p < 0.05). Pts w prior ICIs had higher severity of itch, rash (p < 0.05) from baseline after both dose 1 & 2 vs pts without systemic tx. Post dose 1, pts with prior ICI had higher increase in fatigue, malaise, itch, rash, myalgia, anorexia from their baseline vs pts without systemic tx (p < 0.05). C19 Outcomes: Of 6388 pts, 616 had a C19 test at any time post-dose 1: 23 (0.36%) tested positive of whom 20 (0.3%) were between dose 1 & 2; two (0.031%) were within 7 days post-dose 2, and one patient (0.016%) tested positive 16 days after dose 2, requiring admission. Conclusions: This real-world observational cohort demonstrates post-vaccine symptom burden and outcomes in patients with cancer. Second interim analysis is planned at 16 weeks.

11001 Background: Few studies have used comprehensive validated measures to investigate the incidence and impact of workplace sexual harassment experienced by physicians (and none, to our knowledge, by oncologists). Methods: We conducted a cross-sectional survey of ASCO’s Research Survey Pool with targeted social media outreach to examine the prevalence and types of sexual harassment (SH) experienced by oncologists. Using the Sexual Experiences Questionnaire (SEQ), we measured their work experience of three SH forms (gender harassment [GH], unwanted sexual attention [USA], sexual coercion [SC]) in the past year by institutional insiders (peers/superiors) and patients/families separately. Controlling for race, career stage & specialty, multivariable (MV) regression models assess the impact of SH (independent variable) on 4 dependent variables of mental health (MHI5), perceptions of workplace safety (single item), job satisfaction (MOAQ) & 3-item measure of turnover intentions (in non-trainees). Results: Of 271 respondents, 250 were physicians in practice and 21 were residents/fellows; 153 (56%] were women, 168 (62%) practiced in academic settings & 227 (84%) were medical oncologists. SH by peers/superiors was reported by 189 (70%) overall, including 80% of women and 56% of men (p

TPS12136 Background: Patients w advanced cancer participating in Phase I trials carry a high symptom burden from cancer and prior therapies. Our prior work shows patients on phase I trials w multiple active symptoms impacting their immediate quality of life with implications on toxicities and clinical outcomes on subsequent therapy. To identify an effective scalable approach to comprehensive symptom management for patients w adv cancer on phase I trials, we leveraged the increased technology use to design a technology-enhanced symptom management and palliative care intervention (TEC). Methods: Patients w adv cancer seen in the phase I clinic will be given the Edmonton Symptom Assessment System (ESAS), a validated patient-reported outcomes (PRO) tool of common cancer symptoms to identify those with a high symptom burden defined as ≥4 out of 10 on >1 ESAS symptom and a Global Distress Score (GDS) of ≥20. The GDS, a validated score of overall symptom intensity derived from the ESAS, is comprised of 6 physical (pain, fatigue, nausea, drowsiness, appetite, shortness of breath) & 2 psychosocial symptoms (depression, anxiety), and overall wellbeing. TEC is an innovative patient-centered care program of strategic vigorous symptom management where standard-of-care clinic visits are complemented by proactive symptom monitoring between clinic visits remotely and through provider-initiated calls. In this pilot randomized study, we will determine the effect sizes of High-Intensity TEC (HI-TEC; q3day remote PRO assessments w preset provider-initiated call bw visits), Low-Intensity TEC (LO-TEC; q5day remote PRO assessments w preset provider-initiated call bw visits), and Standard Palliative Care (no preset provider contact bw visits). Our guiding hypothesis is that a comprehensive, proactive, technology-enhanced symptom management program led by a Palliative Care team can mitigate the high symptom burden of patients with advanced cancers enrolling in phase I trials. The primary objective assesses the effect size of each TEC intervention on the GDS measure of symptom burden prior to C1D1 on phase I trial. Our working hypothesis is that HI-TEC and LO-TEC will be associated with a lower overall symptom burden signifying symptom optimization prior to starting on a phase I trial. Secondary objectives aim to estimate the effect size of TEC on the following: Symptom burden over 12 weeks on a phase I trial using ESAS, quality of life using FACIT-Sp, PRO-CTCAE and patient satisfaction using FAMCARE-P13. clinical outcomes at 6 months including OS, treatment outcomes (interruptions, dose reductions, discontinuation, time on trial) and quality metrics for end-of-life (EOL) (chemotherapy in the last 14 days of life, ICU admit in last 30 days of life, death without hospice or < 3d of hospice). Qualitatively assessment of patients’ + caregivers’ perceptions of receiving TEC-based cancer care. Clinical trial information: NCI-2020-07465.

e24129 Background: Few studies have examined the coping mechanisms among patients with advanced cancer seen by palliative care. The objective of the study was to evaluate coping strategies in advanced cancer patients and identity risk factors for maladaptive coping. Methods: The authors conducted a secondary analysis of a cross-sectional survey on chemical coping. We prospectively enrolled patients with advanced cancer from a Supportive Care Clinic and documented the patient demographics, symptom expression (Edmonton Symptom Assessment System), Zubrod performance status, substance use history including tobacco, and coping strategies (the Brief COPE Questionnaire). Univariate and multivariate analyses were performed to identify risk factors for the use of maladaptive coping strategies. Results: Among 399 patients, the most common malignancies were gastrointestinal (21%) and breast (19%). Cancer patients frequently incorporated adaptive coping strategies including acceptance (86.7%), emotional support (79.9%), religion (69.4%), active coping (62.4%), instrumental support (48.4%), positive reframing (48.6%), planning (49.6%), and infrequently, humor (18.5%). Common maladaptive strategies included self-distraction (36.6%) and venting (14.5%), while self-blame (6.3%), denial (4.5%), behavioral disengagement (1.8%), and substance use (1.0%) were infrequently reported. On univariate analysis, venting was significantly associated with anxiety and depression, female gender, and tobacco use; and self-distraction was significantly associated with younger age, gender, depression, dyspnea, and a post-secondary education (P

Patients ≥65 years with cancer remain underrepresented in clinical trials, particularly in phase I clinical trials. We analyzed the clinical course of patients ≥65 years treated on phase I clinical trials with particular emphasis on toxicities. We identified 347 consecutive patients ≥65 years with advanced cancer in our phase I clinic from 01/2004-12/2009 and analyzed disease characteristics, toxicities, survival and response. Overall, 251 patients received a targeted agent, of whom 241 (96%) received an investigational, non-FDA-approved drug. Clinical benefit (complete response + partial response + stable disease ≥ 6 months) was noted in 61 patients (18%). Eighty-nine patients (26%) had grade 3/4 toxicity, commonly hematologic, including 6 dose-limiting toxicities and 1 treatment-related death ( 1, prior radiation, ≥5 prior treatments; p 1, thrombocytosis, >2 metastatic sites, and elevated lactate dehydrogenase (p

The use of artificial intelligence (AI) has become an integral part of patient care, but there are concerns about the impact of non-human decision assistance on patient outcomes. This commentary focuses on how AI can assist oncologists and benefit patients.

