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Post-transplant cyclophosphamide (PTCy) combined with tacrolimus (TAC) as graft-versus-host disease (GvHD) prophylaxis post-hematopoietic cell transplantation (HCT) is safe and effective. Optimal serum levels of TAC in this combination remain undetermined. We hypothesized that TAC at initial steady state (TISS) of

Background KRAS mutations reported in non-small cell lung cancer (NSCLC) represent a significant percentage of patients diagnosed with NSCLC. However, there still remains no therapeutic option designed to target KRAS. In an era with immunotherapy as a dominant treatment option in metastatic NSCLC, the role of immunotherapy in. Kras mutated patients is not clear. Methods Eligible patients diagnosed with NSCLC and found to have a KRAS mutation were identified in an institutional lung cancer database. Demographic, clinical, and molecular data was collected and analyzed. Results A total of 60 patients were identified for this retrospective analysis. Majority of patients were Caucasian (73%), diagnosed with stage IV (70%) adenocarcinoma (87%), and had a KRAS codon 12 mutation (78%). Twenty percent of patients were treated with immunotherapy. Median overall survival was 28 months in the cohort and patients who received immunotherapy were found to have better survival versus those who did not (33 vs. 22 months, P=0.31). Furthermore, there was an association between high survival and patients who received immunotherapy (P=0.007). Conclusions Patients with KRAS mutations have a unique co-mutation phenotype that requires further investigation. Immunotherapy seems to be an effective choice of treatment for KRAS positive patients in any treatment-line setting and yields better outcomes than conventional chemotherapy. The relationship between immunotherapy and KRAS mutations requires further studies to confirm survival advantage.

Background Management of acute lymphoblastic leukemia (ALL) in a socioeconomically vulnerable population without ready access to a hematopoietic stem cell transplant (HCT) center and clinical trials is challenging. Data regarding the outcomes of such patients are sparse. Patients and Methods This retrospective analysis included 90 consecutive patients with ALL who presented to Harbor-UCLA between 2003 and 2018. The primary objective was overall survival (OS), whereas secondary objectives included leukemia-free survival, toxicities of therapy, and referral for HCT and incidence of successful HCT. Results Most patients were male (56.7%) and Hispanic (72.2%). The median age of diagnosis was 36 years (range, 18-63 years). The median OS was 26.8 months (95% confidence interval [CI], 17.4-59.0 months). In patients who achieved complete remission with therapy, the median leukemia-free survival was 16.4 months. Fifty percent of patients experienced at least 1 episode of bacteremia, and nearly 25% of patients developed an invasive fungal infection. Thirty-six percent (n = 32) of patients were referred for HCT. The referral rate increased over time, which led to improved OS in patients who underwent evaluation at a tertiary cancer center (hazard ratio, 0.44; 95% CI, 0.21-0.89; P = .02). Patients who underwent HCT had significantly better OS compared with those who did not (OS not reached vs. 21.9 months; hazard ratio, 0.16; 95% CI, 0.04-0.68; P = .01). Conclusion Risk stratification and evidence-based treatment approaches are important for patients with ALL treated in a resource-limited setting. Most patients can be induced successfully and achieve complete remission with therapy. Partnership with a cancer center with early referral for HCT can facilitate curative HCT to be performed.

Supplemental Digital Content is available in the text., Introduction: Anaplastic lymphoma kinase (ALK) gene rearrangements are observed in about 4% to 8% non–small cell lung cancer (NSCLC). ALK+ tumors have been associated with increased pleural and pericardial disease. Our primary objective was to determine the uncommon sites of metastasis of ALK+ NSCLC. Secondary objectives included study of coexisting mutations and factors impacting survival of ALK+ NSCLC. Methods: All patients with metastatic ALK+ NSCLC at the City of Hope Cancer Center in Duarte, California from 2010 to 2017 were selected for retrospective chart review. The demographic variables were collected. The molecular statuses of patients were evaluated through commercially available platforms for next-generation sequencing. Three-dimensional volumetric images were generated for the primary lesion and different sites of metastasis. Results: Sixty two patients with ALK+ NSCLC were identified from 2010 to 2017. The median age was 59 with 36 (58%) female individuals and only 20 (32%) smokers. Twenty four patients had uncommon sites of metastasis which were thyroid, soft tissue, chest and abdominal wall, spleen, peritoneum, omentum, kidney, and ovary. Common characteristics of the primary lesions were right upper lobe location (N=23 [37%]), oval shape (N=22 [35%]), irregular margins (N=26 [42%]), solid lesions (N=27 [44%]), presence of pleural contact or effusion (N=22 [35%]). Twenty four patients had next-generation sequencing testing which showed coexisting mutations such as TP53 (N=8), EGFR (N=5), KRAS (N=3). Patients with uncommon sites of metastasis had a decreased median survival compared with common sites (39 vs. 82 m, P=0.046). Conclusion: In NSCLC, ALK rearrangements may not be mutually exclusive mutations and can present with unique radiographic patterns. Patients with uncommon sites of metastasis may have worse outcomes.

