Real‐World Toxicity Experience with BRAF/MEK Inhibitors in Patients with Erdheim‐Chester Disease

3 weeks 3 days ago
AbstractBackground.Erdheim‐Chester disease (ECD) is a rare non‐Langerhans cell histiocytosis. The BRAF inhibitor vemurafenib is approved by the U.S. Food and Drug Administration (FDA) for patients with ECD harboring a BRAF V600E mutation. Successful treatment has also been reported with MEK‐targeted therapies, likely because of the fact that BRAF mutant–negative patients harbor MEK pathway alterations. In our Rare Tumor Clinic, we noted that these patients have frequent drug‐related toxicity, consistent with previous reports indicating the need to markedly lower doses of interferon‐alpha when that agent is used in these patients.Patients and Methods.We performed a review of ten patients with ECD seen at the Rare Tumor Clinic at University of California San Diego receiving 16 regimens of targeted BRAF, MEK, or combined therapies.Results.The median age of the ten patients with ECD was 53 years (range, 29–77); seven were men. The median dose percentage (percent of FDA‐approved dose) tolerated was 25% (range, 25%–50%). The most common clinically significant adverse effects resulting in dose adjustments of targeted therapies were rash, arthralgias, and uveitis. Renal toxicity and congestive heart failure were seen in one patient each. In spite of these issues, eight of ten patients (80%) achieved a partial remission on therapy.Discussion.Patients with ECD appear to require substantially reduced doses of BRAF and MEK inhibitors but are responsive to these lower doses.
Ila M. Saunders, Aaron M. Goodman, Razelle Kurzrock

Guardant360 Circulating Tumor DNA Assay Is Concordant with FoundationOne Next‐Generation Sequencing in Detecting Actionable Driver Mutations in Anti‐EGFR Naive Metastatic Colorectal Cancer

3 weeks 3 days ago
AbstractBackground.Direct comparisons between Guardant360 (G360) circulating tumor DNA (ctDNA) and FoundationOne (F1) tumor biopsy genomic profiling in metastatic colorectal cancer (mCRC) are limited. We aim to assess the concordance across overlapping genes tested in both F1 and G360 in patients with mCRC.Materials and Methods.We retrospectively analyzed 75 patients with mCRC who underwent G360 and F1 testing. We evaluated the concordance among gene mutations tested by both G360 and F1 among three categories of patients: untreated, treated without, and treated with EGFR inhibitors, while considering the clonal and/or subclonal nature of each genomic alteration.Results.There was a high rate of concordance in APC, TP53, KRAS, NRAS, and BRAF mutations in the treatment‐naive and non–anti‐EGFR‐treated cohorts. There was increased discordance in the anti‐EGFR treated patients in three drivers of anti‐EGFR resistance: KRAS, NRAS, and EGFR somatic mutations. Based on percentage of ctDNA, discordant somatic mutations were mostly subclonal instead of clonal and may have limited clinical significance. Most discordant amplifications noted on G360 showed the magnitude below the top decile, occurred in all three cohorts of patients, and were of unknown clinical significance. Serial ctDNA in anti‐EGFR treated patients showed the emergence of multiple new alterations that affected the EGFR pathway: EGFR and RAS mutations and MET, RAS, and BRAF amplifications.Conclusion.G360 Next‐Generation Sequencing platform may be used as an alternative to F1 to detect targetable somatic alterations in non–anti‐EGFR treated mCRC, but larger prospective studies are needed to further validate our findings.Implications for Practice.Genomic analysis of tissue biopsy is currently the optimal method for identifying DNA genomic alterations to help physicians target specific genes but has many disadvantages that may be mitigated by a circulating free tumor DNA (ctDNA) assay. This study showed a high concordance rate in certain gene mutations in patients who were treatment naive and treated with non–anti‐EGFR therapy prior to ctDNA testing. This suggests that ctDNA genomic analysis may potentially be used as an alternative to tumor biopsy to identify appropriate patients for treatment selection in mCRC, but larger prospective studies are needed to further validate concordance among tissue and ctDNA tumor profiling.
Rohan Gupta, Tamer Othman, Chen Chen, Jaideep Sandhu, Ching Ouyang, Marwan Fakih

A Phase I Trial Using a Multitargeted Recombinant Adenovirus 5 (CEA/MUC1/Brachyury)‐Based Immunotherapy Vaccine Regimen in Patients with Advanced Cancer

