Search

Doublecortin like kinase 1 (DCLK1) plays a crucial role in several cancers including colon and pancreatic adenocarcinomas. However, its role in squamous cell carcinoma (SCC) remains unknown. To this end, we examined DCLK1 expression in head and neck SCC (HNSCC) and anal SCC (ASCC). We found that DCLK1 is elevated in patient SCC tissue, which correlated with cancer progression and poorer overall survival. Furthermore, DCLK1 expression is significantly elevated in human papilloma virus negative HNSCC, which are typically aggressive with poor responses to therapy. To understand the role of DCLK1 in tumorigenesis, we used specific shRNA to suppress DCLK1 expression. This significantly reduced tumor growth, spheroid formation, and migration of HNSCC cancer cells. To further the translational relevance of our studies, we sought to identify a selective DCLK1 inhibitor. Current attempts to target DCLK1 using pharmacologic approaches have relied on nonspecific suppression of DCLK1 kinase activity. Here, we demonstrate that DiFiD (3,5-bis [2,4-difluorobenzylidene]-4-piperidone) binds to DCLK1 with high selectivity. Moreover, DiFiD mediated suppression of DCLK1 led to G2/M arrest and apoptosis and significantly suppressed tumor growth of HNSCC xenografts and ASCC patient derived xenografts, supporting that DCLK1 is critical for SCC growth.

PURPOSE In the phase III KEYNOTE-181 study ( NCT02564263 ) of patients with advanced esophageal cancer (EC), pembrolizumab monotherapy prolonged overall survival versus chemotherapy as second-line therapy in patients with programmed death ligand 1 combined positive score (CPS) ≥ 10. We present the results of the prespecified health-related quality-of-life (HRQoL) analyses of the squamous cell carcinoma (SCC), CPS ≥ 10, and CPS ≥ 10 SCC populations. PATIENTS AND METHODS HRQoL was measured using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30), EORTC QLQ EC questionnaire (OES18), and EuroQol 5-dimension questionnaire (EQ-5D). Data were analyzed in patients who received ≥ 1 dose of study treatment and completed ≥ 1 HRQoL assessment. Key analyses included baseline to week 9 least squares mean change in global health status/quality of life, functional or symptom subscales, and time to deterioration (≥ 10-point deterioration) for specific subscales. RESULTS The HRQoL population included 387 patients with SCC. Compliance and completion rates for all three questionnaires were similar in both treatment groups at baseline and week 9. No clinically meaningful differences in global health status/quality of life scores were observed between treatment groups from baseline to week 9 (least squares mean difference, 2.80; 95% CI, –1.48 to 7.08); patients in both treatment groups generally exhibited stable functioning and symptom scores of the QLQ-C30 and QLQ-OES18 from baseline to week 9. Time to deterioration for pain (hazard ratio [HR], 1.22; 95% CI, 0.79 to 1.89), reflux (HR, 2.38; 95% CI, 1.33 to 4.25), and dysphagia (HR, 1.53; 95% CI, 1.02 to 2.31) subscales were similar between treatment groups. These findings were generally similar in the CPS ≥ 10 (n = 218) and CPS ≥ 10 SCC (n = 166) subgroups. CONCLUSION In patients with advanced EC, pembrolizumab monotherapy and chemotherapy maintained HRQoL in patients with SCC, CPS ≥ 10, and CPS ≥ 10 SCC.

Introduction Fluoropyrimidines (FP) are cornerstone drugs in the treatment of gastrointestinal (GI) malignancies. Cardiotoxicity secondary to an FP chemotherapy is a serious complication. There are no standardized guidelines on the treatment of FP induced cardiotoxicity which may result in interruption and even discontinuation of life saving treatment. We present our experience in FP rechallenge using a novel outpatient regimen based on our “up-front” triple agent antianginal protocol. Methods We report the retrospective study of the patients with suspected FP induced cardiotoxicity. Patients meeting the criteria were selected by C3OD (curated cancer clinical outcomes database) at Kansas University Medical Center (KUMC). We identified all patients with gastrointestinal malignancies who had suspected FP induced cardiotoxicity from January 2015 to March 2022. We then included the patients who were rechallenged with planned fluoropyrimidine regimen utilizing the three drug KU-protocol. We utilized a novel regimen by repurposing the already FDA-approved anti-anginal drugs in a manner that minimizes the risk of hypotension and bradycardia. Results In this retrospective study, 10 patients with suspected fluoropyrimidine induced cardiotoxicity were included from January-2015 to March-2022 at KUMC. Out of 10 patients who were rechallenged utilizing KU-protocol, eight patients (80%) were able to complete the previously planned fluoropyrimidine regimen. None of the patients required ER visits or hospital admission due to cardiac symptoms during the rechallenge utilizing the KU-protocol. Conclusions Utilizing our novel outpatient regimen, we have successfully and safely allowed re-challenge of FP chemotherapy with good tolerability and completion of the intended course of chemotherapy without recurrent morbidity.

Objectives To compare the efficacy and safety of algenpantucel-L (HAPa; IND# 12311) immunotherapy combined with standard of care (SOC) chemotherapy and chemoradiation to SOC chemotherapy and chemoradiation therapy alone in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (PDAC). Summary background data To date, immunotherapy has not been shown to benefit patients with borderline resectable or locally advanced unresectable PDAC. HAPa is a cancer vaccine consisting of allogeneic pancreatic cancer cells engineered to express the murine α(1,3)GT gene. Methods A multicenter, phase 3, open label, randomized (1:1) trial of patients with borderline resectable or locally advanced unresectable PDAC. Patients received neoadjuvant SOC chemotherapy (FOLFIRINOX or gemcitabine/nab-paclitaxel) followed by chemoradiation (standard group) or the same standard neoadjuvant regimen combined with HAPa immunotherapy (experimental group). The primary outcome was overall survival. Results Between May 2013 and December 2015, 303 patients were randomized from 32 sites. Median (IQR) overall survival was 14.9 (12.2-17.8) months in the standard group (N=158) and 14.3 (12.6-16.3) months in the experimental group (N = 145) (hazard ratio [HR] 1.02, 95% CI 0.66-1.58; P = 0.98). Median progression-free survival was 13.4 months in the standard group and 12.4 months in the experimental group (HR 1.33, 95% CI 0.72-1.78; P = 0.59). Grade 3 or higher adverse events occurred in 105 of 140 patients (75%) in the standard group and in 115 of 142 patients (81%) in the experimental group (P > 0.05). Conclusions Algenpantucel-L immunotherapy did not improve survival in patients with borderline resectable or locally advanced unresectable PDAC receiving SOC neoadjuvant chemotherapy and chemoradiation. Trial registration ClinicalTrials.gov Identifier: NCT01836432.