Objectives To compare the extent of clinical benefit and cost effectiveness of olaparib in ovarian cancer compared to breast, pancreatic, and prostate cancer. Methods Data were extracted from FDA labels for olaparib. We compared the use of olaparib in gBRCAm (germline BRCA mutant) recurrent ovarian, breast, prostate, and pancreatic cancer. Prevalence of the germline BRCA biomarker and survival benefit were compared between gynecologic and other cancer types. Incremental cost effectiveness ratio (ICER) analyses will be performed. Results In ovarian cancer, 15–20% of patients carry gBRCAm. Treatment with olaparib at recurrence with gBRCAm increased PFS by 4.7 months progression-free survival (PFS) versus gBRCAwt (Study 19). In gBRCAm breast cancer, 10–15% of patients carry gBRCAm and had 2.8 month PFS benefit (OlympiAD). In pancreatic adenocarcinoma, gBRCAm is present in 9%, and POLO demonstrated a 3.6 months PFS benefit. Olaparib is approved for gBRCAm or homologous-recombination deficient (HRD) in metastatic castration resistant prostate cancer. With gBRCAm (present in 1–2% of patients), there was a 3.8 month of PFS benefit (PROfound), and 2.3 months including gBRCAm and HRD. Conclusions Across cancer types with FDA approval for olaparib, the clinical benefit and proportion of patients eligible is highest in ovarian cancer. PFS benefit is similar across cancer types (2–5 month range). Prostate cancer is the only cancer with FDA approval for treatment with olaparib in the recurrent setting for both HRD and gBRCA. Additional study is on HRD breast, pancreatic, and ovarian cancer to determine if olaparib therapy could benefit these populations.

Lung cancer remains the leading cause of cancer deaths in the world with 1.69 million deaths in 2015. A total of 85% of lung cancer cases are non-small-cell lung cancers (NSCLCs). Driver mutations associated with anaplastic lymphoma kinase (ALK) have been identified in a variety of malignancies, including NSCLC. An ALK inhibitor (crizotinib, ceritinib and alectinib) is the preferred therapeutic approach to those advanced ALK fusion variant-positive NSCLC patients. Brigatinib, a next-generation ALK inhibitor, shows promising activity in ALK-rearranged NSCLC that have previously received crizotinib with response rates in ALTA ranging from 42–50%, intracranial response 42–67% and median progression-free survival 9.2–12.9 months. Randomized Phase III trial, ALTA-1 L is investigating brigatinib in ALK inhibitor-naive patients.