12044 Background: While safety and dose-finding remain the primary objective of Phase 1 trials, the potential for clinical benefit has taken a greater meaning in the last decade with the novel therapies. With data from phase I trials being submitted for regulatory approval, the finer details of these studies are under even more scrutiny: in particular, do the trial participants reflect the general patient population for whom the drug may be indicated? To that end, we investigated age-based enrollment on phase I clinical trials over time. Methods: We queried a prospectively maintained database at a major phase I trials center to identify eligible patients and demographic + clinical variables including phase I trial characteristics, age at date of enrollment into 3 age-based cohorts: AYA ages 15-39y, mid-age 40-64y, older adults aged 65y+. We calculated descriptive statistics, and explored correlations (Pearson/Spearman) and associations (linear regression) between age and independent variables. Results: Over a 3-year period (1/1/17 to 12/31/19), we identified 6267 pts enrolled on 338 phase I trials. Median overall age 58.4y (range 15.5-95.1y). 729 (12%, median age 34.8y) were AYA, 3652 (58%, median age 55.4y) mid-age and 1886 (30%, median 70y) older adults, of whom 870 pts were aged 70-79y and 76 pts aged 80y+ (18 being >85y). There was no association b/w senior participation and year of enrollment (2017 31%, 2018 29%, 2019 30%, b/w age and type of therapy (i.e. targeted vs immunotherapy, etc.) or b/w age and # of drugs given on trial (single agent vs combo) (all p > 0.05). Conclusions: Older adults remain underrepresented on phase I trials esp. when compared to incidence of cancer in that age group (30% enrollment vs 60% incidence), a discordance more staggering in the oldest old pts (85y+; only 18 pts enrolled over 3 yrs when compared to 140,690 pts 85y+ w a new cancer dx in just 2019). Once enrolled, older adults received similar types of phase I therapies with comparable number of drugs as compared to middle age patients, i.e. older adults were just as likely to get immunotherapy or targeted therapy as well mono- vs combo therapy as mid-age pts. [Table: see text]

e24147 Background: Early referral to palliative care (PC) for patients w/ adv cancer is supported by compelling evidence from large RCTs demonstrating a lower symptom burden, higher QOL, and increased OS. However, these studies reflect pts who have self-selected to accept a PC referral and attend a PC visit. WHO/NCCN/ASCO guidelines support early integration of PC. We sought to characterize the referral patterns in our heme/onc practice to identify and mitigate the barriers to early PC adoption in the community setting. We began a concerted effort to discuss early PC referral w/ pts recently diagnosed w/ adv cancer at the time systemic therapy was initiated. Methods: To ensure real-world applicability of this study, we identified a large satellite clinic of a major academic center w/ access to PC on the main campus (located 20 miles from the satellite clinic). We retrospectively reviewed new pts age 18y+ w/ adv cancer, characterized PC referrals and outcomes. Using qualitative methodology, we identified pt-reported barriers to accepting PC care. Results: 407 new pts were seen; 168 w/ benign heme, 145 w/ early cancers, 94 w/ adv cancers. Of the 94 pts w/ adv cancers, 25 pts had one-time 2ndopinion visits, and 16 pts were not candidates for, or did not desire cancer treatment and directly enrolled on hospice. Our analysis cohort consisted of 53 pts w/ adv cancer pursuing life prolonging therapy. At initiation of treatment, 57 % (n=30) were not offered a PC referral, 22% (n=12) received a PC referral and attended the appt, however 21% (n=11) received a PC referral but did not attend the appt. A qualitative analysis of the 11 patients referred to early PC who did not attend the appt revealed; 5 patients scheduled an appt but did not attend (3-unknown reason, 2-hospitalized during appt, 1-lack of transportation), 2 pts were unreachable, and 4 pts were contacted but declined to schedule stating: “I feel pressured” “I want to hear what other treatment options I have” “I want to be treated first and then see if I need it” "I am overwhelmed with too many new doctors and visits". Conclusions: Despite the benefit of early PC referral in pts w/ adv cancer, we identified a considerable gap in its adoption in our community practice despite access to proximate PC clinic. Further studies are under design to address institutional and pt-related factors to improve real-world adoption of this critical service.

12021 Background: Despite compelling data supporting their use, patient reported outcomes (PROs) are not widely integrated into routine cancer care. In our Palliative Care (PC) practice, all patients complete the Edmonton Symptom Assessment Scale (ESAS), a simple, validated 10-item PRO tool which uses a 0 to 10 rating of 10 common symptoms (pain, fatigue, nausea, drowsiness, appetite, sleep, dyspnea, well-being, anxiety & depression). Our team has previously validated the Global Distress Score (GDS), a sum of 9 physical + psychosocial ESAS items. Here, we studied the implementation of the GDS as a streamlined way to capture the overall symptom burden while providing prognostic value. Methods: We queried a PC database for patients w metastatic cancer at time of 1st PC visit. GDS was calculated & grouped into 3 cohorts based on previous work & clinical experience: high (GDS of 35+), Moderate (16-34) or Low (0-15). Overall Survival was defined as time from 1st PC visit date to death. Regression analysis, ANOVA and t-tests were conducted. Results: 333 patients met the inclusion criteria: median age 62.4y (range 20.5-88.4y), 25 AYA (15-39y), 169 mid age (35-64y), 140 seniors (65y+); 190 female 143 male; median prior therapies 2 (range 0-11), 227 patients were in 2nd line + above therapy. Median ECOG PS 2; 124 patients w ECOG PS 3 & 33 w ECOG PS 4. 262 patients had died at time of analysis. Lower OS was associated w higher GDS (r 0.21, P < 0.001). OS in Low, Mod, High GDS cohorts was 13.1m, 7.9m, & 3.7m, respectively (p < 0.001). There were no sig OS difference between 3 age cohorts (AYA 5.2m, mid age 6m, seniors 5.4m, p0.56). Conclusions: Higher GDS score was associated with a clinically significant decrease in overall survival highlighting the potential of the ESAS as a PRO tool in prognostication and clinical decision making for patients with advanced cancers with a high symptom burden. In the realm of increasingly complex PRO instruments, the ESAS represents a simple, well-validated tool which, in our studies and 25 years of clinical experience, takes the patient less than a minute to complete, with subscores such as the GDS which carry a highly prognostic utility for patients with advanced cancers.

