Modest Improvement In Overall Survival Research Articles

Targeted therapies for gastroesophageal cancers.

Gastroesophageal cancers are some of the most common malignancies worldwide. A significant portion of patients are diagnosed with advanced or metastatic disease given the insidious nature of gastroesophageal cancers. In the instance where surgical resection for cure is no longer an option, the prognosis is poor and generally less than a year. Traditionally, standard front-line chemotherapy included two- to three-drug regimens with modest improvements in overall survival. Over the past two decades, with increased understanding of the biology of cancer, targeted therapies have been developed to stop the actions of molecules that are key in the growth and spread of cancer cells and have been successful in a number of cancers. In gastroesophageal cancer, these gains have been more modest with limited approval—trastuzumab being incorporated into front-line use in HER2-positive disease, and ramucirumab alone or in combination with paclitaxel becoming the preferred second-line regimen in progressive disease. However, with increased understanding of the biology of cancer, new and promising targeted therapies have emerged along with novel strategies in combining targeted therapies with traditional chemotherapy and immunotherapy. In this article, we will review the use of targeted therapies in the treatment of gastroesophageal cancer and touch upon future treatment strategies and therapeutics currently under investigation.

Neuropilins, as Relevant Oncology Target: Their Role in the Tumoral Microenvironment.

Angiogenesis is one of the key mechanisms involved in tumor growth and metastatic dissemination. The vascular endothelial growth factor (VEGF) and its receptors (VEGFR) represent one of the major signaling pathways which mediates angiogenesis. The VEGF/VEGFR axis was intensively targeted by monoclonal antibodies or by tyrosine kinase inhibitors to destroy the tumor vascular network. By inhibiting oxygen and nutrient supply, this strategy was supposed to cure cancers. However, despite a lengthening of the progression free survival in several types of tumors including colon, lung, breast, kidney, and ovarian cancers, modest improvements in overall survival were reported. Anti-angiogenic therapies targeting VEGF/VEGFR are still used in colon and ovarian cancer and remain reference treatments for renal cell carcinoma. Although the concept of inhibiting angiogenesis remains relevant, new targets need to be discovered to improve the therapeutic index of anti-VEGF/VEGFR. Neuropilin 1 and 2 (NRP1/2), initially described as neuronal receptors, stimulate angiogenesis, lymphangiogenesis and immune tolerance. Moreover, overexpression of NRPs in several tumors is synonymous of patients’ shorter survival. This article aims to overview the different roles of NRPs in cells constituting the tumor microenvironment to highlight the therapeutic relevance of their targeting.

Survival outcomes in an older US population with advanced melanoma and central nervous system metastases: SEER-Medicare analysis.

BackgroundCentral nervous system (CNS) metastasis is common in advanced melanoma patients. New treatment options have improved overall prognosis, but information is lacking for patients with CNS metastases. We investigated treatment patterns and survival outcomes in older melanoma patients with and without CNS metastases.MethodsA retrospective analysis of SEER‐Medicare, a population‐based linked database, was undertaken in patients aged > 65 years with advanced melanoma diagnosed from 2004 to 2011 and followed until 2013.ResultsA total of 2522 patients were included. CNS metastases were present in 24.8% of patients at initial metastatic diagnosis; 16.5% developed CNS metastases during follow‐up. Chemotherapy was the most common treatment regardless of CNS metastases. Overall survival (OS) was better for patients without CNS metastases (median, 9.5 months; 95% confidence interval [CI], 8.8‐10.2) vs patients with CNS metastases (3.63 months; 95% CI, 3.4‐3.9). Among patients with CNS metastases, median OS for targeted therapy, immunotherapy, and chemotherapy was 6 (95% CI, 2.5‐9.6), 5.5 (95% CI, 3.8‐7.5), and 4.5 (95% CI, 3.8‐5.4) months, respectively, vs 2.4 (95% CI, 2.1‐2.7) and 2.1 (95% CI, 1.8‐2.7) months for local radiotherapy and no treatment, respectively. Stereotactic radiosurgery demonstrated higher OS vs whole‐brain radiation therapy (median, 4.98 [95% CI, 3.5‐7.5] vs 2.4 [95% CI, 2.1‐2.7] months).ConclusionPatients with CNS metastases from melanoma remain a population with high unmet medical need despite recent advances in treatment. Systemic treatments (eg, BRAF‐targeted therapy and immunotherapy) and stereotactic radiosurgery demonstrated meaningful but modest improvements in OS. Further explorations of combinations of radiotherapy, BRAF‐targeted therapies, and immunotherapies are needed.