Background: In November 2020, the U.S. Food and Drug Administration (FDA) issued emergency use authorization (EUA) for monoclonal antibody (mAb) therapy in patients with mild to moderate COVID-19 who are at high risk for disease progression. These mAbs reduce the risk of hospitalization in the general population. However, its efficacy and safety in immunocompromised hematology patients are not known. Methods: From November 9th, 2020, until February 28th, 2021, all adult hematology patients with mild to moderate COVID-19 disease who received monoclonal antibodies within 10 days of symptoms onset were included. Patients who were asymptomatic, had severe or critical COVID-19 disease, or were hospitalized at the time of COVID-19 diagnosis were excluded. Baseline demographic, clinical outcomes, and hematologic-related data were extracted. All statistical analysis was performed using SAS statistical software. Results: Thirty-eight hematology patients with mild to moderate COVID-19 disease who received mAb therapy under EUA were included in this study. Thirty (79%) patients received bamlanivimab and 8 (21%) casirivimab-imdevimab. Baseline characteristics prior to mAB administration include: 53% female, median age of 51 years (range: 21-80), with 18% above 65 years old. Twenty-eight (74%) patients received cellular therapy: 18 (47%) had undergone allogeneic hematopoietic cell transplantation (HCT), 9 (24%) autologous HCT, and 1 (3%) chimeric antigen receptor T-cell (CAR T) therapy. Among the 17 patients who had COVID-19 disease after HCT, the median time to COVID-19 diagnosis was 22.8 months (range: 2.6-274.4) from HCT to COVID-19 diagnosis. Twelve out of 17 (71%) alloHCT patients were being managed for active graft-vs-host disease (GvHD) at the time of COVID-19 diagnosis (chronic GVHD: n=11 [mild: 4, moderate: 4, severe: 3], acute GVHD (grade 2): n=1). Ten (59%) alloHCT patients were on immunosuppressant therapy at the time of COVID-19 diagnosis. Fifteen (39%) patients were on active treatment for their hematologic malignancy (HM) at the time of COVID-19 diagnosis with a mean of 3 previous lines of treatment (range: 1-6). Additional patient characteristics are shown in Table 1. mAb therapy under EUA was well tolerated in this patient population with only 1 (3%) patient having experienced an adverse reaction characterized as headache. Four (11%) patients were hospitalized due to COVID-19, and 2 (5%) progressed to severe disease. All four patients had received bamlanivimab. The median time for hospitalization from diagnosis of COVID-19 to admission date was 8 days (range: 1-20) while median time from mAB infusion to hospitalization was 7.5 days (range: 0-17). One patient (3%) died within 30 days of COVID-19 diagnosis; the cause of death was COVID-19 disease. Most patients (n=34, 89%) ultimately tested negative for SARS-CoV-2 by PCR after mAb infusion. 34% of patients (n=13) cleared the virus within 2 weeks of receiving mAb infsuion. The median time to clearance of viral shedding was 25.5 days (range: 7-138). After mAb infusion, most patients (10/15; 67%) who were previously on active treatment for HM prior to diagnosis of COVID-19 resumed therapy for their HM with a median delay of 21.5 days (range: 12-42). We observed a significant difference in hospitalization was amongst patients who received a HCT vs. non-HCT (0%, 0/26 and 36%, 4/11 respectively; p Conclusion: This study demonstrates that SARS-COV2 specific mAb use in malignant hematology patients under EUA was safe and may reduce hospitalization as reported in the literature amongst those at high risk for disease progression. Thus, the access to SARS-COV2 mAb in this population who is at increased risk for complications from SARS-COV2 infection is critical in reducing progression to severe COVID-19 disease and hospitalization. Figure 1 Figure 1. Disclosures Ali: Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau. Aribi: Seagen: Consultancy. Artz: Radiology Partners: Other: Spouse has equity interest in Radiology Partners, a private radiology physician practice. Koller: Novartis: Consultancy. Nikolaenko: Rafael Pharmaceuticals: Research Funding; Pfizer: Research Funding. Shouse: Beigene: Honoraria; Kite Pharma: Speakers Bureau. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Marcucci: Abbvie: Other: Speaker and advisory scientific board meetings; Novartis: Other: Speaker and advisory scientific board meetings; Agios: Other: Speaker and advisory scientific board meetings. Forman: Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy. Dadwal: AlloVir: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas: Speakers Bureau; Shire/Takeda: Research Funding; Aseptiscope: Consultancy; Janssen: Other: Investigator; Karius: Other: Investigator. Al Malki: CareDx: Consultancy; Rigel Pharma: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; Neximmune: Consultancy; Hansa Biopharma: Consultancy.