BackgroundPARP inhibitors (PARPi) have recently been approved for various malignancies based on the results of several clinical trials. However, these trials have mostly recruited patients with germline BRCA mutations, and it is unclear whether PARPi have similar efficacy in patients with somatic BRCA mutations. Our study aimed to determine the efficacy of PARPi in patients with somatic BRCA mutations.MethodsWe performed a meta-analysis comparing overall response rate to PARPi in patients harboring somatic versus germline BRCA mutations. We looked at studies including somatic and germline mutations in BRCA patients that received PARPi.ResultsAfter screening and removing duplicates, 18 studies met our criteria for including both somatic and germline BRCA mutations. Only 8 studies reported response rates for both somatic and germline BRCA mutations.In those studies, 24 out of 43 patients with somatic BRCA mutations (55.8%), and 69 out of 157 (43.9%) patients with germline BRCA patients had a response to therapy to PARPi. This difference was not statistically significant (p = 0.399).In all five studies that reported progression-free survival, there was no obvious difference in outcomes between somatic versus germline BRCA patients, however a precise statistical analysis could not be performed.ConclusionOur meta-analysis and systematic review of the literature indicates similar response rates of PARPi therapy in patients with somatic and germline BRCA mutations. Investigation of use of PARPi therapy in a broader patient population, and the inclusion of somatic BRCA mutations in further clinical trials is paramount in improving therapeutic options for our patients.

Gemcitabine plus cisplatin remains the standard first-line systemic therapy for advanced cholangiocarcinoma and offers a median survival of approximately 1 year. No standard regimens beyond the first line and no targeted or immunotherapy agents are approved yet in this disease. Development of molecular targeted therapy in this heterogenous and relatively rare malignancy continues to be a challenging area. The rapidly growing precision medicine efforts have uncovered the underlying mutational landscape of this lethal disease and paved the way for molecularly oriented clinical trials. The early results from such trials like those exploring IDH and FGFR2 derangements have highlighted its promising potential as alternative therapeutic options. Additionally, advances in cancer immunology have identified certain correlates as biomarkers of response to immune modulatory approaches. For instance, the presence of tumor DNA mismatch repair (MMR) deficiency and/or microsatellite instability (MSI), in 5% to 10% of cholangiocarcinoma, is associated with high rates and durability of responses to immune checkpoint blockade. Beside checkpoint inhibitors, other types of immune therapeutics like peptide and dendritic cell-based vaccines and adoptive cell therapies have been developed and are undergoing active evaluation in cholangiocarcinoma. With further research effort, the integration of tumor molecular profiling in trials exploring targeted immunotherapy will lead to better understanding of the predictive role of various molecular and immune biomarkers and ultimately shine the horizon for this patient population.

Purpose of review Cholangiocarcinoma is an aggressive heterogeneous group of cancers of the biliary epithelium and most patients are detected with advanced metastatic disease with poor prognosis. The therapeutic options are limited, and the current standard care as systemic therapy is still cytotoxic chemotherapy. With the understanding of the complex immune microenvironment in the liver and these cancers arising in the milieu of chronic inflammation, recent advances in immune oncology have transformed the landscape of cancer management with breakthroughs in the treatment of several solid tumors. Recent findings With the advances of genome sequencing, subgroups of cholangiocarcinoma with hyper mutated status and rich in cancer neoantigen production may be susceptible to immunotherapies like cancer vaccines and immune checkpoint inhibitors by eliciting a host immune response resulting in tumor rejection or overcoming the immunosuppressive local tumor microenvironment. Summary In this review, we look at the most recent evidence behind immunotherapy and its application in the treatment of cholangiocarcinoma. Though its utility is still in early development it shows great promise in improving response rates that may translate to durable disease control and improve clinical outcomes in this aggressive disease.

PURPOSE Patients with advanced esophageal cancer have a poor prognosis and limited treatment options after first-line chemotherapy. PATIENTS AND METHODS In this open-label, phase III study, we randomly assigned (1:1) 628 patients with advanced/metastatic squamous cell carcinoma or adenocarcinoma of the esophagus, that progressed after one prior therapy, to pembrolizumab 200 mg every 3 weeks for up to 2 years or chemotherapy (investigator’s choice of paclitaxel, docetaxel, or irinotecan). Primary end points were overall survival (OS) in patients with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 10, in patients with squamous cell carcinoma, and in all patients (one-sided α 0.9%, 0.8%, and 0.8%, respectively). RESULTS At final analysis, conducted 16 months after the last patient was randomly assigned, OS was prolonged with pembrolizumab versus chemotherapy for patients with CPS ≥ 10 (median, 9.3 v 6.7 months; hazard ratio [HR], 0.69 [95% CI, 0.52 to 0.93]; P = .0074). Estimated 12-month OS rate was 43% (95% CI, 33.5% to 52.1%) with pembrolizumab versus 20% (95% CI, 13.5% to 28.3%) with chemotherapy. Median OS was 8.2 months versus 7.1 months (HR, 0.78 [95% CI, 0.63 to 0.96]; P = .0095) in patients with squamous cell carcinoma and 7.1 months versus 7.1 months (HR, 0.89 [95% CI, 0.75 to 1.05]; P = .0560) in all patients. Grade 3-5 treatment-related adverse events occurred in 18.2% of patients with pembrolizumab versus 40.9% in those who underwent chemotherapy. CONCLUSION Pembrolizumab prolonged OS versus chemotherapy as second-line therapy for advanced esophageal cancer in patients with PD-L1 CPS ≥ 10, with fewer treatment-related adverse events.

Several targeted agents including multi-tyrosine kinase inhibitors (mTKIs) and immunotherapy (IO) agents have been approved for use beyond the frontline setting in patients with advanced hepatocellular carcinoma (HCC). Due to lack of prospective head-to-head comparative trials, there is no standardized way for alternating those agents beyond frontline. Therefore, we performed a retrospective review of the Kansas University (KU) cancer registry to determine whether IO may be superior to non-IO therapy. Patients with advanced HCC were divided into two groups based on the second-line systemic regimen received (IO vs. non-IO). Progression-free survival (PFS) and overall survival (OS) were calculated under the Kaplan&ndash, Meier and Cox proportional hazards models. No statistically significant differences in PFS and OS were found, although a non-significant delayed separation in the survival curve favoring IO was identified (median PFS 3.9 months vs. 3 months, median OS 10 months vs. 10 months respectively for IO vs. non-IO). This retrospective analysis is one of the earliest and largest studies comparing second-line IO and non-IO therapies thus far reported. Future studies should aim to define specific biomarkers for response prediction and treatment optimization based on individual patient and tumor characteristics. Furthermore, combinatorial therapeutic strategies is an evolving approach showing early promising signal.

Incorporation of new treatment modalities has significantly increased the complexity of the treatment and management of rectal cancer, including perioperative therapy for local advanced disease and organ preservation for those with response to the preoperative treatment. This review may help practitioners better understand the rationale and selection.