In-frame fusion KIF5B (the-kinesin-family-5B-gene)-RET transcripts have been characterized in 1-2% of non-small cell lung cancers and are known oncogenic drivers. The RET tyrosine kinase inhibitor, vandetanib, suppresses fusion-induced, anchorage-independent growth activity. In vitro studies have shown that vandetanib is a high-affinity substrate of breast cancer resistance protein (Bcrp1/Abcg2) but is not transported by P-glycoprotein (P-gp), limiting its blood-brain barrier penetration. A co-administration strategy to enhance the brain accumulation of vandetanib by modulating P-gp/Abcb1- and Bcrp1/Abcg2-mediated efflux with mTOR inhibitors, specifically everolimus, was shown to increase the blood-brain barrier penetration. We report the first bench-to-bedside evidence that RET inhibitor combined with an mTOR inhibitor is active against brain-metastatic RET-rearranged lung cancer and the first evidence of blood-brain barrier penetration. A 74-year-old female with progressive adenocarcinoma of the lung (wild-type EGFR and no ALK rearrangement) presented for therapy options. A deletion of 5'RET was revealed by FISH assay, indicating RET-gene rearrangement. Because of progressive disease in the brain, she was enrolled in a clinical trial with vandetanib and everolimus (NCT01582191). Comprehensive genomic profiling revealed fusion of KIF5B (the-kinesin-family-5B-gene) and RET, in addition to AKT2 gene amplification. After two cycles of therapy a repeat MRI brain showed a decrease in the intracranial disease burden and PET/CT showed systemic response as well. Interestingly, AKT2 amplification seen is a critical component of the PI3K/mTOR pathway, alterations of which has been associated with both de novo and acquired resistance to targeted therapy. The addition of everolimus may have both overcome the AKT2 amplification to produce a response in addition to its direct effects on the RET gene. Our case report forms the first evidence of blood-brain barrier penetration by vandetanib in combination with everolimus. Further research is required in this setting.

Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 455, Houston, TX77030, USA Division of Pediatrics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 455, Houston, TX 77030, USA *Author for correspondence: vsubbiah@mdanderson.org part of

Background: We sought to develop a prognostic scoring system to aid in patient selection for immune checkpoint inhibitor (ICI) phase 1 clinical trials. Methods: Clinical data from patients treated in phase 1 ICI clinical trials at MD Anderson (MDA) Center were analysed. Seventeen clinical factors were studied. Recursive partitioning analysis, a tree-based model, was used to develop a regression tree and identify optimal cut-points based on differences in survival for each clinical factor. A Cox proportional hazards regression model was then used to identify factors independently affecting overall survival. A prognostic scoring system was subsequently developed. Results: A total of 172 patients (105 CTLA4- and 67 PD1-based) were analysed. Seven factors were independently associated with worse overall survival (OS): age>52 years (hazard ratio (HR) 1.59, 95% confidence interval (CI) 1.1–2.4), Eastern Cooperative Oncology Group performance status>1 (HR 2.81, 95%CI 1.3–6.3), lactate dehydrogenase >466 (which is 0.75 × the upper limit of normal at our institution) (HR 2.1, 95% CI 1.4–3.2), platelet count >300 × 103 μL−1 (HR 1.8, 95% CI 1.2–2.8), absolute neutrophil count >4.9 × 103 μL−1 (HR 2.3, 95% CI 1.5–3.5), absolute lymphocyte count

Background: Despite the rising incidence of sarcoma in the geriatric population, there is a paucity of older adults enrolled on clinical trials. Whether older sarcoma patients treated on early phase clinical trials have any meaningful differences in clinical benefit or survival outcomes compared to younger patients remains unknown. Methods: We analyzed clinical and next generation sequencing data from sarcoma patients treated on phase 1 trials at MD Anderson Cancer Center (MDACC) and performed logistic and Cox proportional hazards regression analyses to compare response rate (RR), median time to progression (mTTP), clinical benefit rate (CBR; defined as CR, PR, or SD > 6 months), and median overall survival (mOS) between patients younger and older than 65 years of age. Results: Among the 406 patients with advanced sarcomas (321 soft tissue sarcoma, 85 bone sarcomas) treated on phase 1 trials at MDACC from May 2006 to May 2018, median age was 53 (range 11-84), 48% were female, and patients had a median 3 prior lines of therapy (range 0-9). The most commonly treated soft tissue sarcoma subtypes included leiomyosarcoma (n=66; 16%), liposarcoma (n=52; 13%), GIST (n=44; 11%), UPS (n=14; 3%), and synovial sarcoma (n=11; 3%) and most commonly treated bone sarcomas included osteosarcoma (n=34; 8%), chondrosarcoma (n=28; 7%), and Ewing’s sarcoma (n=25; 6%). 25% (n=102) of sarcoma patients treated on phase 1 protocols were age 65 or older. RR in patients younger than 65 years was 7% compared to 8% in those 65 or older, odds ratio 1.21 (95% CI 0.52, 2.83), p=0.66. mTTP for patients younger than 65 was 2.7 months compared to 3.7 months in those 65 or older, hazard ratio 0.90 (95% CI 0.72, 1.14), p=0.39. CBR in patients younger than 65 years was 22% compared to 31% in those 65 or older, odds ratio 1.65 (95% CI 1.00, 2.72), p=0.05. mOS in patients younger than 65 years was 16.1 months compared to 20.0 months in those 65 years or older, hazard ratio 1.08 (95% CI 0.80, 1.46), p=0.61. Conclusion: Heavily pretreated, metastatic sarcoma patients aged 65 or older enrolled on phase 1 studies at MDACC had no significant differences in response rate, time to progression, and overall survival compared to their younger counterparts. In fact, older sarcoma patients demonstrated an improved clinical benefit rate compared to younger patients. Older patients should be encouraged to enroll on early phase clinical trials when clinically appropriate and broad eligibility criteria for such studies are needed to ensure older sarcoma patients are not excluded from these trials. Citation Format: Shiraj Sen, Roberto C. Pestana, Kenneth Hess, David S. Hong, Ishwaria M. Subbiah, Anthony Conley, Gerald S. Falchook, Robert S. Benjamin, Shreyas Patel, Funda Meric-Bernstam, Vivek Subbiah. Outcomes of geriatric sarcoma patients enrolled in phase 1 clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3997.