Background Rearrangements of lysine methyltransferase 2A (KMT2A) gene, previously known as the MLL gene, occur in 3 to 5% of adult patients with de novo AML and are enriched in therapy-related disease after treatment with topoisomerase II inhibitors (Bill, M et al. PNAS. 2020). KMT2A encodes a histone H3 lysine 4 methyltransferase and KMT2A rearrangements result in fusion proteins that induce aberrant Hox gene expression. (Armstrong, SA et al. Nature. 2002) Among patients with KMT2A rearranged AML (rAML) receiving intensive chemotherapy, the fusion partner impacts prognosis, and KMT2A-MLLT3 is associated with an intermediate risk while other KMT2A rearrangements are associated with adverse risk in the ELN classification. (Dohner, H et al. Blood. 2017) Here we evaluate the outcomes of patients with newly diagnosed and relapsed or refractory (R/R) AML with KMT2A rearrangements receiving venetoclax and hypomethylating agents (HMA). Methods Medical records of 333 patients with newly diagnosed or R/R AML receiving venetoclax in combination with HMAs at City of Hope National Medical Center between 11/1/2015 and 4/15/2020 were reviewed. Criteria for inclusion were a pathologically confirmed diagnosis of AML, age > 18 years, treatment with either decitabine or azacitidine in combination with venetoclax. KMT2A rearrangements were detected by karyotype and confirmed by FISH or RNA sequencing. Responses were evaluated per the ELN criteria (Dohner, H et al. Blood. 2017) Minimal residual disease flow cytometry was performed at the University of Washington. Patient characteristics were summarized by frequency and associations between overall response and patient and disease characteristics were tested by Fisher's exact test. OS was evaluated by the Kaplan-Meier method and the difference between groups was determined by log-rank test. All statistical analyses were performed using SPSS and Prism. Results We identified 18 patients (5.4%) with KMT2A rAML who met criteria for inclusion. MLLT3 was the predominant fusion partner, occurring in nine patients followed by ELL (n=2), AFDN (n=2), MLLT6 (n=1), MLLT10 (n=1), AFF1 (n=1), CBL (n=1), and TET1 (n=1). The cohort included both newly diagnosed (n=10) and R/R (n=8) AML patients. 44% had therapy-related or secondary AML. NRAS or KRAS mutations occurred in 4 out of 13 patients (31%) with available sequencing prior to treatment. Decitabine was the predominant HMA used in combination with venetoclax and 56% of all patients received 10-day dosing during the first cycle. For the total cohort, 9 patients achieved an overall response (ORR 50%), including 8 patients with a complete remission (CR/CRi 44%) and 1 (6%) patient with a morphologic leukemia free state, Figure 1. All six of the responders who were tested for MRD were negative. For treatment naïve patients, we observed a CR/CRi rate of 70% and a median survival of 11 months. On univariate analysis, R/R disease was the only factor associated with a significant decrease in response (ORR 12.5% vs. 80%, p=0.015, Table 1). With a median follow-up of 14.4 months for responding patients, median OS for the cohort was 6.59 months and 19.15 months for responding patients (Figure 2). The presence of NRAS or KRAS mutations was the only factor significantly impacting survival (HR 6.04, log rank 0.05, Table 1). Notably, the KMT2A fusion partner type did not impact response or survival. Allogeneic stem cell transplant was performed in 4 out of 9 (44%) responding patients. Conclusion Here, we show that venetoclax in combination with HMA led to a high rate of response and prolonged survival in a high-risk KMT2A rAML population. The outcomes of newly diagnosed KMT2A rAML patients after treatment with venetoclax and HMA in this study are similar to chemotherapy outcomes in patients aged < 60 years (CR 68% and median OS 0.9 months; Bill, M et al. PNAS. 2020). Consistent with previous studies, we found that MLLT3 was the most common fusion partner, occurring in 50% of patients and that RAS mutations were also common (~30%). In contrast to what has been reported for chemotherapy outcomes and in the ELN classification, the KMT2A-MLLT3 translocation was not associated with improved outcomes when compared to other KMT2A translocations. While this study was limited in being retrospective and having a small and heterogeneous population, our findings suggest that venetoclax and HMA are effective in KMT2A rAML and warrant further investigation. Figure 1 Figure 1. Disclosures Koller: Novartis: Consultancy. Al Malki: Hansa Biopharma: Consultancy; Rigel Pharma: Consultancy; Neximmune: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; CareDx: Consultancy. Aribi: Seagen: Consultancy. Ali: Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Marcucci: Novartis: Other: Speaker and advisory scientific board meetings; Agios: Other: Speaker and advisory scientific board meetings; Abbvie: Other: Speaker and advisory scientific board meetings. Pullarkat: AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees; Amgen, Dova, and Novartis: Consultancy, Honoraria.

Pancreatic cancer remains a deadly disease with a 5-year survival rate of only 8%. Even after surgical resection, most patients have recurrence of their cancer. Over the last 10 years, improvements in chemotherapy regimens led to a doubling in median overall survival. Here we review the management of advanced pancreatic cancer and highlight vaccine therapy as a novel modality of treatment.

Twist-1, a basic helix-loop-helix transcription factor, regulates embryogenesis and epithelial-mesenchymal transition (EMT). Twist-1 is essential for the differentiation and specification of mesoderm-derived tissues and hematopoietic stem cells. In hematopoiesis, Twist-1 plays an important role in maintaining the bone marrow niche to support normal hematopoiesis. In human tumorigenesis, Twist-1 is overexpressed and promotes EMT, a key process in the metastases and drug resistance. In addition, recent evidence indicates that Twist-1-Bmi1 axis confers acute myeloid leukemia (AML), cell self-renewal and apoptosis resistance which highlights the importance of the Twist1-Bmi1 axis in the regulation of self-renewal in both normal hematopoietic and leukemia stem cells (LSCs). The hypothesis of the current study states that dysregulation of Twist-1 is implicated in the pathogenesis of various hematological malignancies, AML. This study demonstrates the efficacy of nanoparticle delivery using hyaluronic-acid conjugated mesoporous silica nanoparticles (MSN-HA) as an intracellular delivery mechanism for siRNA designed to knock down Twist-1 (siTwist-1). The nanoparticle is designed for tumor stem cell specificity as its HA component exclusively targets LSCs through their native ligand, CD44. In addition, the nanoparticles' electrostatically bonded polyethylene (PEI) coat protects the siRNA from nuclease degradation. Using siRNA nanotechnology, previous studies demonstrated the ability to target and silence cytoplasmic Twist-1 mRNA and re-sensitize cancer cells to conventional chemotherapeutic agents in solid tumor models. In this study, we demonstrate the efficacy of this nanoparticle siRNA technology on the knockdown of Twist-1 in the AML cell line, KG1a, and the consequent cascading effect of upregulating the tumor suppressor genes and downregulating stemness genes. Our data indicate that Twist-1 promotes leukemia cell growth and colony-forming units (CFU) through the Twist/c-MPL axis, and knockdown of Twist1 inhibits tumor growth and reduce the number of CFUs. Our Results also showed that Twist-1 interacts with Runt domain of Runx-1, and c-MPL, reported to be negatively regulated by RUNx-1. Thus, nanotechnology which combines CD44 targeting and Twist Knockdown, has shown promising results for LSCs targeting, mitigating metastasis in AML. Further investigations of the role of Twist HSC and bone marrow niche will provide more insight into strategic management and treatment for leukemic stem cells. Citation Format: Ebtesam Nafie, Angelina Flores, Idoroenyi Amanam, Ruining Wang, Jeffrey Zink, Lucy Ghoda, Guido Marcucci, Carlotta Glackin. Twisting stemness in AML using nanoparticle as a delivery system for siRNA targeting Twist [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-225.