BackgroundCabozantinib is a multi-tyrosine kinase inhibitor primarily targeting VEGFR, MET, and AXL. These targets promote a tumor immune permissive microenvironment. Cabozantinib has demonstrated immunomodulatory properties & clinical synergy when paired with PD-L1 inhibitors such as durvalumab. Here, we present final results of phase Ib of the Camilla trial assessing cabozantinib plus durvalumab in advanced GE adenocarcinoma (GEA), colorectal cancer (CRC), and hepatocellular carcinoma (HCC). This is an investigator-initiated trial funded by Exelixis & Astrazeneca.MethodsPatients were administered cabozantinib + durvalumab in a dose escalation (3+3) then expansion to find the Dose Limiting Toxicities (DLTs), Recommended Phase 2 Dose (RP2D), ORR, PFS, and OS. Subgroup analysis was conducted to assess efficacy in patients with PD-L1 Combined Positive Score (CPS) ≥ 5. Dosing of cabozantinib was 20mg QD, 40mg QD, and 60mg QD PO in the 1st, 2nd, and 3rd cohorts. Dosing of durvalumab was 1500mg IV Q4W in all cohorts. DLT window was 28 days. Treatment beyond progression was allowed following modified RECIST v1.1 criteria.Results35 patients (14F, 21M), median age 53 years (range 27–79) were enrolled. 10 patients had GEA, 20 had CRC, and 5 had HCC; none had MMR deficiency. Median number of prior systemic therapies was 3 (range 0–3). No DLTs were observed during dose escalation. Per mature tolerability data, 11/14 patients receiving cabozantinib 60mg required dose-reduction post cycle 2 to 40mg. RP2D was determined to be cabozantinib 40mg QD plus durvalumab 1500mg Q4W. Of the 247 observed Treatment-Related Adverse Events (TRAEs), 10% (24) were grade≥3. Most common TRAEs were grade 1–2 fatigue (57%), nausea (43%), anorexia (40%), diarrhea (37%), transaminitis (34%), hand-foot syndrome (23%), & weight loss (23%). 2 patients each developed grade≥3 fatigue, weight loss, & abdominal pain. Overall, 30 pts were evaluable for efficacy. ORR 26.7%; DCR 83.3%; median PFS 4.5 months; 6-month PFS 36.7%; and median OS 9.1 months. 12 patients had PD-L1 CPS ≥5. In this subgroup, ORR 33.33%; DCR 91.67%; median PFS 6.13 months; 6-month PFS 50%; and median OS was not reached.ConclusionsCabozantinib plus durvalumab demonstrated promising efficacy and was fairly tolerated without new safety signals. High PD-L1 expression defined as CPS ≥ 5 was associated with improved efficacy & survival. The phase II multi-cohort part of the trial is currently ongoing.Trial RegistrationNCT03539822Ethics ApprovalThe study was approved by the participating site’s local IRB.ConsentAll study participants granted a written informed consent prior to treatment initiation.

Introduction. Ampullary cancers represent a subset of periampullary cancers, comprising only 0.2% all gastrointestinal cancers. Localized disease is primarily managed by a surgical intervention, called pancreaticoduodenectomy (PD), followed in many cases by the administration of adjuvant chemotherapy (CT) or chemoradiation therapy (CRT). However, there are no clear evidence-based guidelines to aid in selecting both the modality and regimen of adjuvant therapy for resected Ampullary carcinoma. Methods. We retrospectively analyzed 54 patients at KU Cancer Center, who had undergone endoscopic resection or pancreaticoduodenectomy (PD) for Ampullary cancer from June 2006 to July 2016. We obtained patients’ baseline characteristics, clinical presentation, pathology, treatment modality, recurrence pattern, and survival outcomes. The time-to-events data were compared using Kaplan-Meier methods. A univariate and multivariate Cox proportional hazards regression was performed to evaluate factors associated with overall survival (OS) and generate hazard ratios (HR). Results. The mean age of the 54 patients was 68 (37-90). 38 (70%) were males and 16 (30%) were females. Most of the patients were Caucasian (76%). Approximately half of all patients had a history of smoking, 20% had alcohol abuse, and 13% had pancreatitis. Among the 54 patients with localized cancers, 9 (16%) were treated definitively with nonoperative therapies, usually due to a prohibitive comorbidity profile, performance status, or unresectable tumor. 45 out of 54 patients (83%) underwent surgery. Of the 45 patients who underwent surgery, 18 patients (40% of the study cohort) received adjuvant therapy due to concerns for advanced disease as determined by the treating physician. 13 patients (24%) received adjuvant CT and 5 patients (9.2%) received CRT. The remaining 27 patients (50%) underwent surgery alone. The median OS for the entire study cohort was 30 months. When compared to surgery alone, adjuvant therapy with either CT or CRT had no statistically significant difference in terms of progression-free survival (p=0.56) or overall survival (p=0.80). In univariate Cox proportional hazards regression analysis, high-risk features like peripancreatic extension (16%) and perineural invasion (26%) were found to be associated with poor OS. Lymph node metastasis (29%) did not significantly affect OS (HR 1.42, 95% CI [0.73-1.86]; p=0.84). Lymphovascular invasion (29%) was not associated with poor OS (HR 1.22, 95% CI [0.52, 2.96]; p=0.76). In multivariate Cox regression analysis, only age group>70 years was significantly associated with OS , while other factors, including the receipt of adjuvant therapy, lymph nodes, positive margin, and lymphovascular, perineural, and peripancreatic involvement, were not significantly associated with OS. These results are likely due to small sample size. Conclusions. Despite numerous advances in both cancer care and research, efforts in rare malignancies such as Ampullary cancer remain very challenging with a clear lack of an evidence-based standard of care treatment paradigm. Although adding adjuvant therapies such as chemotherapy or chemoradiotherapy is likely to improve survival in high-risk disease, there is no standardized regimen for the treatment of Ampullary cancer. More research is required to elucidate whether statistically and clinically relevant differences exist that may warrant a change in the current adjuvant treatment strategies.