3 weeks 3 days ago
AbstractLessons Learned.Concurrent ETBX‐011, ETBX‐051, and ETBX‐061 can be safely administered to patients with advanced cancer.All patients developed CD4+ and/or CD8+ T‐cell responses after vaccination to at least one tumor‐associated antigen (TAA) encoded by the vaccine; 5/6 patients (83%) developed MUC1‐specific T cells, 4/6 (67%) developed CEA‐specific T cells, and 3/6 (50%) developed brachyury‐specific T cells.The presence of adenovirus 5‐neutralizing antibodies did not prevent the generation of TAA‐specific T cells.Background.A novel adenovirus‐based vaccine targeting three human tumor‐associated antigens—CEA, MUC1, and brachyury—has demonstrated antitumor cytolytic T‐cell responses in preclinical animal models of cancer.Methods.This open‐label, phase I trial evaluated concurrent administration of three therapeutic vaccines (ETBX‐011 = CEA, ETBX‐051 = MUC1, and ETBX‐061 = brachyury). All three vaccines used the same modified adenovirus 5 (Ad5) vector backbone and were administered at a single dose level (DL) of 5 × 1011 viral particles (VP) per vector. The vaccine regimen consisting of all three vaccines was given every 3 weeks for three doses then every 8 weeks for up to 1 year. Clinical and immune responses were evaluated.Results.Ten patients enrolled on trial (DL1 = 6 with 4 in the DL1 expansion cohort). All treatment‐related adverse events were temporary, self‐limiting, grade 1/2 and included injection site reactions and flu‐like symptoms. Antigen‐specific T cells to MUC1, CEA, and/or brachyury were generated in all patients. There was no evidence of antigenic competition. The administration of the vaccine regimen produced stable disease as the best clinical response.Conclusion.Concurrent ETBX‐011, ETBX‐051, and ETBX‐061 can be safely administered to patients with advanced cancer. Further studies of the vaccine regimen in combination with other agents, including immune checkpoint blockade, are planned.
Margaret E. Gatti-Mays, Jason M. Redman, Renee N. Donahue, Claudia Palena, Ravi A. Madan, Fatima Karzai, Mariȷo Bilusic, Houssein Abdul Sater, Jennifer L. Marte, Lisa M. Cordes, Sheri McMahon, Seth M. Steinberg, Alanvin Orpia, Andrea Burmeister,…

Implementation of Best Practice Recommendations for Palliative Care in German Comprehensive Cancer Centers

3 weeks 6 days ago
AbstractBackground.From 2014 to 2017, the Palliative Medicine Working Group developed and published best practice recommendations for the integration of palliative care in Comprehensive Cancer Centers (CCCs) in Germany. To evaluate the implementation level of these recommendations in the CCCs an online survey was performed. Based on the results of this study, strategic tandem partnerships between CCCs should be built in order to foster further local development.Materials and Methods.Directors of all CCCs were contacted by e‐mail between December 2017 and February 2018. At the time of the survey, 15 CCCs were funded by the German Cancer Aid. The level of implementation of the recommendations in individual CCCs was established using a transtheoretical model.Results.Between December 2017 and February 2018, all 15 contacted directors or their representatives of the CCCs took part in the survey. More than two thirds of the CCCs have a palliative service as well as a day clinic and palliative outpatient clinic. Regional networking and the provision of a palliative care unit were approved by all CCCs.Conclusion.The publication of best practice recommendations was a milestone for the integration of palliative care in the CCCs. The majority of the German CCCs already fulfill essential organizational and structural requirements. There is a particular need for optimization in the provision of a basic qualification for general palliative care and emergency admission personnel.Implications for Practice.In 2017, the Palliative Medicine Working Group in the network of the German Comprehensive Cancer Centers (CCCs) published the best practice recommendations it had developed for the integration of palliative medicine in CCCs in Germany. In order to evaluate the level of implementation of the recommendations, an online survey of the CCC directors was established. The majority of German CCCs fulfil elementary organizational and structural requirements. However, there is still room for improvement in the provision of a basic qualification for general palliative care and emergency admission personnel.
Susanne Gahr, Sarah Lodel, Julia Berendt, Michael Thomas, Christoph Ostgathe

Blinatumomab for Acute Lymphoblastic Leukemia: The First Bispecific T‐Cell Engager Antibody to Be Approved by the EMA for Minimal Residual Disease

4 weeks ago
AbstractOn November 15, 2018, the Committee for Medicinal Products for Human Use (CHMP) recommended the extension of indication for blinatumomab to include the treatment of adults with minimal residual disease (MRD) positive B‐cell precursor acute lymphoblastic leukemia (ALL). Blinatumomab was authorized to treat relapsed or refractory B‐precursor ALL, and the change concerned an extension of use. On March 29, 2018, the U.S. Food and Drug Administration (FDA) granted accelerated approval to blinatumomab to treat both adults and children with B‐cell precursor ALL who are in remission but still have MRD. On July 26, 2018, the CHMP had originally adopted a negative opinion on the extension. The reason for the initial refusal was that although blinatumomab helped to reduce the amount of residual cancer cells in many patients, there was no strong evidence that it led to improved survival. During the re‐examination, the CHMP consulted the scientific advisory group. The CHMP agreed with the expert group's conclusion that, although there was no strong evidence of patients living longer, the available data from the main study (MT103‐203) indicated a good durable response to blinatumomab, with an overall complete response rate for the primary endpoint full analysis set (defined as all subjects with an Ig or T‐cell receptor polymerase chain reaction MRD assay with the minimum required sensitivity of 1 × 10–4 at central lab established at baseline [n = 113]) as 79.6% (90/113; 95% confidence interval, 71.0–86.6), with a median time to complete MRD response of 29.0 days (range, 5–71). Therefore, the CHMP concluded that the benefits of blinatumomab outweigh its risks and recommended granting the change to the marketing authorization.The Committee for Orphan Medicinal Products, following reassessment, considered that significant benefit continued to be met and recommended maintaining the orphan designation and thus 10 years market exclusivity (the Orphan Designation is a legal procedure that allows for the designation of a medicinal substance with therapeutic potential for a rare disease, before its first administration in humans or during its clinical development). The marketing authorization holder for this medicinal product is Amgen Europe B.V.Implications for Practice.Immunotherapy with blinatumomab has excellent and sustainable results, offering new hope for patients with minimal residual disease‐positive acute lymphoblastic leukemia, a disease with poor prognosis. New recommendations and change of practice for treatment of this patient group are detailed.
Sahra Ali, Alexandre Moreau, Daniela Melchiorri, Jorge Camarero, Filip Josephson, Odoardo Olimpier, Jonas Bergh, Dominik Karres, Kyriaki Tzogani, Christian Gisselbrecht, Francesco Pignatti