Role of Focal Adhesion Kinase in Small-Cell Lung Cancer and Its Potential as a Therapeutic Target.

Small-cell lung cancer (SCLC) represents 15% of all lung cancers and it is clinically the most aggressive type, being characterized by a tendency for early metastasis, with two-thirds of the patients diagnosed with an extensive stage (ES) disease and a five-year overall survival (OS) as low as 5%. There are still no effective targeted therapies in SCLC despite improved understanding of the molecular steps leading to SCLC development and progression these last years. After four decades, the only modest improvement in OS of patients suffering from ES-SCLC has recently been shown in a trial combining atezolizumab, an anti-PD-L1 immune checkpoint inhibitor, with carboplatin and etoposide, chemotherapy agents. This highlights the need to pursue research efforts in this field. Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that is overexpressed and activated in several cancers, including SCLC, and contributing to cancer progression and metastasis through its important role in cell proliferation, survival, adhesion, spreading, migration, and invasion. FAK also plays a role in tumor immune evasion, epithelial-mesenchymal transition, DNA damage repair, radioresistance, and regulation of cancer stem cells. FAK is of particular interest in SCLC, being known for its aggressiveness. The inhibition of FAK in SCLC cell lines demonstrated significative decrease in cell proliferation, invasion, and migration, and induced cell cycle arrest and apoptosis. In this review, we will focus on the role of FAK in cancer cells and their microenvironment, and its potential as a therapeutic target in SCLC.

Trends in practice patterns and outcomes: A decade of sarcoma care in the United States

BackgroundSoft tissue sarcomas (STS) represent a rare and heterogeneous group of tumors. We sought to characterize national trends in referral patterns, treatment strategies, and overall survival (OS) over the course of a decade. MethodsAdult patients with extra-abdominal STS were identified using the National Cancer Database and categorized by diagnosis year (2005–2009 and 2010–2014). High-volume hospitals (HVH) were defined as those >90th percentile in volume of STS patients treated, and others were defined as low-volume hospitals (LVH). Standard statistical methods were used to compare treatment strategies and OS by diagnosis period. ResultsOf 55,212 patients, 25,469 (46.1%) were diagnosed in 2005–2009 and 29,743 (53.9%) in 2010–2014. Despite increased utilization of neoadjuvant radiation therapy (26.6% vs. 34.8%, P < 0.001), the rate of R0 resections did not change (75.0% vs. 74.8%, P = 0.067). Furthermore, at a national level, OS did not improve over time (HR 0.99, 95% CI 0.96–1.01). When outcomes were stratified by volume, treatment at HVH compared to LVH was associated with improved rates of R0 resection (OR 1.27, 95% CI 1.20–1.35) and OS (HR 0.92, 95% CI 0.89–0.95). Moreover, there was a modest improvement in OS at HVH (HR 0.95, 95% CI 0.91–1.00), but not at LVH (HR 1.01, 95% CI 0.97–1.04). However, referral to HVH did not change over time (40.7% vs. 40.7%, P = 0.91). ConclusionOS for STS did not change at a national level over the course of a decade, although it improved at HVH. Further outcome improvements will likely require more effective systemic therapies.

Recent lessons learned in the management of acute exacerbation of idiopathic pulmonary fibrosis.

Recognising recent advances, the definition and diagnostic criteria for acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) have been updated by an international working group. The new definition describes any acute, clinically significant respiratory deterioration (both idiopathic and triggered events) characterised by evidence of new widespread alveolar abnormality. The new criteria require a previous or concurrent diagnosis of IPF, an acute worsening or development of dyspnoea typically less than 1 month in duration, chest imaging evidence on computed tomography (CT) of new bilateral ground-glass opacity and/or consolidation superimposed on a background imaging pattern of usual interstitial pneumonia not fully explained by cardiac failure or fluid overload. Due to high in-hospital mortality rates, current treatment guidelines say that the majority of patients with AE-IPF should not receive mechanical ventilation. However, new data suggest that the prognosis may have improved. This modest improvement in overall survival seen in more recent studies may be the result of differences in the diagnostic criteria, study design, baseline clinical risk factors and/or improvements in management. Based on our updated knowledge of possible preventive and therapeutic measures, including mechanical ventilation and pharmacological therapies, the current approach to the treatment of AE-IPF requires careful decision-making.