e15613 Background: Fluoropyrimidines, such as 5-fluorouracil (5-FU) and capecitabine, are commonly used chemotherapies for solid tumors, and essential for curative intent treatment of colorectal cancer. But sometimes, their use may be limited by cardiac toxicity limiting the possibility of cure in some patients. Cardiotoxicity could be asymptomatic (EKG changes) or manifested as chest pain, arrhythmias, acute coronary syndrome or death. Rechallenging may be daunting and it may result in interruption or even discontinuation of planned chemo. Traditionally, nitrates and/or IV/oral calcium channel blockers (CCB) have been used for management of fluoropyrimidine-induced cardiotoxicity but without much benefit. Ranolazine, an oral antianginal drug approved for chronic angina, diminishes myocardial ischemia by reducing calcium overload caused by inhibition of late sodium current and it does not affect heart rate or blood pressure. Our objective was to evaluate the efficacy of our novel approach using ranolazine with other traditional drugs. Methods: 8 patients (median age 49.5 yrs) with fluoropyrimidine induced cardiotoxicity were retrospectively analyzed. They were rechallenged with the planned fluoropyrimidine regimen with our 3 drug cardioprotective regimen (KU protocol). This included oral Ranolazine 1000mg BID and Amlodipine 2.5 mg daily to start the day before starting 5FU infusion/oral capecitabine and to continue it until the day after completion of infusion/treatment, and Nitroglycerin paste 1 inch every 6 hours starting before infusion and continue until it was completed. These meds were discontinued upon completion of chemo. Results: 8 patients were rechallenged with fluoropyrimidine utilizing KU protocol, 6 patients (75%) were able to complete previously planned fluoropyrimidine regimen. One pt (*) discontinued capecitabine due to recurrent chest pain and treatment was switched to 5FU based regimen with KU protocol, which pt was able to complete without chest pain. Another pt (**), 5FU was stopped due to severe diarrhea, not due to cardiotoxicity. All pts tolerated KU protocol well. Conclusions: In our small, single center experience, we were able to safely and effectively rechallenge pts with fluoropyrimidines and complete curative intent treatment with our KU protocol. This protocol uses FDA approved oral and transcutaneous drugs without requiring a healthcare personnel to administer an IV CCB that can cause precipitous bradycardia and/or hypotension. Our results need validation in a larger cohort. [Table: see text]

e16194 Background: Hepatocholangiocarcinoma (HCC-CC) is a rare form of cancer with a poor prognosis. Of all primary liver cancers, the incidence of HCC-CC ranges from 0.4 to 14.2%. HCC-CC is a mixed carcinoma with findings of both hepatocellular carcinoma and cholangiocarcinoma. Immune checkpoint inhibitors are a potent first line treatment in hepatocellular carcinoma with multiple clinical trial showing effectiveness in cholangiocarcinoma. HCC-CC has limited proven treatment options as patients are generally excluded from clinical trials. In this study we reviewed outcomes of patients with HCC-CC who received immune checkpoint inhibitor in a single center. Methods: Records of patients who had a pathological confirmed HCC-CC by a subspecialized hepatic pathologist at the University of Kansas medical center were reviewed. We identified 6 patients with locally advanced unresectable or metastatic HCC-CC that received immune checkpoint inhibitor between February 2017 and January 2021. Baseline characteristics were obtained, as well as best response, line of therapy, and duration of response. Results: Of the six patients 4 (66%) received PD-1 inhibitor alone and 2 (34%) received combination therapy with CTLA-4 inhibitor for the treatment of HCC-CC. There were 3 (50%) females and 6 (100%) with prior hepatitis C infection. four (66%) patients had metastatic disease and 2 had locally unresectable advanced disease. Objective response rate was 83.3%. One patient achieved complete response and had a treatment holiday after receiving treatment for 2 years, and restarted immunotherapy upon relapse. Four patients had a partial response, of which two passed away after disease progression. One patient had stable disease on 2 different lines of immunotherapy then progressed. Of those who responded, one patient received immunotherapy, 3 (50%) received liver directed therapy and two received chemotherapy or Lenvatinib as first line treatment (Table). Conclusions: Immune checkpoint inhibitors demonstrate potential activity in patients with HCC-CC without unexpected side effect in this unmet need high-risk population. Larger studies are needed to confirm activity and efficacy in this setting.[Table: see text]

4086 Background: Pemigatinib (PEMI), a potent, selective, oral FGFR1-3 inhibitor, has shown efficacy and safety in patients (pts) with CCA and FGFR2 rearrangements/fusions in FIGHT-202 (NCT02924376; objective response rate [ORR], 35.5%; duration of response [DOR], 7.2 months [mo]). Overall survival (OS: 21.1 mo) was not mature in the primary report (Abou-Alfa. Lancet Oncol 2020; cutoff: Mar 22, 2019); herein we report matured efficacy and safety data from FIGHT-202 (cutoff: Apr 7, 2020). Methods: Pts (≥18 y) with known FGF/FGFR alterations and progression after ≥1 prior therapy had FGFR2 rearrangements/fusions (cohort A), other FGF/FGFR alterations (B), or no FGF/FGFR alterations (C). Pts received PEMI 13.5 mg QD (21-d cycle; 2 wks on, 1 wk off) until progression or toxicity. Primary endpoint: independent, centrally confirmed ORR (cohort A); secondary endpoints: ORR (cohorts B, C; cohorts A and B combined); DOR, disease control rate (DCR), progression free survival (PFS), OS, and safety. A post-hoc analysis in cohort A evaluated mOS in responders (pts with complete response [CR] or partial response [PR]) vs non-responders (pts with progressive disease [PD] or stable disease (SD]). Results: At cutoff, 147 pts were enrolled (cohort A, n=108; B, n=20; C, n=17; FGF/FGFR status undetermined, n=2); median follow-up was 30.4 (range, 4.9–38.7) mo and median treatment duration was 5.9 (0.2–36.5) mo. In cohort A, 9.3% of pts remained on therapy at cutoff; in cohorts B and C, all pts had discontinued. Pts discontinued mainly for PD (67.6%, 75%, and 64.7% in cohorts A, B, and C respectively). Independent, centrally confirmed ORR was 37.0%; mOS was 17.5 mo (95% CI, 14.4-22.9) in cohort A (Table 1). mOS for responders (n=40) vs non-responders (n=68) was 30.1 (95% CI, 21.5-NE) mo vs 13.7 (9.6-16.1) mo. Overall, most common all-cause treatment-emergent adverse events (TEAEs) were hyperphosphatemia (58.5%; grade ≥3, 0%), alopecia (49.7%; 0%), diarrhea (46.9%; 3.4%), fatigue (43.5%; 5.4%), nausea (41.5%; 2%), and dysgeusia (40.8%; 0%); 10.2%, 13.6% and 42.2% of pts discontinued, had dose reduction, and treatment interruption due to TEAEs, respectively. Conclusions: These results reinforce the primary data, showing continued, durable responses and sustained tolerability in pts receiving PEMI for CCA harboring FGFR2 rearrangements/fusions. Notably, the matured OS is longer than historical data; OS for responders was more than twice as long vs for non-responders. Clinical trial information: NCT02924376. [Table: see text]