Bioelectrical Impedance Analysis for the Assessment of Sarcopenia in Patients with Cancer: A Systematic Review

1 month ago
AbstractBackground.The loss of muscle mass, known as sarcopenia, is a natural process of aging that is associated with adverse health outcomes regardless of age. Because cancer is a disease of aging, interest in sarcopenia and its potential impact in multiple cancer populations has increased significantly. Bioelectrical impedance analysis (BIA) is a guideline‐accepted method for sarcopenia detection. This systematic review assesses the literature pertaining to BIA use in the detection of sarcopenia in adults with cancer.Materials and Methods.In this systematic review, a search of the literature for randomized controlled trials and observational studies was conducted using MEDLINE, Cochrane CENTRAL, and EMBASE, through July 15, 2019. The study is registered at Prospero (CRD 42019130707). For study inclusion, patients had to be aged 18 years or older and diagnosed with solid or hematological neoplasia, and BIA had to be used to detect sarcopenia.Results.Through our search strategy, 5,045 articles were identified, of which 24 studies were selected for inclusion in the review (total number of 3,607 patients). In five studies, BIA was rated comparable to axial computed tomography (CT) scan, calf circumference, or grip strength for sarcopenia screening. In 14 studies, BIA‐identified sarcopenia was associated with adverse clinical outcomes.Conclusion.BIA is an accurate method for detecting sarcopenia in adults with cancer prior to treatment and is a viable alternative to CT, dual‐energy x‐ray absorptiometry, and magnetic resonance imaging in oncology clinical practice.Implications for Practice.Bioelectrical impedance analysis (BIA) is an attractive method for identifying sarcopenic patients in clinical practice because it provides an affordable, noninvasive test that can be completed within a few minutes during a clinic visit. BIA does not require highly skilled personnel, and results are immediately available. This systematic review summarizes the literature pertaining to BIA assessment of sarcopenia in adults with cancer, with a focus on its use in diverse cancer populations.
Gabriel F.P. Aleixo, Shlomit S. Shachar, Kirsten A. Nyrop, Hyman B. Muss, Claudio L. Battaglini, Grant R. Williams

Biliary Stone Disease in Patients with Neuroendocrine Tumors Treated with Somatostatin Analogs: A Multicenter Study

1 month ago
AbstractBackground.Somatostatin analogs (SSAs) are the mainstay of neuroendocrine tumor (NET) treatment. Biliary stone disease is reported as a common side effect of SSAs, with a frequency ranging from 10% to 63%. Studies on SSA‐treated patients for acromegaly report an increased incidence of biliary stone disease compared with the general population, whereas data on patients with NETs are few. Guidelines are based on weak evidence, thus resulting in conflicting recommendations. The aim of the study is to evaluate biliary stone disease incidence, complications, and risk factors in a large population of SSA‐treated patients with NETs.Materials and Methods.A retrospective analysis of a prospectively collected database was performed. Patients with a diagnosis of NET in seven dedicated centers from 1995 to 2017 were included at the time of SSA start.Results.A total of 754 SSA‐treated patients were evaluated. Patients with history of cholecystectomy or with known biliary stone disease were excluded; 478 patients were included. Among them, 118 patients (24.7%) received prophylactic ursodeoxycholic acid (UDCA). During the study period, 129 patients (27.0%) developed biliary stone disease; of them, 36 (27.9%) developed biliary complications. On multivariate analysis, primary gastrointestinal (GI)‐NET (hazard ratio [HR] 1.76) and related surgery (HR 1.58) were independent risk factors for biliary stone disease.Conclusion.We report a high incidence of biliary stone disease particularly in GI‐NET or GI surgery. UDCA prophylaxis does not seem to have a protective role. Our data suggest that all patients with primary GI‐NET or undergoing abdominal surgery should be considered for prophylactic cholecystectomy; no conclusion could be drawn on the indication of prophylactic cholecystectomy in patients with primary pancreatic or thoracic NET for whom abdominal surgery is not planned.Implications for Practice.The results of this study confirm an increased rate of gallstones development and related complications in patients with neuroendocrine tumors (NETs) treated with somatostatin analogs (SSAs). NETs of the gastrointestinal (GI) tract and related surgery are independent risk factors for biliary stone disease development. Therefore, all patients with primary GI‐NET or undergoing abdominal surgery should be considered for prophylactic cholecystectomy. Data on other subgroups are not exhaustive, and management also evaluating additional clinical features (life expectancy, surgical and anesthesiological risks) should be considered. Prophylactic treatment with ursodeoxycholic acid does not seem to be a protective factor for SSA‐related biliary stone disease.
Nicole Brighi, Francesco Panzuto, Roberta Modica, Fabio Gelsomino, Manuela Albertelli, Sara Pusceddu, Sara Massironi, Giuseppe Lamberti, Maria Rinzivillo, Antongiulio Faggiano, Andrea Spallanzani, Diego Ferone, Natalie Prinzi, Roberta Elisa Rossi, Bruno…