Objective: The aim of this study was to determine the genomic alterations of cancer-related genes in advanced medullary thyroid carcinoma during the course of clinical care. Methods: Hybrid-capture-based comprehensive genomic profiling was performed on 34 consecutive medullary thyroid carcinoma cases to identify all four classes of genomic alterations, and outcome for an index patient was collected. Results:RET was mutated in 88% (30/34) of cases, with RET M918T being responsible for 70% (21/30) of the RET alterations. The other RET alterations were RET E632_L633del, C634R, C620R, C618G/R/S, V804M, and RET amplification. Two of the four RET wild-type patients harbored mutations in KRAS or HRAS (1/34 each). The next most frequent genomic alterations were amplifications of CCND1, FGF3, and FGF19 and alterations in CDKN2A (3/34 each). One case with a RET M918T mutation developed acquired resistance to progressively dose-escalated vandetanib. When the mTOR inhibitor everolimus was added to continued vandetanib treatment, the patient achieved a second 25% reduction of tumor volume (RECIST 1.1) for 8 months. Conclusions: Comprehensive genomic profiling identified the full breadth of RET alterations in metastatic medullary thyroid carcinoma and possible cooperating oncogenic driver alterations. This approach may refine the use of targeted therapy for these patients.

e18714Background: Patients with cancer aged 15-39 years, the Adolescent and Young Adults (AYA), are significantly underrepresented on late phase clinical trials overall particularly in comparison t...

9035Background: RET fusions (RET+) occur in 1-2% of NSCLCs. Tumors eventually become refractory to multi-kinase RET inhibitor monotherapy. We evaluated the pre-clinical and clinical activity of the...

e15066Background: Patients with advanced cancers are referred to early phase clinical trials after progression on standard-of-care regimens. However early phase I/II trials tend to have stringent e...

152 Background: Older adults (65y+) with cancer are underrepresented in trials of novel drugs notably in phase I clinical trials with immunotherapies. The trepidation over immune-related toxicities in the context of older age and associated comorbidities may function as a barrier to participation. To that end, we investigated the enrollment and incidence of immune related adverse events of older adults enrolled in phase 1 immunotherapy trials. Methods: We identified 422 consecutive pts w advanced cancer treated on immunotherapy-based phase I trials bw 04/2009-09/2015, and collected pt/disease characteristics and immune-related adverse events (irAE) such as endocrinopathies, diarrhea/colitis, pneumonitis, constitutional (fatigue, fever, anorexia), myalgia, and dermatitis. Results: Older adults comprised 27% of trial participants (116 of 422 pts, median age 70y) while 256 pts were mid age (61%, median 56y). Most common cancers were GI (n = 108, 26%), thoracic/head/neck (n = 84, 20%), GU (n = 54, 13%), and GYN (n = 47, 11%). Median PFS was comparable among older pts (2.4m) and mid age (2.1m). Older adults had a higher incidence of irAE than mid age (low grade [G1/2] 49% vs 34%, p 0.02; high grade [G3/4] 19% vs 11%. p 0.14). The odds ratio of high grade events among older adults vs mid age pts was 1.81 (95% CI 1.01, 3.24; p 0.05) and low grade events was 1.85 (95% CI 1.20, 2.85; p 0.0055). Most common G1/2 irAE among all patients was fatigue (n = 76, 18%), dermatitis (n = 59, 14%), fever (n = 29, 7%) and anorexia (n = 28, 7%) with older adults having a greater incidence of low grade fatigue (25% vs 15%, OR 1.84, 95% CI 1.09, 3.10, p 0.025). Conclusions: Older adult participation remained under 30% for immunotherapy-based phase I trials. This early analysis suggests a higher incidence of toxicities among older adults, which calls for the urgent integration of comprehensive supportive care strategy to guide seniors through therapy. This work lays the foundation for future studies investigating the early involvement of supportive care through treatment on early phase clinical trials with immunotherapeutic agents.

Purpose Several indices have been developed to predict overall survival (OS) in patients with breast cancer with brain metastases, including the breast graded prognostic assessment (breast-GPA), comprising age, tumor subtype, and Karnofsky performance score. However, number of brain metastases—a highly relevant clinical variable—is less often incorporated into the final model. We sought to validate the existing breast-GPA in an independent larger cohort and refine it integrating number of brain metastases. Patients and Methods Data were retrospectively gathered from a prospectively maintained institutional database. Patients with newly diagnosed brain metastases from 1996 to 2013 were identified. After validating the breast-GPA, multivariable Cox regression and recursive partitioning analysis led to the development of the modified breast-GPA. The performances of the breast-GPA and modified breast-GPA were compared using the concordance index. Results In our cohort of 1,552 patients, the breast-GPA was validated as a prognostic tool for OS (P < .001). In multivariable analysis of the breast-GPA and number of brain metastases (> three v ≤ three), both were independent predictors of OS. We therefore developed the modified breast-GPA integrating a fourth clinical parameter. Recursive partitioning analysis reinforced the prognostic significance of these four factors. Concordance indices were 0.78 (95% CI, 0.77 to 0.80) and 0.84 (95% CI, 0.83 to 0.85) for the breast-GPA and modified breast-GPA, respectively (P < .001). Conclusion The modified breast-GPA incorporates four simple clinical parameters of high prognostic significance. This index has an immediate role in the clinic as a formative part of the clinician's discussion of prognosis and direction of care and as a potential patient selection tool for clinical trials.