Short- and Long-Term Survival in Metastatic Pancreatic Adenocarcinoma, 1993-2013.

Background: During the past 2 decades, numerous clinical trials have focused on improving outcomes in patients with metastatic pancreatic cancer (mPDAC). The efficacy of new treatments has been demonstrated among highly selected patients in randomized phase III trials; hence, it is not clear to what extent these advances are reflected within the broader mPDAC population. Materials and Methods: Survival statistics were extracted from the SEER database for patients diagnosed with mPDAC between 1993 and 2013. Survival was analyzed using the Kaplan-Meier method and proportional hazard models. Results: The study population consisted of 57,263 patients diagnosed with mPDAC between 1993 and 2013; 52% were male, with a median age of 69 years (range, 15-104). Superior prognosis correlated with younger age, being married, tumor located within the head of the pancreas, lower grade disease, and more recent year of diagnosis. Median overall survival (OS) remained stable at 2 months between 1993 and 2013. Improvements in OS were seen for younger patients (age <50 years) and those with a more recent year of diagnosis (2009-2013). The percentage of patients who died within 2 months of initial diagnosis decreased between 1993 and 2013 (from 63.5% to 50.6%; P<.0001). The percentage of patients surviving ≥12 months improved from 4.9% in 1993 to 12.7% in 2013 (P<.0001). Conclusions: In recent years a modest improvement in OS has been seen among younger patients with mPDAC. The percentage of patients living beyond 1 year has significantly increased over time; however, the percentage of those dying within 2 months remains substantial.

Repurposing Established Compounds to Target Pancreatic Cancer Stem Cells (CSCs).

The diagnosis of pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis, in particular, when patients present with unresectable disease. While significant progress has been made in understanding the biology of PDAC, this knowledge has not translated into a clear clinical benefit and current chemotherapeutic strategies only offer a modest improvement in overall survival. Accordingly, novel approaches are desperately needed. One hypothesis that could—at least in part—explain the desolate response of PDAC to chemotherapy is the so-called cancer stem cell (CSC) concept, which attributes specific traits, such as chemoresistance, metastatic potential and a distinct metabolism to a small cellular subpopulation of the whole tumor. At the same time, however, some of these attributes could make CSCs more permissive for novel therapeutic strategies with compounds that are already in clinical use. Most recently, several publications have tried to enlighten the field with the idea of repurposing established drugs for antineoplastic use. As such, recycling drugs could present an intriguing and fast-track method with new therapeutic paradigms in anti-cancer and anti-CSC treatments. Here, we aim to summarize important aspects and novel findings of this emerging field.

Phase Ib trial of tepotinib in Asian patients with advanced hepatocellular carcinoma (HCC): Final data including long-term outcomes.