Comprehensive Analysis of AR Alterations in Circulating Tumor DNA from Patients with Advanced Prostate Cancer

1 month ago
AbstractBackground.Somatic alterations in circulating tumor DNA (ctDNA) may be associated with treatment response or prognosis in prostate cancer (PCa). The goal was to characterize androgen receptor gene (AR) amplifications and mutations detected in ctDNA from patients with PCa and to further understand the somatic genetic heterogeneity of advanced prostate cancer.Patients and Methods.This study included a heterogeneous group of 892 patients with advanced PCa (predominantly castrate‐resistant prostate cancer) with AR alterations detected in ctDNA that underwent next‐generation sequencing of 54 to 73 genes via Guardant360 testing (Guardant Health, Inc., Redwood City, CA). Distribution and summary of AR alterations detected, the association of AR alterations with other genes, and a pathway analysis are reported.Results.The median absolute plasma copy number of AR amplifications was 3.3 (range, 1.2–165.2). Many patients had multiple AR mutations; a total of 112 unique mutations were identified in AR, including L702H (25%), T878A (14%), H875Y (11%), W742C (8%), W742L (4%), F877L (2%), and T878S (2%). Other ctDNA gene alterations in the Guardant assays included TP53 (50%), MYC (34%), BRAF (32%), PIK3CA (29%), MET (25%), CDK6 (26%), EGFR (24%), FGFR1 (21%), and APC (12%). Many of these non‐AR alterations are not tissue verified in other studies. AR amplification cosegregated with alterations in MYC (p < .001), BRAF (p < .001), PIK3CA (p < .001), MET (p < .001), CDK6 (p < .001), EGFR (p < .001), FGFR1 (p = .391), and more. Alterations in APC were significantly associated with mutations in AR (p < .001).Conclusion.Several AR alterations and concomitant non‐AR alterations that associate with drug resistance were detected. These findings provide additional insights into the heterogeneity of advanced prostate cancer.Implications for Practice.The goal was to characterize androgen receptor gene (AR) amplifications and mutations detected in circulating tumor DNA (ctDNA) from patients with prostate cancer in relation to non‐AR gene alterations detected in the ctDNA landscape. The study included 892 patients with prostate cancer with AR alterations in ctDNA. AR alterations were significantly associated with other gene alterations detected in ctDNA. The common AR mutations found are linked to resistance to abiraterone, enzalutamide, or bicalutamide. Characterization of the circulating AR landscape and gene alterations provides potential additional insight into the somatic genetic heterogeneity of advanced prostate cancer.
Elisa M. Ledet, Michael B. Lilly, Guru Sonpavde, Edwin Lin, Roberto H. Nussenzveig, Pedro C. Barata, Mark Yandell, Rebecca J. Nagy, Lesli Kiedrowski, Neeraj Agarwal, Oliver Sartor

Association Between Skin Reaction and Clinical Benefit in Patients Treated with Anti‐Programmed Cell Death 1 Monotherapy for Advanced Non‐Small Cell Lung Cancer

1 month ago
AbstractBackground.Anti‐programmed cell death 1 antibody is a standard therapy for advanced non‐small cell lung cancer (NSCLC). However, immune‐related adverse events (irAEs), such as skin reactions, are frequently observed. Although skin reactions are associated with clinical efficacy in melanoma, this association in advanced NSCLC and predictors of irAEs remain unclear. Accordingly, this study identified potential correlations of skin reactions with clinical efficacy and clinical predictors of development of skin reactions.Subjects, Materials, and Methods.We retrospectively surveyed patients with advanced NSCLC who received nivolumab or pembrolizumab monotherapy at Sendai Kousei Hospital (n = 155) during January 2016 to April 2018. Treatment efficacy was evaluated in patients with and without skin reactions, and associated predictive markers were determined. A 6‐week landmark analysis was conducted to assess the clinical benefit of early skin reactions.Results.Skin reactions were observed in 51 patients with a median time to onset of 6.4 weeks. The overall response rate (ORR) was significantly higher in patients with skin reactions (57% vs. 19%, p < .001). Median progression‐free survival (PFS) durations of 12.9 and 3.5 months and overall survival durations of not reached and 11.4 months were observed in patients with and without skin reactions, respectively. In the 6‐week landmark analysis, the ORR was significantly higher in patients with skin reactions, and skin reactions were significantly associated with increased PFS. A multivariate analysis identified pre‐existing rheumatoid factor (RF) as an independent predictor of skin reactions.Conclusion.Skin reactions appeared beneficial in patients treated with nivolumab/pembrolizumab for advanced NSCLC and could be predicted by pre‐existing RF. Further large‐scale validations studies are warranted.Implications for Practice.This single‐institutional medical record review that included 155 patients with advanced non‐small cell lung cancer who were treated with nivolumab or pembrolizumab monotherapy revealed that overall response rate and progression‐free survival were significantly better in patients with skin reactions. Pre‐existing rheumatoid factor was an independent predictor of skin reactions.
Mari Aso, Yukihiro Toi, Jun Sugisaka, Tomoiki Aiba, Sachiko Kawana, Ryohei Saito, Takahiro Ogasawara, Kyoji Tsurumi, Kana Ono, Hisashi Shimizu, Yutaka Domeki, Keisuke Terayama, Yosuke Kawashima, Atsushi Nakamura, Shinsuke Yamanda, Yuichiro Kimura,…