The goal of this study is to characterize the genomic and immune profiles of metaplastic breast cancer (MpBC) and identify the association with survival through an analysis of archived tumor tissue. A next-generation sequencing-based mutational assay (Onco-48) was performed for 21 MpBC patients. Clinicopathologic characteristics were captured, including relapse free survival (RFS) and overall survival (OS). Immunohistochemistry (IHC) for CD3, CD4, CD8, and programmed death-ligand 1 (PD-L1) was also performed. Recurrence free survival (RFS) at 5 years was 57% (95% CI 0.34-0.75) and overall survival (OS) at 5 years was 66% (95% CI 0.41-0.82). The most commonly altered genes were TP53 (68.4%, 13/19), PIK3CA (42.1%, 8/19), and PTEN (15.8%, 3/19. For patients with PIK3CA mutations, RFS and OS were significantly worse than for those without (HR 5.6, 95% CI 1.33-23.1 and HR 8.0, 95% CI 1.53-41.7, respectively). Cox regression estimated that PD-L1 expression was associated with worse RFS and OS (HR 1.08, 95% CI 1.01-1.16 and HR 1.05, 95% CI 1.00-1.11, respectively, for an absolute increase in PD-L1 expression of 1%). In conclusion, PIK3CA mutation and PD-L1 expression confer poor prognosis in this cohort of patients with MpBC.

The treatment landscape for non-small-cell lung cancer (NSCLC) has dramatically shifted over the past two decades. Targeted or precision medicine has primarily been responsible for this shift. Older paradigms of treating metastatic NSCLC with cytotoxic chemotherapy, while still important, have given way to evaluating tumor tissues for specific driver mutations that can be treated with targeted agents. Patients treated with targeted agents frequently have improved progression-free survival and overall survival compared to patients without a targetable driver mutation, highlighting the clinical benefit of precision medicine. In this chapter, we explore the historic landmark trials, the current state of the field, and potential future targets under investigation, in this exciting, rapidly evolving discipline of precision medicine in lung cancer.

Small cell lung cancer (SCLC) is an aggressive illness with an overall poor prognosis. A large number of therapeutics have been utilized in the past without much success. Cisplatin (or carboplatin) and etoposide are the hallmarks of the therapy. A large number of current novel therapeutics are targeting the immune system, and based on the recent results, nivolumab and atezolizumab have been approved in certain settings. Targeting with antibody conjugates and bispecifics are coming to fruition. Also, downstream targeting with transcription inhibitors such as EZH2 inhibitors, aurora kinase inhibitors, mitochondrial inhibitors of BCL-2, DLL3/DLL4, and stem cell signaling are currently being tested in the clinics. With novel therapies and immune therapies, there is hope that the bleak overall survival for SCLC will be improved considerably.

ObjectivesOncology has become more reliant on new testing methods and a greater use of electronic medical records, which provide a plethora of information available to physicians and researchers. However, to take advantage of vital clinical and research data for precision medicine, we must initially make an effort to create an infrastructure for the collection, storage, and utilization of this information with uniquely designed disease-specific registries that could support the collection of a large number of patients.Materials and methodsIn this study, we perform an in-depth analysis of a series of lung adenocarcinoma patients (n = 415) with genomic and clinical data in a recently created thoracic patient registry.ResultsOf the 415 patients with lung adenocarcinoma, 59% (n = 245) were female; the median age was 64 (range, 22-92) years with a median OS of 33.29 months (95% CI, 29.77-39.48). The most common actionable alterations were identified in EGFR (n = 177/415 [42.7%]), ALK (n = 28/377 [7.4%]), and BRAF V600E (n = 7/288 [2.4%]). There was also a discernible difference in survival for 222 patients, who had an actionable alteration, with a median OS of 39.8 months as compared to 193 wild-type patients with a median OS of 26.0 months (PConclusionThe use of patient registries, focused genomic panels and the appropriate use of clinical guidelines in community and academic settings may influence cohort selection for clinical trials and improve survival outcomes.