4087 Background: The incidence of hepatocellular carcinoma (HCC), a leading cause of cancer death, is increasing with the increasing incidence of chronic liver disease. Sorafenib, the only approved systemic therapy for advanced HCC, provides modest improvement in overall survival. Preclinical studies suggest c-Met is a valid target in HCC, but non-selective TKIs with c-Met inhibitory activity have not shown efficacy in trials, possibly due to lack of c-Met inhibition. Tepotinib (MSC2156119J) is a highly selective c-Met inhibitor that has favorable safety and promising activity, particularly against c-Met+ solid tumors. We report the final results of a phase Ib trial of tepotinib in patients (pts) with advanced HCC. Methods: Pts were Asian adults with confirmed HCC of BCLC Stage C, Child-Pugh Class A liver function without encephalopathy, and ECOG PS 0–2. Pts received tepotinib 300, 500 (the RP2D) or 1,000 mg/day on a 21-day cycle. c-Met expression status was retrospectively determined by IHC. Results: 27 pts were enrolled (median age 57 [38-69]; male 23; ECOG PS 0/1 11/16); 7 received tepotinib 300 mg/day, 14 500 mg/day, and 6 1,000 mg/day (3 with dose reduction). No DLTs were observed. 22 pts experienced treatment-related treatment-emergent adverse events (TRTEAEs), most commonly diarrhea (n = 10), nausea (8), elevated AST (7), and elevated ALT (6). 9 pts had grade ≥3 TRTEAEs, including elevated AST (3) and elevated ALT (3). Best overall response (BOR) was partial response (PR) in 2 pts, one of whom received tepotinib 500 mg (response duration 16.1 months) and one 1,000 mg (4.4 months); both had c-Met+ tumors. A further 8 pts had a BOR of stable disease (SD), 1 pt non-complete response (CR)/non-progressive disease (PD), and 14 pts had PD (2 pts not evaluable). Five pts had progression free survival &gt; 8 months. PK were as expected from previous studies. Conclusions: Tepotinib at doses of up to 1,000 mg/day was well tolerated by Asian pts with advanced HCC and a maximum tolerated dose was not reached. Antitumor activity was observed, particularly in pts with c-Met+ tumors. The ongoing phase II part of this study is comparing the efficacy and safety of first-line tepotinib and sorafenib in pts with c-Met+ HCC. Clinical trial information: NCT01988493.

A meta-analysis of trials of etoposide plus platinum agent versus irinotecan/topotecan plus platinum agent in first-line therapy of extensive stage small cell lung cancer (ES SCLC).

e20019 Background: Etoposide plus a platinum agent (EP) represents the standard treatment of ES SCLC. A trial conducted in Japan demonstrated improved overall survival (OS) for irinotecan and cisplatin (IP), but subsequent trials could not consistently replicate these findings. Genotypic differences may explain these findings. These trials have not undergone systematic analysis. Methods: We conducted a systematic review and metaanalysis of randomized trials (RCT) comparing etoposide plus a platinum agent (EP) with irinotecan (IP) or topotecan (TP) plus a platinum agent. A literature search was undertaken of Cochrane Database, MEDLINE and Embase from 1996 to June 2016 to identify RCTs addressing this question. Data were extracted by one author and checked independently, then synthesized using RevMan software using a random effects model. Outcomes of interest were OS, quality of life (QoL) and toxicity. Results: Three RCTs compared TP and EP. There was no difference in OS (HR 0.97, 95%CI 0.87 – 1.07). Eight RCTs compared IP and EP, although only 7 had data that could be combined. IP significantly improved OS compared with EP (HR 0.84, 95%CI 0.74 – 0.95). The estimated improvement in 12 month OS is 6.4%. There was evidence of statistical heterogeneity. After removal of the trial by Noda et al, there was still a significant improvement in OS (HR 0.88, 95%CI 0.79 – 0.98). IP was associated with less grade 3/4 neutropenia, febrile neutropenia, anemia, thrombocytopenia, but more diarrhea. QoL was assessed in 2 trials and no differences observed. Conclusions: IP results in modest improvements in OS in comparison with EP. IP is associated with less hematological toxicity but more diarrhea and should be considered an acceptable alternative to EP in the first-line treatment of ES SCLC. [Table: see text]

Long-Term Follow-Up of the Intergroup Exemestane Study.