Validity and Reliability of the Memorial Delirium Assessment Scale‐Thai Version (MDAS‐T) for Assessment of Delirium in Palliative Care Patients

1 month ago
AbstractBackground.Delirium, a neuropsychiatric syndrome that occurs throughout medical illness trajectories, is frequently misdiagnosed. The Memorial Delirium Assessment Scale (MDAS) is a commonly used tool in palliative care (PC) settings. Our objective was to establish and validate the Memorial Delirium Assessment Scale‐Thai version (MDAS‐T) in PC patients.Materials and Methods.The MDAS was translated into Thai. Content validity, inter‐rater reliability, and internal consistency were explored. The construct validity of the MDAS‐T was analyzed using exploratory factor analysis. Instrument testing of the MDAS‐T, the Thai version of the Confusion Assessment Method for the Intensive Care Unit (CAM‐ICU‐T), and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition as the gold standard was performed. The receiver operating characteristic (ROC) curve was used to determine the optimal cutoff score. The duration of each assessment was recorded.Results.The study enrolled 194 patients. The content validity index was 0.97. The intraclass correlation coefficient and Cronbach's α coefficient were 0.98 and 0.96, respectively. A principal component analysis indicated a homogeneous, one‐factor structure. The area under the ROC curve was 0.96 (95% confidence interval [CI], 0.93–0.99). The best combination of sensitivity and specificity (95% CI) of the MDAS‐T were 0.92 (0.85–0.96) and 0.90 (0.82–0.94), respectively, with a cutoff score of 9, whereas the CAM‐ICU‐T yielded 0.58 (0.48–0.67) and 0.98 (0.93–0.99), respectively. The median MDAS‐T assessment time was 5 minutes.Conclusion.This study established and validated the MDAS‐T as a good and feasible tool for delirium screening and severity rating in PC settings.Implications for Practice.Delirium is prevalent in palliative care (PC) settings and causes distress to patients and families, thereby making delirium screening necessary. This study found that the MDAS‐T is a highly objective and feasible test for delirium screening and severity monitoring in PC settings and can greatly improve the quality of care for this population.
Watanachai Klankluang, Panate Pukrittayakamee, Wanlop Atsariyasing, Arunotai Siriussawakul, Pratamaporn Chanthong, Sasima Tongsai, Supakarn Tayjasanant

Brain Metastases from Biliary Tract Cancers: A Case Series and Review of the Literature in the Genomic Era

1 month ago
AbstractBackground.Biliary tract cancers (BTCs) are highly fatal malignancies that make up less than 1% of all cancers. BTC is often diagnosed at an unresectable stage; surgical resection remains the only definitive treatment. Brain metastases (BMs) from BTC are extremely rare, and few studies on patients with BMs from BTC exist. The aim of this study was to identify clinical characteristics associated with poor prognosis for patients with BMs from BTC.Materials and Methods.We performed a retrospective review of electronic medical records for patients with BMs from BTC managed at Mount Sinai Hospital from 2000 to 2017. Data on patient characteristics, magnetic resonance imaging findings, treatment regimens, and clinical outcomes were analyzed.Results.We identified 1,910 patients with BTC. Nine patients developed BMs, with an incidence of 0.47%. Of these nine patients, six had intrahepatic cholangiocarcinoma, two had extrahepatic cholangiocarcinoma, and one had gallbladder cancer. Six (66.7%) patients had one BM, one (11.1%) patient had two BMs, and two (22.2%) patients had three or more BMs. Four (44.4%) patients underwent BM resection, and seven (77.8%) received BM radiation. Median overall survival from time of BM diagnosis was 3.8 months (95% confidence interval 0.1–16.9).Conclusion.Development of BMs from BTC is rare; however, prognosis is less than 4 months. BM diagnosis can occur within 2 years of primary diagnosis. As targeted therapeutics emerge, future studies ought to focus on identifying genomic BM markers associated with BTC subtypes.Implications for Practice.In the largest retrospective study of biliary tract cancer brain metastases, the clinical presentation and outcomes are reported of nine patients with an extremely rare clinical entity. The genomic literature and potential therapeutic targets for these patients with limited treatment options is comprehensively and exhaustively discussed.
Megan R. D'Andrea, Corey M. Gill, Melissa Umphlett, Nadejda M. Tsankova, Mary Fowkes, Joshua B. Bederson, Priscilla K. Brastianos, Raj K. Shrivastava