Recurrent, metastatic mesenchymal myxoid tumors of the gynecologic tract present a management challenge as there is minimal evidence to guide systemic therapy. Such tumors also present a diagnostic dilemma, as myxoid features are observed in leiomyosarcomas, inflammatory myofibroblastic tumors (IMT), and mesenchymal myxoid tumors. Comprehensive genomic profiling was performed in the course of clinical care on a case of a recurrent, metastatic myxoid uterine malignancy (initially diagnosed as smooth muscle tumor of uncertain malignant potential (STUMP)), to guide identify targeted therapeutic options. To our knowledge, this case represents the first report of clinical response to targeted therapy in a tumor harboring a DCTN1-ALK fusion protein. Hybridization capture of 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer was applied to >50 ng of DNA extracted from this sample and sequenced to high, uniform coverage. Therapy was given in the context of a phase I clinical trial ClinicalTrials.gov Identifier: ( NCT01548144 ). Immunostains showed diffuse positivity for ALK1 expression and comprehensive genomic profiling identified an in frame DCTN1-ALK gene fusion. The diagnosis of STUMP was revised to that of an IMT with myxoid features. The patient was enrolled in a clinical trial and treated with an anaplastic lymphoma kinase (ALK) inhibitor (crizotinib/Xalkori®) and a multikinase VEGF inhibitor (pazopanib/Votrient®). The patient experienced an ongoing partial response (6+ months) by response evaluation criteria in solid tumors (RECIST) 1.1 criteria. For myxoid tumors of the gynecologic tract, comprehensive genomic profiling can identify clinical relevant genomic alterations that both direct treatment targeted therapy and help discriminate between similar diagnostic entities.

10034 Background: Senior adults ≥ 65 yrs remain underrepresented in early phase clinical trials in particular trials with novel immunotherapies. One general limitation to enrollment is the concern for immune-related toxicities in the context of older age and comorbidities. We analyzed the enrollment and incidence of toxicities of seniors in comparison to mid age and adolescent/young adult (AYA) pts enrolled in phase 1 immunotherapy trials. Methods: We identified 422 consecutive pts w advanced cancer treated on immunotherapy-based phase I trials bw 04/2009-09/2015. We divided pts into 3 cohorts based on age at start of trial (AYA 15-39y, mid age 40-64y, seniors 65y+) and collected pt/disease characteristics and immune-related adverse events (irAE) including endocrinopathies, diarrhea/colitis, pneumonitis, constitutional (eg fatigue, fever, anorexia), myalgia, and dermatitis. Results: Of 422 patients treated, 116 were seniors (27%, median 70y), 50 AYA (12%, median 30y), 256 mid age (61%, median 56y). Most common cancers were GI (n = 108, 26%), thoracic/head/neck (n = 84, 20%), GU (n = 54, 13%), and GYN (n = 47, 11%). Median PFS was comparable in all 3 cohorts (2.4m seniors, 2.1m AYA, 2.1m mid age). The incidence of irAE was higher in elderly than mid age or AYA (low grade [G1/2] 49% vs 34% vs 34%, p 0.02; high grade [G3/4] 19% vs 11% vs 12%. p 0.14). When comparing irAE rates of seniors to AYA and mid age pts, the odds ratio of high grade events was 1.81 (95% CI 1.01, 3.24; p 0.05) and low grade events was 1.85 (95% CI 1.20, 2.85; p 0.0055). Most common G1/2 irAE among all cohorts was fatigue (n = 76, 18%), dermatitis (n = 59, 14%), fever (n = 29, 7%) and anorexia (n = 28, 7%) with seniors having a greater incidence of low grade fatigue (25% vs 15%, OR 1.84, 95% CI 1.09, 3.10, p 0.025). Conclusions: Senior adults accounted for < 1/3 of pts on immunotherapy-based phase I trials. When compared to mid age and AYA pts, seniors had a higher likelihood of experiencing a toxicity. Early phase immunotherapy trials may be an option for older adults but with a particular vigilance for adverse events in this population.

Objective: Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare variant of HCC. We report an analysis of the clinicopathologic features, treatment outcomes, and prognostic indicators of 94 cases. Methods: We retrospectively collected clinicopathologic and treatment outcome data from 94 FLHCC patients (48 males and 46 females). Median overall survival (OS) and recurrence-free survival (RFS) were calculated using Kaplan-Meier curves, and survival rates were compared by the log-rank test. The Cox proportional hazard model was used for univariate and multivariate estimation of hazard risk ratios and 95% confidence intervals (CI) for factors that correlated with survival and disease recurrence after resection. Results: Median age was 23 years (14-75); median OS was 57.2 months (95% CI, 36.4-77.9), and median RFS was 13.9 months (95% CI, 8.8-18.9). White race, female gender, early tumor stage, and tumor resection including metastasectomy were positively associated with longer OS, while female gender was the only significant positive predictor of longer RFS. Finally, the 5-fluorouracil-interferon combination was the most frequently used systemic therapy. Conclusions: Our analyses indicate that surgical approaches including metastasectomy as the first-line treatment in FLHCC correlated with better outcome. Multimodality approaches, including neoadjuvant and adjuvant therapies, prolonged patient survival.

9073Background: RET gene aberrations have been identified in several types of cancer, including lung, thyroid, colon and breast cancers. Inhibition of RET signaling in preclinical tumor models using vandetanib (VAN), a TKI that targets VEGFR2/EGFR and RET, in combination with everolimus (EV), an mTOR inhibitor, was found to overcome intrinsic and /or acquired tumor resistance to either agent alone, suggesting the combined therapy warrants investigation in patients. Methods: A “3+3” dose escalation and expansion trial was designed to determine the safety, maximum tolerated dose , recommended Phase II dose (RP2D), dose-limiting toxicities (DLTs) and activity of VAN+EV in advanced/refractory solid tumors. Tumor responses were assessed by RECIST. The molecular correlates of clinical response were analyzed by next generation sequencing (NGS) and/or FISH if available. Results: Among the 96 pts treated to date, median age was 56 years (18-82 yrs) and 43 pts (45%) were male. Most common diagnoses were sarcoma (20...

10049Background: Older adults (aged 65 and above) with advanced cancers are underrepresented in clinical trials particularly early phase clinical trials. To assess their participation and clinical ...