Importance Standard therapy for locally advanced rectal cancer includes concurrent chemoradiotherapy followed by surgery and adjuvant chemotherapy (CRT plus A). An alternative strategy known as total neoadjuvant therapy (TNT) involves administration of CRT plus neoadjuvant chemotherapy before surgery with the goal of delivering uninterrupted systemic therapy to eradicate micrometastases. A comparison of these 2 approaches has not been systematically reviewed previously. Objective To determine the differences in rates of pathologic complete response (PCR), disease-free and overall survival, sphincter-preserving surgery, and ileostomy between patients receiving TNT vs standard CRT plus A. Data sources MEDLINE (via PubMed) and Embase (via OVID) were searched from inception through July 1, 2020, for the following terms: anal/anorectal neoplasms OR anal/anorectal cancer AND total neoadjuvant treatment OR total neoadjuvant therapy. Only studies in English were included. Study selection Randomized clinical trials or prospective/retrospective cohort studies comparing outcomes in patients with locally advanced rectal cancer who received TNT vs CRT plus A. Data extraction and synthesis Data regarding the first author, publication year, location, sample size, and rates of PCR, sphincter-preserving surgery, ileostomy, and disease-free and overall survival were extracted using Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and pooled using a random-effects model. Main outcomes and measures Rates of PCR, sphincter-preserving surgery, ileostomy, and disease-free and overall survival. Results After reviewing 2165 reports, 7 unique studies including a total of 2416 unique patients, of whom 1206 received TNT, were selected. The median age for the patients receiving TNT ranged from 57 to 69 years, with 58% to 73% being male. The pooled prevalence of PCR was 29.9% (range, 17.2%-38.5%) in the TNT group and 14.9% (range, 4.2%-21.3%) in the CRT plus A group. Total neoadjuvant therapy was associated with a higher chance of achieving a PCR (odds ratio [OR], 2.44; 95% CI, 1.99-2.98). No statistically significant difference in the proportion of sphincter-preserving surgery (OR, 1.06; 95% CI, 0.73-1.54) or ileostomy (OR, 1.05; 95% CI, 0.76-1.46) between recipients of TNT and CRT plus A was observed. Only 3 studies presented data on disease-free survival, and pooled analysis showed significantly higher odds of improved disease-free survival in patients who received TNT (OR, 2.07; 95% CI, 1.20-3.56; I2 = 49%). Data on overall survival were not consistently reported. Conclusions and relevance The findings of this systematic review and meta-analysis suggest that TNT is a promising strategy in locally advanced rectal cancer, with superior rates of PCR compared with standard therapy. However, the long-term effect on disease recurrence and overall survival needs to be explored in future studies.

4563 Background: Cabo targets multiple tyrosine kinases, including VEGFR, MET, and AXL, and has been reported to show immunomodulatory properties that may counteract tumor-induced immunosuppression, providing a rationale for combining it with PD-L1 inhibitors like durva. We conducted a phase Ib GI basket trial to evaluate the safety & efficacy of this regimen in advanced GE adenocarcinoma (GEA), colorectal cancer (CRC), & hepatocellular carcinoma (HCC). Methods: Patients received cabo and durva in 3+3 dose escalation then expansion to determine the dose limiting toxicity (DLT), Recommended Phase 2 Dose (RP2D), ORR, PFS & OS. Cabo was dosed at 20mg QD, 40mg QD, and 60mg QD in the first, second, and third cohorts respectively. Durva was dosed at 1500mg IV Q4W in all cohorts. DLT window was 28 days. Scans were obtained every 8 wks. Treatment beyond progression was allowed. Results: 23 Pts (16 M, 7 F), median age 60 yrs (range 33-79) were currently enrolled. 12 in the dose escalation cohort with cabo 20mg (6 pts), or 40mg (3 pts), or 60mg (3 pts). 11 pts enrolled in the dose expansion cohort with cabo 60mg. 8 pts had GEA, 13 pts had CRC, and 2 pts had HCC. Median number of prior chemotherapies was 3 (range 1-3). 3 pts were not evaluable for DLT due to missing ≥30% of DLT window doses, not related to DLT. No DLTs were observed. Drug-related Grade (G) 1&2 AEs included fatigue (83%), abnormal LFTs (39%), anorexia (26%), diarrhea (26%), nausea (13%), & hand foot syndrome (13%). One pt each developed drug related G3 hypertension, hyperthyroidism, thrombocytopenia, & thromboembolic event, all occurring outside the DLT window. 19 pts were evaluable for response: 4 PR (2 GEA & 2 CRC), 12 SD, 3 PD; ORR 21%; clinical benefit rate 84%; median time to PD 16 wks (range 8-40+). Conclusions: RP2D was determined to be Cabo 60mg QD and Durva 1500mg Q4W. Enrollment to phase I dose expansion is ongoing. RP2D may be adjusted based on additional experience & long-term tolerability. Early efficacy data was encouraging. This is an investigator-initiated trial funded by Exelixis & Astrazeneca. Clinical trial information: NCT03539822 .

e16803 Background: Pancreatic cancer has a dismal 5 year survival of 5-10%. Deaths commonly occur in-hospital as they present with acute complications. The purpose of this study is characterize this population compared to all pancreatic deaths, identify causes for admission, trends in palliative care utilization and its effect on costs and patient stay. Methods: From the years of 2002 to 2014, admissions for patients with a diagnosis of pancreatic cancer were identified using the National Inpatient Sample. Annual trends in death were compared to overalls deaths using SEER data. Trends in hospital length of stay (LOS) and total charges (TC) were assessed, as well as utilization of palliative care. The effect of palliative care utilization on hospital LOS and TC were also identified. Results: 97,389 (weighted) patient deaths occurred from 2002 to 2014, with 7,634 in 2002, compared to 7,200 in 2014. Compared to total overall deaths of 38,026 and 42,047 respectively. Signifying 25% (2002) to 21% (2014) total patients expiring in an in-patient setting. The most common billed primary diagnosis was sepsis at 15.5%, followed by acute renal failure and fluid disorder (12.5%) and liver failure (5.3%). Overall length of stay trended down from 9.0 days to 7.5 days (p < 0.001). And total charges for admission increased from $36,704 to $88,063 (p < 0.001). Palliative care consults increased from 12% in 2002 to 45% in 2014. In 2014, the TC for deaths among those who received palliative care consults was $52,612 (p < 0.001 when compared to all deaths). LOS among these patients also decreased from 7.5 days to 6.2 days. When looking at patients with sepsis who did not die, a palliative care consult decreased costs from $86,738 to $74,544 (p < 0.001). LOS was not significantly different at 8.8 days compared to 8.5 days (p = 0.15). Conclusions: A quarter of patients with pancreatic cancer die in an in-hospital setting. Palliative involvement decreased health care resource utilization. In reviewing patients who developed sepsis without in-hospital mortality, a palliative care consult decreased total charges of admission.