International audience; Respiratory diseases affect millions of people worldwide, and account for significant levels of disability and mortality. The treatment of lung cancer and asthma with therapeutic antibodies (Abs) is a breakthrough that opens up new paradigms for the management of respiratory diseases. Antibodies are becoming increasingly important in respiratory medicine; dozens of Abs have received marketing approval, and many more are currently in clinical development. Most of these Abs target asthma, lung cancer and respiratory infections, while very few target chronic obstructive pulmonary disease-one of the most common non-communicable causes of death-and idiopathic pulmonary fibrosis. Here, we review Abs approved for or in clinical development for the treatment of respiratory diseases. We notably highlight their molecular mechanisms, strengths, and likely future trends.

The modern treatment of locoregionally advanced disease often requires a multimodality combination approach. A number of chemotherapeutic agents can be combined with radiation, but the platinum agent cisplatin, a potent radiation sensitizer, is best studied in head and neck cancer. Newer agents such as cetuximab can be used in combination with radiation therapy for those patients who cannot tolerate cisplatin. For chemotherapy-naive patients with metastatic head and neck cancer who demonstrate a good performance status, platinum doublet regimens are commonly used. Doublet regimens generally improve response rates compared to single-agent chemotherapies, although they have not demonstrated a survival benefit over single agents and they have added toxicity. Immunotherapies, alternative cytotoxic chemotherapies, and targeted therapies are second-line options for patients with disease that has progressed on platinum-based therapy. Immunotherapy, in particular, has gained focus by enhancing the ability of the immune system to recognize and destroy malignant cells. When multimodal approaches are used, as in combined chemotherapy and radiation therapy, toxicities are increased. It is imperative that patients are followed closely in order to maximize treatment benefit while minimizing complications.

Pancreatic cancer is the third leading cause of cancer related death and by 2030, it will be second only to lung cancer. We have seen tremendous advances in therapies for lung cancer as well as other solid tumors using a molecular targeted approach but our progress in treating pancreatic cancer has been incremental with median overall survival remaining less than one year. There is an urgent need for improved therapies with better efficacy and less toxicity. Small molecule inhibitors, monoclonal antibodies and immune modulatory therapies have been used. Here we review the progress that we have made with these targeted therapies.

Background Despite advances in cancer research, the majority of drug applications submitted to the U.S. Food and Drug Administration (FDA) are not approved. It is important to identify the concerns of the Oncologic Drugs Advisory Committee (ODAC) from rejected applications. Methods All applications referred to the ODAC from 2001 to 2012 were reviewed. Results Of 46 applications, 31 (67%) were for full and 15 (33%) were for supplemental approval, 34 (74%) were for solid and 12 (26%) were for hematologic tumors. In all, 22 (48%) were not approved. ODAC comments addressed missing or inadequate data (65%), excessive toxicity (55%), inappropriate study endpoints (45%), poor study design (40%), and insufficient sample size (30%). To define efficacy, 19 applications used response rates (RR) (median = 38%), and 19 applications used hazard ratios (HR) (median = 0.67). For all organ systems combined, the median cumulative grade 3 or 4 toxicity was 64%. Drugs with higher RR, lower HR, and lower toxicity were more likely to be approved versus other drugs (89% vs. 45%; p = .02). Over time (2001–2004, 2005–2008, 2009–2012), there was an increase in the following: number of applications submitted for review (from 11 to 12 to 23, respectively), number of approvals (from 6 to 6 to 12, respectively), and proportion of trials using progression-free survival as a primary endpoint (from 0% to 50% to 70%, respectively; p = .01). Conclusion. Of all applications, common ODAC concerns included inadequate data, excessive toxicity, and inappropriate study endpoints. Over time, there was an approximate doubling of FDA application submissions and approved oncology drugs.

e18258 Background: The 15-year Women’s Health Initiative (WHI) sponsored by the NIH has provided a robust dataset on health risks for post-menopausal black women (BW), including the impact of hormone therapy (HRT) on cancer risk. Women enrolled in the WHI randomized, placebo-controlled trial and taking HRT demonstrated no increase in lung cancer incidence, but a statistically significant increase in mortality. However, effects of estrogen plus progestin on non-small cell lung cancer (NSCLC) incidence and outcomes has not been extensively examined, especially in African Ancestry (AA) and smoking history. Methods: Study participants were identified who met WHI clinical trial entry criteria. Cox regression models and Kaplan-Meier method plots were utilized. Analyses adjusted for age, BMI, education, smoking status, alcohol use, health status, and physical activity. A secondary analysis was performed on BW based on AA via Affymetrix Human SNP Array. Results: 161, 808 pts were enrolled from October 1993 to December 1998 (after exclusions total analytic cohort = 142,503). 128,682 (90%) were white (WW) and 13,821 (10%) were BW. BW had lower incidence of NSCLC compared to WW (HR 0.68; P < .0001). HRT participants had a 55% increase in incidence of NSCLC (p < .0001). Former alcohol users had highest risk of NSCLC incidence (HR 2.72; p < 0.0001). Age groups (55-59 years; 60-69 years; 70-79 years) were significantly less associated with BW compared to the youngest(50-54 years; P < .0001). HRT participants were more likely BW (OR 1.17; p < .0001). More current smokers were BW compared to WW (OR 1.75; p < .0001). HRT participants had increased risk of death to NSCLC (HR 1.29; p < .001). There was a trend for survival (p = 0.3667) in WW participants compared to BW (32 vs 28.0 months, respectively). BW who had > 80% AA had a decreased incidence NSCLC trend compared to BW with < 80% AA (HR 0.81; p = 0.2806). Conclusions: BW, especially those with high levels of AA had decreased incidence of NSCLC. Those patients who received HRT had higher incidence and death from NSCLC. Further investigations are required to understand the mechanisms that AA and HRT alter risks associated with NSCLC.