Liver metastases in patients with cancer are associated with poor survival. We hypothesized that hepatic arterial infusion (HAI) of oxaliplatin combination therapy would have antitumor activity in these patients.Patients with advanced cancer and predominant liver metastases were treated on a phase I study of HAI oxaliplatin in combination with systemic bevacizumab, with or without HAI or systemic fluorouracil and/or leucovorin and/or cetuximab. Patients were divided into two treatment arms according to KRAS mutational status and physician choice. A "3 + 3" design was used.Among 76 patients (median age 61 years; 34 women; median number of prior therapies 4), the most common cancer was colorectal (CRC) (n = 58). Overall, the only dose-limiting toxicity was Grade 3 diarrhea (n = 2). The most common treatment-related toxicities were hypertension (n = 40), nausea (n = 29), fatigue (n = 28), and transaminitis (n = 26). Of 76 patients, one (1 %) had a complete response (CR), 12 (16 %) had a partial response (PR), and 12 (16 %) had SD for ≥ 6 months (total CR/PR/SD ≥ 6 months 25/76 = 33 %). In CRC (n = 58), total CR/PR/SD ≥ 6 months was 31 % (n = 18). Both patients with pancreatic neuroendocrine tumors achieved a PR (24+ months) and a CR (6+ months). Time to treatment failure (TTF) on the current regimen was 3.5 versus 2.8 months on patients' prior systemic treatment (p = 0.37).HAI oxaliplatin combination therapy with 5-fluorouracil, leucovorin, bevacizumab, and/or cetuximab was well tolerated and had antitumor activity in selected heavily pretreated patients with predominant liver disease.

Background: RET gene aberrations including fusions have been identified across several types of solid malignancies, including lung adenocarcinomas, thyroid, colorectal and invasive breast cancers. Preclinical models has shown that the combination of vandetanib (VAN), a multi tyrosine kinase inhibitor of VEGFR2/EGFR and RET pathways) and everolimus (EV), an mTOR pathway inhibitor, overcomes intrinsic and /or acquired tumor resistance to either agent alone, suggesting a rationale for investigating this combination in cancer patients, including those harboring aberrations in the drug targets. Methods: We designed a dose escalation and expansion trial with “3+3” design to determine the safety, maximum tolerated dose (MTD), recommended Phase II dose (RP2D), dose-limiting toxicities (DLTs) and activity of the combination. During the escalation phase, the study drugs (VAN, EV) were given at the following doses, respectively: level 0 (100 mg, 2.5 mg), level 1 (200mg, 2.5mg), level 2 (200mg, 5mg), level 3 (300 mg, 5mg), and level 4 (300mg, 10mg). Both study drugs are given continuously on a 28 day schedule. Tumor responses are assessed using RECIST v1.1. Tumor molecular aberrations were detected by Next Generation Sequencing (NSG) and/or Fluorescence In Situ Hybridization (FISH). Results: To date, 72 adult patients have been treated. Median age was 56 years (range 18-82 years) and 38 patients (53%) were male. The most common diagnoses were sarcoma (n = 15); renal cell carcinoma (n = 11); thyroid cancer (n = 10; n = 3 medullary) lung cancer (n = 10). Thirty patients (41%) had 3 or more sites of metastases. Nine patients were treated at dose level 0 (VAN 100 mg daily + EV 2.5 mg daily), five at dose level 1 (VAN 200 mg daily + EV 2.5 mg daily), and 6 patients at dose level 4 (highest dose VAN 300 mg daily + EV 10 mg daily). The most common adverse events observed in patients across different dose levels included G1 rash (n = 10), G1-G3 diarrhea (n = 21); G1-G4 thrombocytopenia (n = 9); G1-G2 hypertriglyceridemia/hypercholesterolemia (n = 8); G1-G2 hypertension (n = 6), G1-G2 QTc prolongation (n = 4); G1-G transaminitis (n = 4). Dose escalation has been completed and the expansion phase is currently ongoing in patients with advanced malignancies harboring RET, or P13K, PIK3R1, TSC1/2 and AKT genomic aberrations. The best responses were PR (n = 7), and SD (n = 33). Ten patients with reported SD (30.3%) experienced durable responses (> 6 months). One RET M918T mutant medullary thyroid cancer patient, who developed acquired resistance to VAN, achieved a 25% reduction on this combination. Three NSCLC patients with RET fusions (100%) responded with one reaching 48% decrease per RECIST. In addition there was evidence of blood-brain barrier penetration in 2 patients with RET fusion patients who had brain metastases. Conclusions: The combination of VAN and EV was reasonably well tolerated at the highest doses of each of the drugs. Evidence of response was noted in heavily pre-treated patients with refractory solid tumors and targetable genomic aberrations specifically RET. The combination has CNS penetration in RET fusion NSCLC. Citation Format: Tina Cascone, Kenneth R. Hess, Sarina Piha-Paul, David S. Hong, Michael Roxas, Ishwaria M. Subbiah, Siquing Fu, Aung Naing, Filip Janku, Daniel Karp, Steven I. Sherman, Funda Meric-Bernstam, John V. Heymach, Vivek Subbiah. A phase I study of everolimus (mTOR inhibitor) in combination with vandetanib (multikinase inhibitor of VEGFR, EGFR, and RET) in advanced solid tumors including molecularly matched aberrations. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C17.

Background. Vascular-disrupting agents (VDAs) represent a new class of chemotherapeutic agent that targets the existing vasculature in solid tumors. Preclinical and early-phase trials have demonstrated the promising therapeutic benefits of VDAs but have also uncovered a distinctive toxicity profile highlighted by cardiovascular events. Methods. We reviewed all preclinical and prospective phase I–III clinical trials published up to August 2010 in MEDLINE and the American Association of Cancer Research and American Society of Clinical Oncology meeting abstracts of small-molecule VDAs, including combretastatin A4 phosphate (CA4P), combretastatin A1 phosphate (CA1P), MPC-6827, ZD6126, AVE8062, and ASA404. Results. Phase I and II studies of CA1P, ASA404, MPC-6827, and CA4P all reported cardiovascular toxicities, with the most common cardiac events being National Cancer Institute Common Toxicity Criteria (version 3) grade 1–3 hypertension, tachyarrhythmias and bradyarrhythmias, atrial fibrillation, and myocardial infarction. Cardiac events were dose-limiting toxicities in phase I trials with VDA monotherapy and combination therapy. Conclusions. Early-phase trials of VDAs have revealed a cardiovascular toxicity profile similar to that of their vascular-targeting counterparts, the angiogenesis inhibitors. As these agents are added to the mainstream chemotherapeutic arsenal, careful identification of baseline cardiovascular risk factors would seem to be a prudent strategy. Close collaboration with cardiology colleagues for early indicators of serious cardiac adverse events will likely minimize toxicity while optimizing the therapeutic potential of VDAs and ultimately enhancing patient outcomes.