e16802 Background: PARP inhibitor (PARPi) has recently been approved for various cancers. However, trials have mostly recruited pts with germline BRCA (gBRCA) mutations, and it is unclear whether PARPi have similar efficacy in pts with somatic BRCA (sBRCA) mutations. We aimed to determine the efficacy of PARPi in pts with sBRCA mutations. Methods: Per PRISMA guidelines, systematic review of PubMed, Embase, Cochrane RCT, and Web of Science Collection was performed from inception thru Jan 2020 to identify studies. Our inclusion criteria were clinical trials and retrospective studies that reported use of PARPi in pts with both s and g BRCA mutations. We performed a meta-analysis comparing overall response rate and PFS with PARPi in pts with s versus g BRCA mutations. Results: After screening, 18 studies met our criteria for including both s and g BRCA mutations. Only 8 studies reported response rates for both s and g BRCA mutations (Table). In those studies, 24 out of 43 pts with sBRCA mutations (55.8%), and 69 out of 157 (43.9%) pts with gBRCA had a response to PARPi (pooled OR 1.13, p value = 0.399, I2 = 0). In all five studies that reported PFS, there was no obvious difference in outcomes between sBRCA (HR in these studies ranged 0.23 to 0.27) versus gBRCA (HR ranged 0.17 to 0.27), however a precise statistical analysis could not be done. Conclusions: Our meta-analysis and systematic review of the literature indicates similar outcomes of PARPi therapy in pts with s and g BRCA mutations. Investigation of use of PARPi therapy in a broader patient population, and the inclusion of sBRCA mutations in future clinical trials is essential. [Table: see text]

e16673 Background: Liver cancer and bile duct cancer remain among of the most deadly cancers with a dismal 5 year survival of 2-15%. Patients often end up dying in an in-hospital setting as a result of acute complication of cancer progression. The purpose of this study is to identify annual trends in this sub-population, including cause of admission, palliative care utilization and economic impact on healthcare. Methods: From the years of 2002 to 2014, admissions for patients with a diagnosis of liver and bile duct cancer were identified using the National Inpatient Sample. Annual trends in incidence were compared to overall deaths via the SEER database. Trends were identified in hospital length of stay (LOS), total charges (TC), as well as utilization of palliative care. The effect of palliative care utilization on hospital length of stay and costs were also studied. Results: 73,833 (weighted) patient deaths were recorded from 2002 to 2014, 4,577 in 2002, compared to 6,595 in 2014. Signifying 33% (2002) to 32% (2014) of total deaths related to these cancers. The most common billed primary diagnosis was liver failure at 16.9%, sepsis (15.3%) and renal failure (6.7%). Overall LOS trended down from 5.9 days to 4.8 days (p < 0.001). Palliative consults increased from 8.2% in 2002 to 39.4% in 2014. In 2014, the mean TC for those who received palliative consults versus those who did not was $52,612 and $64,388 respectively (p < 0.001). LOS among these patients did not significantly change at 5.9 and 5.6 days (p = 0.13). When looking at patients with sepsis who did not die, a palliative care consult decreased costs from $87,564 to $75,223 (p < 0.001). LOS was not significantly different at 8.8 days to 8.5 days (p = 0.15). Conclusions: A third of patients with liver and bile duct cancers die in an in-hospital setting. More effort needs to be undertaken to identify these patients and establish appropriate goals of care prior to such an event. Nonetheless, palliative involvement decreased health care resource utilization. Even among patients with sepsis who did not die, a palliative care consult decreased total charges of admission.

Summary Background Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements. Methods In this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13·5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov , NCT02924376 , and enrolment is completed. Findings Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17·8 months (IQR 11·6–21·3). 38 (35·5% [95% CI 26·5–45·4]) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 [60%] of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 [12%]), arthralgia (nine [6%]), stomatitis (eight [5%]), hyponatraemia (eight [5%]), abdominal pain (seven [5%]), and fatigue (seven [5%]). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven [5%]), pyrexia (seven [5%]), cholangitis (five [3%]), and pleural effusion (five [3%]). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 [42%]); no deaths were deemed to be treatment related. Interpretation These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements. Funding Incyte Corporation.

TPS3165 Background: Mutations in p53 contribute to tumor progression. A rational approach is to destabilize mutant (m) p53. The group at the University of Kansas Cancer Center screened compounds that suppress m p53 in a preclinical model. Luciferase-based reporter assay identified statins as suppressors of m p53 expression. In vitro validation assay demonstrated atorvastatin (A) suppressed m p53 level and cell growth selectively; and depletion of mevalonic acid lead to degradation of m p53. These effects were limited to mutations in the conformation of p53, while wild-type and DNA contact mutations were not as sensitive to statin-induced degradation of p53. M p53 xenograft model confirmed that A could suppress tumor growth at a concentration that can decrease LDL level. The primary objective of this trial is to determine if A decreases the level of conformational m p53. The secondary objective is to assess the effects of A on Ki-67 and caspase-3 in conformational m p53 tumors. Methods: This is an open-label, window of opportunity pilot trial to see if A given for 1 to 4 weeks at a dose of 80 mg/day is sufficient to reduce the levels of conformational m p53 in the tumor tissues. Subjects with new diagnosis of malignancy with a planned surgical therapy, and subjects with previously treated AML, in between treatment regimens, are eligible. Tissues from solid tumors, and bone marrow or peripheral blood samples from AML will be used to screen for m p53 by immunohistochemistry (IHC). Subjects will receive A at 80 mg/day po for 1 to 4 weeks. Pharmacokinetics at pre-dose and 1-hour post-dose on Day 1 and on the day of surgery will be done. Mutational analysis using exome sequencing technique will be done on m p53. Using IHC, the amount of p53 in pre-treatment and post-treatment samples will be measured and compared simultaneously. The levels of Ki67 and caspace-3 will be tested and compared between pre-treatment and post-treatment samples in subjects with conformational m p53, between conformational and non-conformational m p53, and in wild-type p53 tumors. The trial is actively enrolling subjects. The results of this trial will determine further investigations on the role of atorvastatin in tumors with p53 mutations in a placebo-controlled, randomized trial. Clinical trial information: NCT03560882.

TPS4168 Background: Attempts to improve therapy for patients with pancreatic adenocarcinoma with traditional chemotherapy have largely failed to meaningfully improve survival. Therefore, there is a critical need for identification of specific molecular changes that define prognosis and potentially guide therapy decisions. Defective DNA damage response pathways in pancreatic cancer represent a targeted opportunity for treatment. PARP inhibitors exert activity in tumor cells that may not be effectively able to repair initially single-stranded and cumulatively double-stranded DNA breaks and can have a heightened susceptibility in tumor cells over normal tissue. This concept is referred to as synthetic lethality. Niraparib is an orally available, potent, highly selective PARP-1 and -2 inhibitor. We are studying the efficacy of Niraparib in pancreatic cancer patients that harbor DNA repair defects. Methods: This study is funded by a research grant from TESARO. Pre-screening of patients to find biomarker positive patients is funded by KU Cancer Center. This is a phase II open label single arm trial in metastatic pancreatic cancer patients with germline or somatic mutations, either already known, or tested after consent to pre-screening tumor tissue analysis in BRCA1/2, PALB2, ATM, NBN, ATR, BRIP1, IDH1/2, RAD51, RAD51B/C/D, RAD54L, CDK12, BARD1, FAM175A, BAP1, CHEK1/2, GEN1, MRE11A, XRCC2, SHFM1, FANCD2, FANCA, FANCC, FANCG, RPA1, ARID1A. Patients are being treated with Niraparib 300mg or 200mg by mouth daily for 28 days (1 cycle = 28 days) (200mg dose is for participants whose baseline weight is < 77 kg [169.756 lbs] or baseline platelet count is < 150,000 µL). The primary objective is to assess antitumor efficacy of niraparib using Objective Response Rate per RECIST 1.1. Secondary objectives include PFS, OS, DCR, DOR, and safety. Eligible patients received > 1 line of therapy, no prior PARP inhibitor(s), have measurable disease, and ECOG PS 0-1. Accrual target enrollment of 18 patients over a period of 24 months with a study duration of 30 months. Correlative studies include assessment of pharmacokinetics, circulating tumor cells and storing samples for future research. The trial is currently enrolling. Clinical trial information: NCT03553004.