Purpose The Intergroup Exemestane Study, an investigator-led study of 4,724 postmenopausal patients with early breast cancer (clinical trial information: ISRCTN11883920), has previously demonstrated that a switch from adjuvant endocrine therapy after 2 to 3 years of tamoxifen to exemestane was associated with clinically relevant improvements in efficacy. Here, we report the final efficacy analyses of this cohort. Patients and Methods Patients who remained disease free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to exemestane to complete a total of 5 years of adjuvant endocrine therapy. Given the large number of non-breast cancer-related deaths now reported, breast cancer-free survival (BCFS), with censorship of intercurrent deaths, was the primary survival end point of interest. Analyses focus on patients with estrogen receptor-positive or unknown tumors (n = 4,599). Results At the time of the data snapshot, median follow-up was 120 months. In the population that was estrogen receptor positive or had unknown estrogen receptor status, 1,111 BCFS events were observed with 508 (22.1%) of 2,294 patients in the exemestane group and 603 (26.2%) of 2,305 patients in the tamoxifen group. The data corresponded to an absolute difference (between exemestane and tamoxifen) at 10 years of 4.0% (95% CI, 1.2% to 6.7%), and the hazard ratio (HR) of 0.81 (95% CI, 0.72 to 0.92) favored exemestane. This difference remained in multivariable analysis that was adjusted for nodal status, prior use of hormone replacement therapy, and prior chemotherapy (HR, 0.80; 95% CI, 0.71 to 0.90; P < .001). A modest improvement in overall survival was seen with exemestane; the absolute difference (between exemestane and tamoxifen) at 10 years in the population that was estrogen receptor positive or had unknown estrogen receptor status was 2.1% (95% CI, -0.5% to 4.6%), and the HR was 0.89 (95% CI, 0.78 to 1.01; P = .08). For the intention-to-treat population, the absolute difference was 1.6% (95% CI, -0.9% to 4.1%); the HR was 0.91 (95% CI, 0.80 to 1.03, P = .15). No statistically significant difference was observed in the proportion of patients who reported a fracture event in the post-treatment period. Conclusion The Intergroup Exemestane Study and contemporaneous studies have established that a strategy of switching to an aromatase inhibitor after 2 to 3 years of tamoxifen can lead to sustained benefits in terms of reduction of disease recurrence and breast cancer mortality.

Dendritic cell based vaccination strategy: an evolving paradigm.

Malignant gliomas (MG), tumors of glial origin, are the most commonly diagnosed primary intracranial malignancies in adults. Currently available treatments have provided only modest improvements in overall survival and remain limited by inevitable local recurrence, necessitating exploration of novel therapies. Among approaches being investigated, one of the leading contenders is immunotherapy, which aims to modulate immune pathways to stimulate the selective destruction of malignant cells. Dendritic cells (DCs) are potent initiators of adaptive immune responses and therefore crucial players in the development and success of immunotherapy. Clinical trials of various DC-based vaccinations have demonstrated the induction of anti-tumor immune responses and prolonged survival in the setting of many cancers. In this review, we summarize current literature regarding DCs and their role in the tumor microenvironment, their application and current clinical use in immunotherapy, current challenges limiting their efficacy in anti-cancer therapy, and future avenues for developing successful anti-tumor DC-based vaccines.

An analysis of the National Cancer Database (NCDB): Immunotherapy and survival in stage III melanoma.

159 Background: High dose Interferon (IFN) was the standard adjuvant treatment used for stage III melanoma between 2004-2010. To our knowledge, this is the largest study using the NCDB to determine the impact of immunotherapy used prior to 2011 in stage III melanoma. Methods: We identified 19,864 patients with stage III melanoma between 2004-2010. Among these, 5,406 of them received immunotherapy. Chi-square analysis was used to determine demographic differences between those with versus without immunotherapy. Between-therapy survival differences were estimated by the Kaplan-Meier method and associated log-rank tests; Tukey-Kramer adjusted p &lt; 0.05 indicated statistical significance. Results: Patients who received immunotherapy had a mean survival of 89.8 months while those who did not had a mean survival of 71 months. The percentage of patients alive at 5 and 10 years was 62% and 52% (among those who received immunotherapy) compared to 46% and 32% (among those who did not receive immunotherapy) respectively. A much higher percentage of these patients were privately insured (73% vs. 47.1%, p&lt;0.001). Those who received immunotherapy were more likely to be younger, have a higher income (36.2% vs. 34.8%, p&lt;0.001), and a greater percentage of females received immunotherapy compared to males. (See Table 1.) Conclusions: Previously, Kirkwood et al. demonstrated a modest improvement in overall survival with IFN by 12 months (2.8 to 3.8 years). In our study, patients who received immunotherapy had a significant improvement in mean survival by 19 months. It was observed that patients who received immunotherapy were substantially younger, had private insurance and fewer comorbidities. [Table: see text]

Short and long-term survival in metastatic pancreatic adenocarcinoma, 1993-2013.