Background: Patients with advanced carcinoma of unknown primary (CUP) have limited effective therapeutic options given the challenges of phenotypic and genotypic diversity. To identify future novel therapeutic strategies we conduct an ongoing exploratory analysis of next-generation sequencing (NGS) of relapsed, refractory CUP. Methods: We identified CUP patients referred to our phase I clinic with adequate FFPE sections from archival tissue for a targeted CLIA-certified NGS assay (Foundation One, MA). Over 2000 exons of 186 cancer-related genes plus over 30 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: Of 19 patients seen (10 male, 9 female; median age at diagnosis 49 years), 17 demonstrated genomic alterations (median 3 aberrations/tumor, range 0 - 10); two patients had no reportable genomic alterations. Of the 71 detected aberrations, 17 (24%) have been implicated in impaired cell cycle regulation and arrest; specifically in genes which encode the cyclin-dependent kinases (CDK12 Q570*, CDKN2A/B loss, CDKN2A p16INK4a loss and p14ARF exon 2-3 loss) or their associated proteins including amplification of CCND1 and CCNE1 (n = 3). Of these 8 patients with impaired cell cycle regulation, 5 (63%) demonstrated concurrent mutations associated with epigenetic deregulation and impaired DNA methylation, most commonly ARID1A Y1211fs*5 and S1929fs*25, which encodes the AT-rich interactive domain-containing protein 1A, Arid1a, a member of the SWI/SNF chromatin remodeling complex); other mutations observed are CREBBP S893L (encoding a ubiquitously expressed transcriptional coregulatory protein controlling chromatin remodeling via its histone acetyltransferase activity); MLL2 R4904* (encoding an H3K4-specific histone methyltransferase) and KDM6A S466* (encoding the histone H3 lysine 27 demethylase UTX). Overall 5 of 19 (26%) patients with advanced relapsed CUP demonstrated a profile of aberrations that concurrently impact cell cycle arrest and epigenetic regulation. Conclusion: Through NGS-based molecular profiling, we can a subset of patients with advanced carcinoma of unknown primary with coexisting mutations leading to impaired cell cycle arrest and epigenetic deregulation, highlighting a therapeutic combination with a cell cycle inhibitor (such as Cdk4/6 inhibitors currently in clinical trial) and histone deacetylase inhibitors. Note: This abstract was not presented at the meeting. Citation Format: Ishwaria M. Subbiah, Gauri Varadhachary, Apostolia M. Tsimberidou, Jennifer J. Wheler, Vivek Subbiah, Filip Janku, Sinchita Roy Chowdhuri, Ralph Zinner, David S. Hong. Impaired cell cycle arrest with concurrent epigenetic deregulation identified through next generation sequencing in patients with advanced carcinoma of unknown primary: Implications for personalized medicine. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 604. doi:10.1158/1538-7445.AM2015-604

Background: Relapsed refractory colorectal adenocarcinoma (CRC) is evolving as a disease with distinct molecular subsets rather than a singular histology. Given the varied outcomes of CRC patients treated on clinical trials particularly with targeted therapies, we aimed to identify a molecular phenotype for future therapeutic targeting. Methods: We identified CRC patients referred to our Phase I clinic with adequate tissue for next generation sequencing (NGS) on a commercially available platform (FoundationOne, Boston, MA). Over 2000 exons of 186 cancer-related genes plus over 30 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: Overall, 60 relapsed CRC patients (31 male, 29 female; median age 55 years; 56 colon primary, 4 rectum primary). 48 (80%) patients had a mutation linked to aberrant Wnt pathway signaling (most commonly, APC 43 pts, 90%). Of these 48 patients, over half (n = 26, 54%) demonstrated a concurrent mutation affecting the PI3K cascade (PIK3CA in 12 patients [4 E545K, 3 Q546K, 2 E542K, 1 H1047Y, 1 E453K, 1 R38C]). Of these 26 pts with concurrent aberrant Wnt and PI3K pathways, 22 also demonstrated a concomitant MAPK pathway mutation (17 KRAS and 3 BRAF). Of the 60 CRC pts overall, 22 (37%) patients had coexisting aberrations linked to in all three (Wnt, PI3K, and MAPK) cascades. Conclusions: Concomitant mutations in three pathways (Wnt, MAPK, PI3K) implicated in cancer occur frequently in patients with advanced CRC, emphasizing the need for a combinatorial therapeutic strategy ideally targeting all three cascades. Note: This abstract was not presented at the meeting. Citation Format: Ishwaria M. Subbiah, Filip Janku, Apostolia M. Tsimberidou, Aung Naing, Vivek Subbiah, Jennifer J. Wheler, Ralph Zinner, Cathy Eng, Michael J. Overman, Scott Kopetz, David S. Hong. Concurrent aberrations in the Wnt, MAPK and PI3K pathways identified through next generation sequencing of relapsed refractory colorectal adenocarcinoma (CRC): Implications for future therapeutic trials. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4263. doi:10.1158/1538-7445.AM2015-4263

605 Background: Advanced relapsed colorectal adenocarcinoma (CRC) is emerging as a cancer not with a singular phenotype but rather as a multitude of ‘diseases’ subdivided based on its molecular genotype. Given the heterogeneity in outcomes of CRC patients on targeted therapy clinical trials, we sought to identify a unique molecular subset within this disease. Methods: To that end, we identified advanced CRC patients in our Phase I clinic on whom adequate tissue was available for next generation sequencing (NGS) on a commercially available platform (FoundationOne, Boston, MA). Over 2000 exons of 186 cancer-related genes plus over 30 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: We identified 51 patients with advanced relapsed CRC (26 male, 25 female; median age 54 years; 49 colonic primary lesion, 4 rectum primary). Overall, 44 (86%) harbored a mutation linked to aberrant Wnt pathway signaling (most commonly, APC 40 pts, 78%). Of these 44 patients, half (n=22, 50%) had ≥1 concurrent mutation affecting the PI3K/AKT/MTOR pathway, most commonly PIK3CA in 11 patients (4 E545K, 3 Q546K, 2 E542K, 1 H1047Y, 1 E453K). Furthermore, 20 of these 22 pts with both Wnt and PI3K pathway mutations also demonstrated a concomitant MAPK pathway abnormality, most commonly KRAS (n=16) and 3 BRAF (V600E, G466R, D594G). Overall 20 of 51 (39%) patients had coexisting mutations implicated in all three signaling pathways (Wnt, PI3K, and MAPK). Conclusions: Three prominent pathways linked to the continuum of development and progression of cancer (Wnt, MAPK, PI3K) occur frequently in concurrence in patients with advanced CRC, thereby highlighting the role for an innovative therapeutic combination targeting all three pathways.