e21130Background: ALK gene rearrangements are observed in about 4-8% Non-small cell lung cancer (NSCLC). Due to low incidence there is limited knowledge about patterns of metastasis in ALK+ tumors....

e14551Background: To determine progress in FDA approved drugs for cancer therapies in over the past 12 years. Methods: Data from all approved oncologic or malignant hematologic indications were obt...

e12041 Background: Metaplastic breast cancer (MpBC) is a rare malignancy with aggressive clinical presentation and poor prognosis. The goal of this study is to characterize MpBC at the genomic level with targeted exome sequencing and correlate with clinical-pathological characteristics. Methods: We have Identified 23 patients (pts) with a diagnosis of MpBC through the COH Cancer Registry from 1995 to 2013. A next generation sequencing based panel (Onco48) was performed on 21 pts on using the Ion AmpliSeq™ Kit. Molecular testing for two pts was performed at FoundationOne®. Patient’s clinical-pathological characteristics were also captured (age, race, stage, chemotherapy, radiation therapy history, and 5-year relapse free survival (RFS)). Results: Of the 21 specimens tested with COH Onco48, 3 failed to yield results. Of the 20 pts included in the analysis, 1 pt did not have survival information available. The median age at time of diagnosis was 68 years (range 35-93). All of the tumors were TNBC. The subtypes of MpBC were: squamous (35%), spindle (30%), mixed squamous and spindle (15%) and chondroid (20%). A total of 70% of pts received (neo)adjuvant chemotherapy, and 65% received radiation therapy. Median follow-up of alive pts is 63 months. Median RFS and OS have not been reached for entire cohort with a lower 95% of PFS of 22.2 months. The most commonly mutated genes included TP53 (65%), PIK3CA (45%), PTEN (15%).In a univariate analysis, the association of p53, PTEN, PIK3CA mutations and breast cancer specific survival. RFS at 2 years was 33% (0.03-0.64) for those with PIK3CA mutations, and 100% for those without (p

11624 Background: Disease heterogeneity with variable molecular mutations is one of the main contributory factors in non-small cell lung cancer (NSCLC). The goal of this study was to better understand the KRAS patients with co-occurring mutations. Methods: We identified 60 patients with a diagnosis of NSCLC and a KRAS mutation in the COH Cancer Registry from 2009 to 2016. Next generation sequencing was performed. Results: Of the 60 patients identified, 42 (70%) were Stage IV at diagnosis, 7 (12%) Stage I and 7 (12%) stage II and 4 (6%) Stage III. 47 (78) patients were smokers. Caucasian was the most common (n = 44, 73%) racial group, followed by Asians (n = 9, 15%), African-Americans (n = 3, 5%), other (n = 3, 5%) and Pacific Islander (n = 1, 1.7%). The average age at diagnosis was 67 (median 69.50) years; 30 patients (50%) were over 70 years, 23 (38%) patients were 51-69 years, and 7 (12%) 50 years or below. Majority of the patients had metastatic disease (n = 52, 87%) with 20% (n = 12) having brain metastasis with average metastatic sites 1.6. An average of 1.97 (range = 0-5) lines of therapy including chemotherapy, biologic agents or immunotherapy were received. 12 (20%) patients received immunotherapy, radiation in 28 (47%) and surgery in 22 (37%) with a median overall survival at 15 months. The most frequent molecular alteration was codon 12 mutation (n = 47, 78%), followed by codon 13 (n = 7, 12%) and codon 61 (n = 6, 10%) mutations. The most common co-occurring mutations in this cohort were TP53 (n = 15, 25%), ATM (n = 9, 15%), LRP1B (n = 9, 15%), ARID1A (n = 8, 13%), STK11 (n = 8, 13%), ARID1B (n = 7, 12%), TERT (n = 7, 12%), EGFR (n = 6, 10%), RBM10 (n = 6, 10%), SPTA1 (n = 6, 10%). We are currently evaluating the relevance of the Circos plot analysis for these mutations, clinical response to immunotherapy and potential biomarkers. Conclusions: KRAS mutations are among the most common molecular alterations identified in NSCLC. Effective treatments targeting KRAS mutations have represented a challenge so far. Understanding the significance of co-mutations and their therapeutic implications, especially in response to immunotherapy and other agents represents an important step to develop better treatment options for KRAS mutated lung cancers.

e14111Background: In 2015, The FDA approved the most number of novel drugs in the last 19-years. We propose to evaluate the factors associated with the significant increase in FDA approved oncologi...