232 Background: Over the previous two decades several new agents have been approved for the treatment of metastatic pancreatic cancer (mPDAC). Their efficacy was demonstrated amongst highly selected patients that participate in randomized phase III trials, hence it is not clear to what extent these advances are reflected within the broader mPDAC population. We performed a population-based survival analysis of newly diagnosed patients who presented with mPDAC. Methods: Survival statistics were extracted from the Survival, Epidemiology and End Results (SEER) Database for patients diagnosed with mPDAC between 1993-2013. Demographic variables collected included age, gender, race, and marital status. Tumor characteristics collected included location and grade. Survival was analyzed using the Kaplan-Meier method and proportional hazard models as appropriate. Exclusion criteria included diagnosis at autopsy, unknown histology and pancreatic neuroendocrine tumors. Results: The study population consisted of 57,263 patients diagnosed with mPDAC from 1993-2013, 52% male, median age 69 years (range 15-104). Prognosis correlated with age, gender, race, marital status, tumor location, grade and year of diagnosis. Median overall survival (OS) stayed stable at 2 months between 1993 and 2013. Improvements in OS were seen for all patients, but especially for younger patients ( &lt; 50 years of age) and more recent year of diagnosis group (2009-2013). The percentage of patients who died within two months of initial diagnosis decreased between 1993 and 2013 (from 63.5% to 50.6%, p &lt; 0.0001). The subgroup of patients achieving longer-term survival has increased, with 12-month survival improving from 4.9 % to 12.7% (p &lt; 0.0001) between 1993 and 2013. Conclusions: There has been a continuous but modest improvement in OS of patients diagnosed with mPDAC between 1993 and 2013. The percentage of patients living beyond one year has significantly increased over time; however the percentage of patients dying within 2 months has only slightly decreased.

Mortality trends and the impact of lymphadenectomy on survival for renal cell carcinoma patients with distant metastasis.

Current treatment paradigms for metastatic renal cell carcinoma (mRCC) invoke a combination of surgical and systemic therapies. We sought to quantify trends in mortality and performance of lymphadenectomy, as well as impact on survival for patients with mRCC. The Surveillance, Epidemiology, and End Results registry (SEER) (1988-2011) identified patients with mRCC. Kaplan-Meier curves and Cox proportional hazards models with competing risks regression were employed to assess survival. 15 060 patients with mRCC were identified, with 6316 (41.9%) undergoing cytoreductive nephrectomy. Mean number of lymph nodes removed was 6.2, with mean 3.3 positive nodes among 1018 (43.9%) patients with positive nodes. Median overall survival (OS) increased from seven to 11 months (1999-2010), and finding a positive node decreased median cancer survival from 22 to nine months. Cancer-specific survival (CSS) showed significant decreases in mortality after 2005 (hazard ratio [HR] 0.71 [0.60-0.83] comparing 2010 to 1990). Lymphadenectomy was associated with decreased OS (HR 1.10 [1.03-1.16]; p=0.002) due to decreased CSS (HR 1.10 [1.04-1.17]; p<0.001) without increase in other-cause mortality (HR 0.94 [0.79-1.11]; p=0.455). However, more extensive lymphadenectomy ≥3 lymph nodes removed did not significantly impact OS or CSS. Number of positive lymph nodes was associated with decreased CSS. mRCC continues to carry a poor prognosis, but current treatment paradigms have led to modest improvements in OS and CSS in recent years. Lymphadenectomy was found to play a prognostic rather than therapeutic role in the management of mRCC. The performance of lymphadenectomy should be limited based on clinical judgment and better incorporated into randomized trials of new systemic therapies to identify scenarios where implementation may improve survival.

Myelodysplastic/Myeloproliferative Neoplasms Unclassified (MDS/MPN-U) Overlap: Can We Alter the Natural History?