Diagnosis and Management of Rare Immune‐Related Adverse Events

1 month ago
AbstractOncologic treatment is being revolutionized by a burgeoning number of immune checkpoint inhibitors (ICPis). To date, seven ICPis have received Food and Drug Administration approval, targeting cytotoxic T‐lymphocyte antigen, programmed cell death, or programmed cell death ligand. Adverse events associated with checkpoint inhibition have been described in the literature. Guidelines exist for the most common of these, but as the use of ICPis becomes more common, the number of patients presenting with rare events will increase. This article reviews the diagnosis and management of rare ocular, hematological, luminal gastrointestinal, and rheumatological toxicities arising from ICPi treatment.Key Points.As the use of immune checkpoint inhibitors (ICPis) becomes more common, the number of rare immune‐related adverse events (irAEs) will increase. A high level of suspicion is required to identify and treat these toxicities.Although it can be difficult to definitively attribute rare irAEs to ICPis, a temporal and mechanistic relationship and the absence of other etiologies should make the treating physician suspicious for a rare irAE.Certain rare irAEs, such as celiac disease, do not require treatment with glucocorticoids. Thus, differentiating this irAE from other gastrointestinal irAEs has important implications for treatment.
Sara R. Schoenfeld, Mary E. Aronow, Rebecca Karp Leaf, Michael Dougan, Kerry L. Reynolds

Metastatic Thymoma Harboring a Deleterious BRCA2 Mutation Derives Durable Clinical Benefit from Olaparib

1 month 1 week ago
AbstractThymomas comprise a group of rare epithelial neoplasms of the anterior mediastinum. Whereas localized disease carries a favorable prognosis, the majority of patients with metastatic thymomas experience progression or recurrence over a 10‐year period. Although targeted therapies have become standard of care in many malignancies, no clinically actionable mutations have consistently been identified in metastatic thymomas. Here, we describe a patient with an aggressive thymoma complicated by extensive pleural metastases. Over a 16‐year period, she progressed on multiple treatment regimens. To identify additional treatment options, tissue from a pleural metastasis was sent for next‐generation sequencing, revealing mutations in BRCA2, tyrosine kinase 2, and SET domain containing 2. Based on supporting evidence for poly (ADP‐ribose) polymerase (PARP) inhibition in other BRCA‐mutated tumors, the patient was started on the PARP inhibitor olaparib. She derived significant clinical benefit from treatment, with imaging showing overall stabilization of her disease. Here, we review the genotyping results of her tumor and discuss the functional and clinical significance of the mutations in her cancer as well as implications for managing patients with advanced BRCA‐mutant thymomas.Key Points.Targeted therapy has yet to enter the standard clinical management of metastatic thymomas.Patients with BRCA2‐mutant thymomas may benefit from poly (ADP‐ribose) polymerase inhibition.
Daniel R. Principe, Suneel D. Kamath, Hidayatullah G. Munshi, Nisha A. Mohindra

The EORTC QLQ‐C30 Summary Score as Prognostic Factor for Survival of Patients with Cancer in the “Real‐World”: Results from the Population‐Based PROFILES Registry

1 month 1 week ago
AbstractBackground.Health‐related quality of life (HRQoL) has been shown to be a prognostic factor for cancer survival in randomized clinical trials and observational “real‐world” cohort studies; however, it remains unclear which HRQoL domains are the best prognosticators. The primary aims of this population‐based, observational study were to (a) investigate the association between the novel European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire‐Core30 (QLQ‐C30) summary score and all‐cause mortality, adjusting for the more traditional sociodemographic and clinical prognostic factors; and (b) compare the prognostic value of the QLQ‐C30 summary score with the global quality of life (QoL) and physical functioning scales of the QLQ‐C30.Materials and Methods.Between 2008 and 2015, patients with cancer (12 tumor types) were invited to participate in PROFILES disease‐specific registry studies (response rate, 69%). In this secondary analysis of 6,895 patients, multivariate Cox proportional hazard regression models were used to investigate the association between the QLQ‐C30 scores and all‐cause mortality.Results.In the overall Cox regression model including sociodemographic and clinical variables, the QLQ‐C30 summary score was associated significantly with all‐cause mortality (hazard ratio [HR], 0.77; 99% confidence interval [CI], 0.71–0.82). In stratified analyses, significant associations between the summary score and all‐cause mortality were observed for colon, rectal, and prostate cancer, non‐Hodgkin lymphoma, chronic lymphocytic leukemia, and multiple myeloma. The QLQ‐C30 summary score had a stronger association with all‐cause mortality than the global QoL scale (HR, 0.82; 99% CI, 0.77–0.86) or the physical functioning scale (HR, 0.81; 95% CI, 0.77–0.85).Conclusion.In a real‐world setting, the QLQ‐C30 summary score has a strong prognostic value for overall survival for a number of populations of patients with cancer above and beyond that provided by clinical and sociodemographic variables. The QLQ‐C30 summary score appears to have more prognostic value than the global QoL, physical functioning, or any other scale within the QLQ‐C30.Implications for Practice.The finding that health‐related quality of life provides distinct prognostic information beyond known sociodemographic and clinical measures, not only around cancer diagnosis (baseline) but also at follow‐up, has implications for clinical practice. Implementation of cancer survivorship monitoring systems for ongoing surveillance may improve post‐treatment rehabilitation that leads to better outcomes.
Olga Husson, Belle H. de Rooi&#x0237;, Jacobien Kieffer, Simone Oerlemans, Floort&#x0237;e Mols, Neil K. Aaronson, Winette T.A. van der Graaf, Lonneke V. van de Poll-Franse