4048 Background: KEYNOTE-181 (NCT02564263) is an open-label, randomized, phase 3 trial in ACC and SCC of the esophagus that evaluated IV pembro 200 mg Q3W for up to 2 years vs investigator choice of single-agent paclitaxel/docetaxel/irinotecan (control). Pembro was superior to control for OS in patients with PD-L1 CPS ≥10 (N = 222; median 9.3 vs 6.7 months; P= 0.0074). Here we present results of prespecified HRQoL analyses in this population. Methods: The EORTC QLQ-C30 and EORTC QLQ-OES18 were administered at baseline; weeks 2, 3, 4, 6, 9, 12, 18; every 9 weeks up to 1 year/end of treatment; and 30-day safety follow-up visit. Data from patients receiving ≥1 dose of study treatment and completing ≥1 HRQoL assessment were analyzed. Least squares mean (LSM) score change from baseline to week 9, 95% CI, and nominal P values were calculated. Time to deterioration (TTD) (≥10-point decline from baseline) was assessed by Kaplan-Meier method and Cox regression model. HRs, 95% CIs, and nominal P values are provided. Results: The HRQoL population included 218 PD-L1 CPS ≥10 patients (107 pembro, 111 control). QLQ-C30 compliance at week 9 was 88.9% for pembro and 83.9% for control. There was no significant difference in LSM between arms (3.68; 95% CI –2.28, 9.64; P= 0.2248) in global health status (GHS)/QoL score. Week 9 QLQ-OES18 compliance was 88.4% for pembro and 83.3% for control. QLQ-OES18 scores were not significantly different between arms. TTD for pain (HR 1.02; 95% CI 0.58, 1.81; P= 0.5282), reflux (HR 1.69; 95% CI 0.83, 3.47; P= 0.9254), and dysphagia (HR 1.81; 95% CI 0.97, 3.37; P= 0.9693) subscales were not significantly different between arms. Conclusions: Over 9 weeks, patients treated with pembro had stable GHS/QoL scores similar to those of patients treated with single-agent docetaxel/paclitaxel/irinotecan. Combined with the superior OS and lower rate of treatment-related AEs seen with pembro, these data support clinically meaningful benefit of pembro in esophageal cancer patients with PD-L1 CPS ≥10. Clinical trial information: NCT02564263.

TPS56 Background: GI malignancies including Gastric (GC), esophageal (EAC), colon (CRC), and hepatocellular carcinoma (HCC) remain a significant health problem in the US & globally. The current standard upfront therapy has < 12 month median survival. Hypoxia mimetic agents such as VEGFR targeted therapy down regulate the angiogenesis pathway and sensitize tumors to chemotherapy. Cabozantinib targets multiple tyrosine kinases, including VEGFR, MET, and AXL, and has been reported to show immunomodulatory properties that may counteract tumor-induced immunosuppression, providing a rationale for combining it with PD-1 or PD-L1 inhibitors. We believe that modulating the tumor microenvironment with small molecule inhibitors like cabozantinib will have synergistic effect when combined with checkpoint based immunotherapy like durvaluamb in patients with chemo refractory GC, EAC, CRC and HCC. Methods: The study is funded by research grants from both Exelixis and AstraZeneca. A phase 1 dose escalation is followed by an open-label single arm expansion. Dose escalation will be conducted using a 3+3 design. Starting dose for cabozantinib is 20mg daily. Single agent durvalumab MTD has been used, given that a regimen with full dose durvalumab may be better accepted as a backbone for comparison in future studies. MTD of cabozantinib in combination with standard dose durvalumab will be defined as the highest safely tolerated dose where 0/6 or 1/6 patients experience a DLT and ≥ 2 patients have experienced a DLT at the next higher dose level. Primary objective is to determine the Recommended Phase 2 Dose (RP2D). Secondary objectives include safety, ORR, PFS and OS. Eligible patients received > 1 line of therapy, no prior checkpoint inhibitors, have measurable disease, & ECOG PS 0-1. Phase 1 dose escalation will enroll 9-18 patients and the expansion phase will enroll 12-21 patients. Correlative studies include assessment of tumor microenvironment, angiogenesis & immune molecular markers. The dose escalation phase is currently enrolling. Clinical trial information: NCT03539822.

e15150 Background: HCC pts often present with Child Pugh (CP) B liver dysfunction but are poorly represented in trials. GIDEON showed median dose (duration) was 742 mg (17.6 weeks) in CP A vs 677 m...

369 Background: Sorafenib (SOR) is the only FDA-approved systemic therapy for advanced hepatocellular carcinoma (HCC). In clinical practice, there are limited efficacy data related to dose modifications, which are often required. Given the high prevalence of HCC in South Texas, we assessed the efficacy and safety of SOR therapy in relation to dose and Child Pugh score (CP). Methods: Retrospective analysis of HCC patients (pts) receiving SOR from 2008-2013. Median progression-free survival (mPFS) and median overall survival (mOS) were estimated from Kaplan-Meier curves and groups were statistically compared with the log rank test. The magnitude of association between dichotomous factors and survival was estimated with the hazard ratio (HR). A proportional hazards regression model was used to assess the significance of SOR (low, high) by CP (A, B) interaction. Results: 107 pts were included. Median age 57 (41-93). Males 83%. Hispanic 72%, White 24%. ECOG PS 0–1 93%. Causes of cirrhosis: Hepatitis C 67%, Hepatitis B 5%, EtOH 60%. Portal vein thrombosis 33%, extrahepatic disease 39%. CP (available for 106 pts): A 57%, B 43%. mOS was 10.2 months (mo) (95% CI: 7.8-13.5); mPFS was 5.2 mo (95% Cl: 3.8-7.2). In subgroup analysis, mOS for 800 mg/day was 12.8 mo vs 6.6 mo for 400 mg/day (HR 0.59, p=0.04). mPFS for 800 mg/day was 5.9 mo vs 3.5 mo for 400 mg/day (HR 0.66, p=0.07). In CP A pts, higher SOR dose did not improve survival; however, in CP B pts, there were statistically significant improvements in mPFS and mOS (Table). The effect of dosage varied significantly with CP category (A, B) for both OS (p=0.002) and PFS (p=0.03). Conclusions: Historically, CP B advanced HCC pts have worse survival and tolerability to higher doses of SOR when compared to CP A. Our study suggests CP B pts should be considered for SOR 800 mg/day to improve survival with optimal management of toxicity but warrants further prospective studies. [Table: see text]