Introduction:The 2008 World Health Organization classification recognized a unique overlap category that combines features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). The least well characterized of the 4 overlap diseases is a rare entity known as MDS/MPN Unclassifiable (MDS/MPN-U), comprising <5% of myeloid disorders. The outcome of this subtype has been reported to be poor. The response to and impact of hypomethylating agents (HMA) on outcome is not well studied.Methods:We identified MDS/MPN-U patients within the Moffitt MDS database, baseline characteristics were reviewed, and responses to HMA utilizing IWG 2006 response criteria were assessed. The Kaplan-Meier method was applied to estimate overall survival (OS).Results:Among 127 patients with MDS/MPN-U, 62 patients received HMA treatment. There was no difference in baseline characteristics among those who received HMA or not, except that those treated with HMA were less likely to have low risk disease by IPSS, MD Anderson model or very low risk by revised IPSS (R-IPSS). Among 16 patients who had NextGen sequencing data, the 5 most common mutations were ASXL-1 (56%), TET2 (31%), JAK2 (33%), SRSF2 (25%), as well as SETBP1, DNMT3A, and EZH2(19%). The best overall response to HMA (hematological improvement [HI] or better) according to the International Working Group (IWG) 2006 criteria was 26%. Only 11 patients (low risk) underwent allogeneic stem cell transplant (allo-SCT) with no improvement or decrease in OS.The median OS was 33 months (mo). Among patients with IPSS low/int-1 risk disease, the median OS was 39 and 33 mo respectively for those treated with HMA vs. HMA untreated. (p=0.50). For Int-2/high risk IPSS, the median OS was 11 and 5 mo for those who received HMA and those who did not. (p=0.02). Based on R-IPSS the median OS for very low/low risk was 47 and 39 mo respectively for those treated with HMA and without (p=0.96), for intermediate risk, the median OS was 39 and 25 mo respectively (p 0.75), and for high and very high risk the median OS was 13 and 5 mo respectively for those treated with HMA and those who did not. (p < 0.005). The median OS for patients with HI+, stable disease or progressive disease was 68, 59, and 36 mo respectively (p=0.08).Conclusions:Treatment with HMA is associated with modest improvement in OS among higher risk MDS/MPN-U, reinforcing the unmet need to improve outcomes in this group. Targeted therapy may prove to be of benefit as allo-SCT does not appear to be beneficial for patients even with low risk disease. Furthermore, these data demonstrate the need for prospective analysis of the outcomes of allo-SCT in patients with MDS/MPN-U to determine potential benefit to high risk patients. DisclosuresKomrokji:Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Immune checkpoint inhibitors in non-small cell lung cancer: is simultaneous blockade better?

Immunotherapy has proven to be a major breakthrough in the treatment of a variety of cancers, having been called the major oncologic achievement in 2015 by the American Society of Clinic Oncology. Two immune checkpoint inhibitors, antibodies to the programmed cell death protein-1 receptor (PD-1), received FDA approval in 2015 for the treatment of advanced non-small cell lung cancer, and others similar agents are actively being studied. Advancements in the treatment of lung cancer have been desperately needed as treatment strategies utilizing platinum-based doublet therapy result in modest improvements in overall survival with a median of 8–10 months and 2-year survival rates of 10–15% in patients with metastatic disease (1).

A first-in-class therapy for the treatment of advanced stage liver cancer.

e14061Background: Hepatocellular carcinoma (HCC) is the second most common cause of death from cancer worldwide. Current standard of care provides only a modest improvement in overall survival and ...

Encouraging results for PD-1 inhibition in gastric cancer

The prognosis for advanced gastric cancer is poor: less than 10–15% of patients with metastases live for more than 2 years. Trastuzumab and ramucirumab have resulted in modest improvements in overall survival for patients with HER2-positive gastric cancer and in the second-line setting, respectively. 1 Bang YJ Van Cutsem E Feyereislova A et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010; 376: 687-697 Google Scholar , 2 Wilke H Muro K Van Cutsem E et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014; 15: 1224-1235 Google Scholar However, these drugs are notable for their success in a field in which there have been many failures. 1 Bang YJ Van Cutsem E Feyereislova A et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010; 376: 687-697 Google Scholar , 2 Wilke H Muro K Van Cutsem E et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014; 15: 1224-1235 Google Scholar , 3 Ohtsu A Shah MA Van Cutsem E et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011; 29: 3968-3976 Google Scholar , 4 Waddell T Chau I Cunningham D et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol. 2013; 14: 481-489 Google Scholar Within this challenging therapeutic context, the results of the KEYNOTE-012 study by Kei Muro and colleagues 5 Muro K Chung HC Shankaran V et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol. 2016; (published online May 3.)http://dx.doi.org/10.1016/S1470-2045(16)00175-3 Google Scholar are promising. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trialIn this population of patients with recurrent or metastatic PD-L1-positive gastric cancer, pembrolizumab had a manageable toxicity profile and promising antitumour activity, warranting further study in phase 2 and 3 trials. Full-Text PDF