ONKOTEV Score as a Predictive Tool for Thromboembolic Events in Pancreatic Cancer—A Retrospective Analysis

1 month 1 week ago
AbstractBackground.Venous thromboembolism (VTE) is a frequent complication in patients with cancer and causes considerable morbidity and mortality. The risk of VTE is higher in patients with pancreatic cancer and is often associated with treatment delays or interruptions. Recently, the ONKOTEV score was proposed as a VTE risk predictor model for patients with cancer, but its validation is still ongoing.Patients and Methods.We conducted a retrospective study to determine the incidence of VTE and to evaluate the ONKOTEV score as a VTE predictive tool in a population of patients with pancreatic cancer.Results.Between February 2012 and May 2017, 165 patients were included in the study. The median age was 73 years, 45.5% of patients were female, and 55.8% had stage IV disease. Fifty‐one patients had a VTE (30.9%); 23.5% had pulmonary embolism, 25.5% had deep venous thrombosis, and 51.0% had visceral VTE (VsT). At a median follow‐up time of 6.3 months, cumulative incidence of VTE was less than 10% for ONKOTEV scores 0 or 1 and approximately 40% and 70% for scores 2 and ≥3, respectively.Conclusion.The high VTE incidence observed in this study is consistent with prior reports. Patients at high risk for VTE with no increase in hemorrhagic risk should be considered for primary thromboprophylaxis. The ONKOTEV score may stratify VTE risk in patients with pancreatic cancer, with ONKOTEV score ≥2 being associated with a higher VTE occurrence.Implications for Practice.Venous thromboembolism (VTE) is a frequent complication of patients with pancreatic cancer and causes considerable morbidity, treatment delays or interruptions, and mortality. Thromboprophylaxis is not used routinely in ambulatory patients. Tools to stratify the risk of VTE are important to help select patients who may benefit from thromboprophylaxis. Recently, the ONKOTEV score was proposed as a VTE risk predictor model for patients with cancer, but its validation is still ongoing. In this patient series, ONKOTEV score ≥2 was associated with high VTE occurrence and may stratify VTE risk in patients with pancreatic cancer, suggesting that ONKOTEV can be considered to select patients with pancreatic cancer for primary thromboprophylaxis.
Joao Godinho, Mafalda Casa-Nova, Joao Moreira-Pinto, Pedro Simoes, Francisco Paralta Branco, Luisa Leal-Costa, Ana Faria, Fabio Lopes, Jose Alberto Teixeira, Jose Luis Passos-Coelho

Survival Analysis for Patients with ALK Rearrangement‐Positive Non‐Small Cell Lung Cancer and a Poor Performance Status Treated with Alectinib: Updated Results of Lung Oncology Group in Kyushu 1401

1 month 1 week ago
AbstractLessons Learned.Alectinib confers a pronounced survival benefit in patients with ALK rearrangement‐positive non‐small cell lung cancer and a poor performance status.Survival benefit of alectinib for patients with a poor performance status was consistent regardless of the presence of central nervous system metastases.Background.We previously reported a marked objective response rate (ORR) and safety for alectinib treatment in patients with ALK rearrangement‐positive non‐small cell lung cancer (NSCLC) and a poor performance status (PS) in the Lung Oncology Group in Kyushu (LOGiK) 1401 study. It remained unclear, however, whether alectinib might also confer a long‐term survival benefit in such patients.Methods.Eighteen patients with ALK rearrangement‐positive advanced NSCLC and a PS of 2, 3, or 4 (n = 12, 5, and 1, respectively) were enrolled in LOGiK1401 between September 2014 and December 2015 and received alectinib. We have now updated the survival data for the study.Results.The median follow‐up time for all patients was 27.3 months. The median progression‐free survival (PFS) was 16.2 months (95% confidence interval [CI], 7.1–30.8 months), and the median survival time (MST) and the 3‐year overall survival rate were 30.3 months (95% CI, 11.5 months to not reached) and 43.8% (95% CI, 20.8–64.7%), respectively. This survival benefit was similarly manifest in patients with a PS of 2 (MST, 20.5 months) and those with a PS of ≥3 (MST, not reached). PFS did not differ between patients with or without central nervous system (CNS) metastases at baseline (median of 17.5 and 16.2 months, respectively, p = .886).Conclusion.Alectinib showed a pronounced survival benefit for patients with ALK rearrangement‐positive NSCLC and a poor PS regardless of the presence of CNS metastases, a patient population for which chemotherapy is not indicated.
Eiji Iwama, Yasushi Goto, Haruyasu Murakami, Shinsuke Tsumura, Hiroyuki Sakashita, Yoshiaki Mori, Noriaki Nakagaki, Yuka Fujita, Masahiro Seike, Akihiro Bessho, Manabu Ono, Masaru Nishitsuji, Hiroaki Akamatsu, Ryotaro Morinaga, Takanori Akagi, Takayuki…

Endocrine‐Related Adverse Events Related to Immune Checkpoint Inhibitors: Proposed Algorithms for Management