Background: Carcinoma of unknown primary (CUP) represents a heterogeneous group of cancers without an identifiable primary disease site where staining for a vast array of immunohistochemical markers is undertaken to identify tumor lineage. Given rapid advances in characterizing cancer genomes, we sought to describe the molecular profiles of patients with advanced CUP treated with novel targeted therapies on phase I clinical trials to identify pathways of interest to drive future therapeutic strategies. Methods: Of patients with advanced malignancies seen in the Phase I clinic, we identified 16 CUP patients on whom adequate tissue was available to perform next-generation sequencing (NGS) from FFPE sections using a targeted NGS assay in a CLIA laboratory (Foundation One, MA). Over 2000 exons of 186 cancer-related genes plus over 30 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: Of 16 tumor specimen, 14 demonstrated genomic alterations with a median of 4 aberrations within each specimen (range 0 - 10, total of 69 alterations); two patients did not demonstrate any tested changes. All patients with detected mutations possessed an exclusive unique molecular profile of aberrations with no two patients demonstrating an identical panel of mutations. A total of 69 alterations were identified of which 18 (26%) led to aberrant cell signaling within the PI3K/AKT/MTOR (including 4 with PIK3CA mutations) or the MAPK signaling cascades, primarily KRAS mutations in 3 patients. Also noted were 13 (19%) alterations impairing cell cycle arrest most commonly affecting cyclin dependent kinases, 10 (14%) impacting epigenetic regulation and DNA methylation, 10 (14%) affecting known tumor suppressor genes including TP53 in 8 patients, and 10 (14%) unique alternations in transcriptional regulators. Conclusion: With thorough molecular profiling, we can identify the unique fingerprint of potential actionable aberrations in a subset of advanced CUP patients. Herein we identified activation of the PI3K/AKT/MTOR and RAS/RAF/MEK signaling pathways combined with impaired cell cycle arrest in 8 of 16 (50%) tested patients, suggesting that a combination of PI3K and MAPK cascade inhibitors in combination with a cell cycle inhibitor may be of therapeutic value to these patients. Further matching patients to these actionable aberrations is underway, thereby translating these therapeutic targets to the bedside with the development of novel targeted therapies. Note: This abstract was not presented at the meeting. Citation Format: Ishwaria M. Subbiah, Gauri Varadhachary, Apostolia M. Tsimberidou, Jennifer J. Wheler, Vivek Subbiah, Filip Janku, Sinchita Roy Chowdhury, Ralph Zinner, Funda Meric-Bernstam, David S. Hong. One size does not fit all: Fingerprinting advanced carcinoma of unknown primary through comprehensive profiling identifies aberrant activation of the PI3K and MAPK signaling cascades in concert with impaired cell cycle arrest. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4700. doi:10.1158/1538-7445.AM2014-4700

TPS2639 Background: Preclinical models have shown that concurrent inhibition of the mammalian target of rapamycin (mTOR) pathway signaling cooperates with epidermal growth factor (EGFR)/vascular en...

e22154 Background: Patients with advanced carcinoma of unknown primary (CUP) have limited effective therapeutic options given the challenges of phenotypic and genotypic diversity. To identify futur...

232 Background: Octreotide LAR (LAR) and E have well known anti-cancer effects in WD NETs. Preclinical data also show that inhibition of the insulin like growth factor receptor (IGF-1R) may sensitize NETs to mTOR inhibitors such as E. Methods: Patients (pts) with WD NETs, ECOG performance status ≤ 2 and adequate organ function were treated with LAR 20 mg IM q 21days (d), E 10 mg po daily and escalating doses of I iv q 21 d in 21 d cycles in cohorts of 6 until maximum tolerated dose (MTD). Recommended phase II dose (RP2D) was defined as dose level below MTD. An expansion cohort of 9 pts was planned at RP2D. Plasma samples for everolimus pharmacokinetics (PK), IGF, mTOR pathway pharmacodynamics (PD) in addition to paired tissue biopsies were obtained. Results: 19 pts with previously treated (median prior systemic therapy, 1, range 0-3) WDNET (4 pancreatic NET, 11 carcinoid, 4 unknown primary) were enrolled in this single institution study. Ten pts in dose escalation and 9 in expansion phases received a median of 8.5 cycles (range, 3-19+). Dose limiting toxicities (DLTs) were grade (g) 3 mucositis in 2 pts at 2nddose level of I 15 mg/m2 q 21 d. Most frequent adverse events (AEs) observed while on study were fatigue, hyperlipidemia, weight loss (74%), dysguesia (68%), hyperglycemia and mucositis (63%). Most common g3 AEs were fatigue (21%), mucositis, transaminitis and electrolyte disturbances (all 11%). Other g 3 AEs included anorexia, anemia, injury, retinal detachment, dehydration and thromboembolism. One g 4 AE of hyperglycemia was noted during the expansion phase. One pt with pancreatic NET had confirmed partial response and 17 had stable disease as best response. The median progression free survival was 34+ weeks. Conclusions: The RP2D of this combination is I 10 mg/m2, LAR 20 mg IM q 21 d, E 10 mg po daily. PK, PD and other correlative analyses are ongoing and will be presented at the meeting. Although adequate safety and a sign of activity were noted in this study, these will need to be reconciled with data from larger studies of anti-IGF-1R MoAb in NET and other cancers that have been disappointing. Clinical trial information: NCT01204476.