Effect of Anti-Fungal Prophylaxis on the Fungal Mycobiome after Allogeneic Bone Marrow Transplantation

Background: Intestinal bacteria shape the immune system and have been shown to contribute to GI tract inflammation. Modification of the lower GI tract bacterial microbiota has been correlated with decreased acute graft-versus-host disease (aGvHD) [1]. Additionally, decreased intestinal bacterial diversity has been associated with increased nonrelapse mortality following allogeneic stem cell transplantation (alloSCT), largely due to an association with severe aGvHD[2]. However, the role of the fungal mycobiome during aGvHD has been largely ignored. Antifungal prophylaxis with fluconazole has been found to decrease long-term transplant mortality following alloSCT. We wanted to determine (1) effect of anti-fungal prophylaxis on the fungal mycobiome and (2) whether enteric fungi contributes to aGvHD by promoting a pro-inflammatory environment in the GI tract, similar to certain bacteria.Methods: B6D2 recipient mice were lethally irradiated, and the following day, recipient mice received 3 x106 T cell depleted bone marrow cells and 4 x 106 naïve T cells from B6 donor mice. Recipient mice were followed for survival and scored for clinical GvHD using a standard scoring system. Mice were treated daily with the antifungal agent fluconazole at 5mg/kg/day. Stool samples were collected on days 0, 7, and 14 post-transplant, and DNA was isolated from stool. The fungal ribosomal internal transcribed spacer region (specifically ITS-1) was amplified by PCR and sequencing libraries generated using Illumina chemistry and evaluated on a MiSeq sequencer. Additionally, real-time PCR was performed on DNA from stool samples to quantitate fungi in the colon. Colons were harvested, immune cells isolated and evaluated for flow cytometric analysis after bone marrow transplantation. Intestinal permeability was assessed by oral administration of FITC-labeled dextran 4000, followed by peripheral blood collection to assess plasma FITC-dextran levels.Results: In B6D2 mice, the most common fungal species found in the colon before and after bone marrow transplantation was Candida tropicalis. We found a 50-75% decrease in the quantity of fungi present in the colon in fluconazole treated mice. However there was no alteration in the percentages of fungi found in the GI tract indicating that anti-fungal therapy alter the quantity and not the quality of the fungal microbiome. Specifically, we did not find that the administration of fluzonazole was associated with an increase in fluconazole-resistant Candida species such as C kruseii or with fungi intrinsically resistant to fluconazole such as Aspergillus organisms. While there was no difference in clinical scoring of GVHD or weight loss in fluconazole treated mice, there was a modest improvement in overall survival in the treated group. We found no differences in IFN-γ or IL-17 production by colonic T cells from mice treated with fluconazole as compared to control mice evaluated 14 days after transplant. Additionally, the percentage of Foxp3+ T cells was also similar between treated and control mice. We also found no change in aGvHD mediated intestinal permeability suggesting that fluconazole treatment has no effect on epithelial barrier function.Conclusion: These studies demonstrate that fluconazole decreases total colonic fungi without altering the relative frequency of fungal organisms and is not associated in mice with an increase in the presence of fluconazole-resistant fungi. Fluconazole treatment was associated with a modest improvement in overall survival. However, no differences were found in the percentage/number of donor TH1, TH17 or Treg cells in the colon. These data suggest that, in the B6->B6D2 model, decreasing fungal burden in the colon is associated with a modest improvement in overall survival without substantially altering the generation of pro-inflammatory T cells or Tregs.1. Jenq RR et al. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J Exp Med. 2012 May 7;209(5):903-11. doi: 10.1084/jem.20112408. Epub 2012 Apr 30.2. Taur Y, et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood. 2014 Aug 14;124(7):1174-82. doi: 10.1182/blood -2014-02-554725. Epub 2014 Jun 17. DisclosuresNo relevant conflicts of interest to declare.