1 month 1 week ago
AbstractImmune checkpoint inhibitors have proven to be effective for various advanced neoplasia. Immune‐related adverse events (irAEs) as a result of increased T cell activation are unique and potentially life‐threating toxicities associated with the use of immune checkpoint inhibitors. Multiple endocrine irAEs, including primary hyperthyroidism and hypothyroidism, thyroiditis, primary adrenal insufficiency, type 1 diabetes mellitus, and hypophysitis, have been reported with the use of various immune checkpoint inhibitors. In some cases, these irAEs can lead to discontinuation of treatment. Here we propose for the general oncologist algorithms for managing endocrine irAEs to aid in the clinical care of patients receiving immunotherapy.Key Points.There is a relative high risk of endocrine immune‐related adverse events (irAEs) during therapy with checkpoint inhibitors, particularly when combination therapy is implemented.Patients treated with anti‐CTLA‐4 antibodies have an increased risk of hypophysitis, whereas patients treated with anti‐PD‐1/PD‐L1 antibodies have a higher risk of primary thyroid dysfunction.Rarely, patients develop T1DM and central diabetes insipidus, and hypoparathyroidism is a rare occurrence.A growing clinical understanding of endocrine irAEs has led to effective treatment strategies with hormone replacement.
Jaydira Del Rivero, Lisa M. Cordes, Joanna Klubo-Gwiezdzinska, Ravi A. Madan, Lynnette K. Nieman, James L. Gulley

Association of Age with Efficacy of Immunotherapy in Metastatic Melanoma

1 month 2 weeks ago
AbstractManagement of melanoma has been revolutionized by the use of immune checkpoint inhibitors. Immune system changes associated with aging may affect the efficacy of immune‐based therapies. Using the National Cancer Database, we evaluated the impact of age on the receipt and efficacy of modern immunotherapies in patients with metastatic melanoma. We identified 11,944 patients from 2011–2015, of whom 25% received immunotherapy. Older (≥60 years), compared with younger, patients were less likely to receive immunotherapy (odds ratio, 0.69; 95% confidence interval [CI], 0.61–0.78; p < .001). Immunotherapy was associated with a survival benefit in both younger and older patients (<60 years: hazard ratio [HR], 0.64; 95% CI, 0.57–0.72; p < .001; ≥60 years: HR, 0.55; 95% CI, 0.50–0.60; p < .001). Importantly, there was a statistically significant interaction between age and survival with immunotherapy, where a greater benefit was observed for older patients (pinteraction = 0.013). Further work studying the age‐related response to immunotherapy is warranted.
Varsha Jain, Wei-Ting Hwang, Sriram Venigalla, Kevin T. Nead, John N. Lukens, Tara C. Mitchell, Jacob E. Shabason

Survivorship Care Plans in Cancer: A Meta‐Analysis and Systematic Review of Care Plan Outcomes

1 month 2 weeks ago
AbstractBackground.The Institute of Medicine recommends that survivorship care plans (SCPs) be included in cancer survivorship care. Our meta‐analysis compares patient‐reported outcomes between SCP and no SCP (control) conditions for cancer survivors. Our systematic review examines the feasibility of implementing SCPs from survivors' and health care professionals' perspectives and the impact of SCPs on health care professionals’ knowledge and survivorship care provision.Methods.We searched seven online databases (inception to April 22, 2018) for articles assessing SCP feasibility and health care professional outcomes. Randomized controlled trials comparing patient‐reported outcomes for SCP recipients versus controls were eligible for the meta‐analysis. We performed random‐effects meta‐analyses using pooled standardized mean differences for each patient‐reported outcome.Results.Eight articles were eligible for the meta‐analysis (n = 1,286 survivors) and 50 for the systematic review (n = 18,949 survivors; n = 3,739 health care professionals). There were no significant differences between SCP recipients and controls at 6 months postintervention on self‐reported cancer and survivorship knowledge, physical functioning, satisfaction with information provision, or self‐efficacy or at 12 months on anxiety, cancer‐specific distress, depression, or satisfaction with follow‐up care. SCPs appear to be acceptable and potentially improve survivors’ adherence to medical recommendations and health care professionals’ knowledge of survivorship care and late effects.Conclusion.SCPs appear feasible but do not improve survivors’ patient‐reported outcomes. Research should ascertain whether this is due to SCP ineffectiveness, implementation issues, or inappropriate research design of comparative effectiveness studies.Implications for Practice.Several organizations recommend that cancer survivors receive a survivorship care plan (SCP) after their cancer treatment; however, the impact of SCPs on cancer survivors and health care professionals is unclear. This systematic review suggests that although SCPs appear to be feasible and may improve health care professionals’ knowledge of late effects and survivorship care, there is no evidence that SCPs affect cancer survivors’ patient‐reported outcomes. In order to justify the ongoing implementation of SCPs, additional research should evaluate SCP implementation and the research design of comparative effectiveness studies. Discussion may also be needed regarding the possibility that SCPs are fundamentally ineffective.
Rebecca E. Hill, Claire E. Wakefield, Richard J. Cohn, Joanna E. Fardell, Mary-Ellen E. Brierley, Emily Kothe, Paul B. Jacobsen, Kate Hetherington, Rebecca Mercieca-Bebber
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