2582 Background: To evaluate the association of relative survival benefit (additional benefit / historic control) as a modality to predict for oncology drug approval. Methods: Data was extracted fr...

Cancer patients receiving chemotherapy are at increased risk of venous thromboembolism (VTE). The presence of cancer and anticoagulant use are risk factors for bleeding, yet data on bleeding risk are limited in these patients. This analysis evaluated the risk of major bleeding in cancer patients receiving chemotherapy using a US claims database. This retrospective cohort study used the MarketScan® databases, a nationwide database containing data from about 100 payers and covering > 30 million patients annually. Adult cancer patients receiving chemotherapy within 6 months of cancer diagnosis between January 2004 and December 2010 were included. Cancers of interest were: lung, colon/rectum, pancreas, bladder, stomach, and ovary. The index date was the first date of chemotherapy. Patients were followed until the earliest of: 1) first diagnosis of major bleeding; 2) termination of enrolment in the health plan; 3) end of study. The primary outcome was the first occurrence of major bleeding, based on selected ICD-9-CM/CPT codes, following chemotherapy initiation. Of 74,575 patients identified, exclusion of those with prior history of bleeding at baseline (∼5%) resulted in 70,822 patients included in the analysis. Mean age was 62 years, 37% were ≥ 65 years, and 52% were male. Average time of follow up and chemotherapy were 14.3 and 8.6 months, respectively; 6% had a history of VTE within 6 months prior to the index date. Major bleeding occurred in 5.8% of patients and the incidence rate for all cancers combined was 4.9 per 100 person-year (PY) and 10.5, 9.3, 6.2, 4.3, 3.6, and 3.3/100 PY for pancreatic, stomach, lung, bladder, colon/rectum, and ovarian cancer, respectively. Approximately 14% of patients (N = 10,456) developed VTE after chemotherapy initiation (> half in the first 3 months of chemotherapy treatment). Of these, 7.8% experienced major bleeding with incidence rates ranging from 5.9-17.7/100 PY after VTE. Major bleeding incidence in cancer patients receiving chemotherapy varies by cancer type with the highest rates in patients with upper gastrointestinal cancer. Compared to the overall cohort, major bleeding risk was higher in cancer patients who developed VTE. Disclosure J.H. Zong: Employee of Sanofi. L. Eckert: Employee of Sanofi. L. Zhang: Employee of Sanofi. W.S. Dai: Employee of Sanofi. A.T. Cohen: Consult: Astellas, AZ, Bayer, BI, BMS, Daiichi, GSK, JJ ResFund: AZ, Bayer, BI, BMS, Daiichi, GSK, JJ BoardSpeakerAdvis comm: Bayer, BI, BMS, Daiichi, GSK, J&J, Mitsubishi, Pfizer, Sanofi. All other authors have declared no conflicts of interest.

Objectives To evaluate the progress and trends for cancer drug approval over the last decade. Methods From 2001 to 2011, applications from (Oncologic Drug Advisory committees) ODAC session were reviewed. Results Of 46 applications, 34 (74%) involved solid and 12 (26%) hematologic tumors. These drugs were for leukemia (n = 8, 17%), lymphoma (n = 8, 17%), breast (n = 5, 11%), prostate (n = 5, 11%), and others (n = 20, 44%). 30 (65%) were phase III and 16 (35%) were phase II trials. 67% (n = 31) were full applications and 33% (n = 15) were for accelerated approval. 22 (48%) drugs were not approved with most common concerns being: missing or inadequate data (65%), excessive toxicity (55%) and inappropriate study endpoints (45%). 19 applications used hazard ratios (HR), (median = 0.67) and 18 used response rates (RR) (median = 0.42%). In a predictive model combining efficacy and toxicity, drugs with lower HR or higher RR with lower toxicity were more likely to be approved vs. other drugs (89% vs. 46%; p = 0.025). We then divided applications into 3 periods with their corresponding approval rates: 2001-2004 (n = 11; 55%), 2005-2008 (n = 12; 50%), and 2009-2011 (n = 23; 53%). Over time, there was a significant increase in the proportion of applications using progression-free survival as an endpoint (0% to 50% to 70%; p = 0.01). Conclusion In this analysis of oncology drug applications, our model employing hazard ratio and toxicity correlates with a high rate of approval. The most common concerns of the rejected applications involved missing or inadequate data, excessive toxicity, and inadequate study endpoints. Clinical researchers need to consider these FDA recommendations in the future design of clinical trials. Disclosure All authors have declared no conflicts of interest.