e15171 Background: Sorafenib (SOR) is the first systemic therapy to improve survival in patients (pts) with advanced (HCC), mainly amongst pts with Child-Pugh (CP) A cirrhosis. In the US however, HCC pts often present with ECOG status ≥ 1 and CP B cirrhosis. The GIDEON study reported variation in disease characteristics and treatment patterns for US pts compared to rest of the world. Our aim was to further assess clinical efficacy and safety of SOR at our institution’s minority rich South Texas HCC population. Methods: We reviewed medical records of HCC pts who received SOR from 2008-2011. The association between demographic, clinical and laboratory variables with overall survival (OS) and progression free survival (PFS) were assessed by comparison of Kaplan-Meier curves. Groups were statistically compared by the log rank test and the magnitude of association with outcome was summarized as the hazards ratio with 95% confidence interval (CI). Results: A total of 67 pts were included. Median age 55 (range 41-93), males 83%, Hispanic 76%, CP A 59% vs B 39%. The median OS (mOS) was 10.0 months (mo) (95% CI: 7.2-18.3) and median PFS (mPFS) was 4.9 mo (95% CI: 3.1-7.1); both comparable to reported efficacy of the SHARP trial. In subgroup analysis, mOS was 12.8 (95% CI: 7.7–18.3) vs 7.2 mo (95% CI: 2.6–24.4) for CP A and B (HR 0.72, 95% CI: 0.37–1.38, p = 0.32), respectively. CP A pts had a mPFS of 5.9 (95% CI: 1.6–10.0) vs 3.6 mo (95% CI: 4.4–7.6) with CP B pts (HR 0.77, 95% CI: 0.45–1.34, p = 0.36). Pts on SOR daily dose of 800 mg had a better mOS at 12.8 (95% CI: 6.9–24.4) vs 8.7 mo (95% CI: 2.0–15.8) compared to those on 400 mg (HR 0.58, 95% CI: 0.29–1.15, p = 0.11). Although no significant difference in efficacy was noted between ethnicities, pts ≥ 60 years had an improved mOS at 15.9 (95% CI: 6.9–24.4) vs 7.9 mo (95% CI: 2.0–15.8) amongst pts < 60 (HR 0.56, 95% CI: 0.28-1.12, p = 0.10). There was no difference in toxicity observed. Conclusions: SOR was well tolerated in both CP A and B groups. Efficacy analysis showed a trend towards improved survival among pts with CP A treated with a daily dose of 800mg. The improved efficacy of SOR among pts ≥ 60 may be related to a more indolent HCC in this age group.

Abstract 2144 Background: Nilotinib is a second generation bcr-abl tyrosine kinase inhibitor (TKI) that has at least 30 times the potency of Imatinib (IM). Nilotinib has been approved by the FDA for the treatment of adults with chronic myeloid leukemia (CML) in chronic phase (CP) in the frontline, and for CP or accelerated phase (AP) who are either resistant or intolerant to prior therapies, including IM. Philadelphia chromosome positive (Ph+) acute lymphocytic leukemia (ALL) and lymphoid blast crisis of CML (Ly-BC) is aggressive and rapidly fatal. Complete remissions rates are low and have short durability. Relapse is inevitable unless patients (pts) receive an allogeneic stem cell transplant (SCT). The use of TKIs against Ph+ ALL or Ly-BC has shown limited durability of response as single agents. The transient nature of response to TKI is because only some of the blasts are still sensitive to bcr-abl inhibition, while the rest of the clones are not and require the addition of chemotherapy. Hyper-CVAD combined with the first generation TKI, IM is one such chemotherapy regimen that has been used in the management of adults with Ph+ ALL or Ly-BC (Thomas D, et al. Blood, 2004). Despite achieving >90% complete remission (CR) during induction phase, some pts have resistant disease or relapse shortly after attaining remission. We hypothesized that combining nilotinib with hyper-CVAD would achieve greater rates of sustained CR which ultimately translate into lower relapse rates, superior disease free survival, long term survival, and potential cure post SCT. The goal of our pilot case series was to study the feasibility of combining the more potent TKI, nilotinib to hyper-CVAD in pts with Ph+ ALL or Ly-BC, so as to improve the efficacy. Methods: Our case series involves 5 pts at our institution diagnosed with either Ph+ ALL or Ly-BC treated with a combination of hyper-CVAD and nilotinib given orally 400mg twice daily (initiated the day after completion of chemotherapy until the start of next cycle). After completion of eight cycles of chemotherapy, pts received either SCT or maintenance POMP in combination with nilotinib. Supportive care included prophylactic antibiotics, granulocyte colony stimulating factor, and transfusions as needed. None of them had central nervous system (CNS) involvement, but received intrathecal prophylaxis. Clinical characteristics at baseline, safety assessments, and efficacy evaluations including morphologic, cytogenetic, and molecular responses were analyzed. Results: All 5 pts (p190 Ph+ ALL-4, p210 Ly-BC-1; all males; Hispanic-2, Caucasian-3) received the combination for a median of 5 months. The median age was 29 (range 22–72) and the median follow-up period was 14 months. The Ly-BC pt was treated upfront with IM during CP and achieved major molecular remission (MMR) for 39 months, however due to noncompliance, relapsed with progression. All 5 patients achieved complete remission (CR), 60% after the first course. All of them achieved complete cytogenetic remission (CCyR) while 4 achieved MMR. Of the 2 Ph+ ALL pts who completed eight cycles, 1 received SCT and is in MMR for 20 months, while the other pt remains in MMR on POMP-nilotinib maintenance for over 19 months. Another pt is in MMR for 5 months. Two patients relapsed and died: the Ly-BC pt who achieved CR (without MMR) for 3 weeks and another pt that was in CCyR and MMR for 11 months. Most common adverse events included pancytopenia, fever, and infections (with no treatment related life threatening events). Conclusions: Our pilot study is the first to demonstrate the feasibility of combining nilotinib with hyper-CVAD. The results thus far are encouraging and will be expanded into a larger investigator initiated phase II study that can potentially prevent the emergence of resistant clones and improve survival in patients with Ph+ ALL or Ly-BC. Disclosures: Off Label Use: Pilot study of Nilotinib and hyper-CVAD in Ph+ ALL.