Phase 1/2 trial of avelumab combined with utomilumab (4-1BB agonist), PF-04518600 (OX40 agonist), or radiotherapy in patients with advanced gynecologic malignancies.

BACKGROUND: Immune checkpoint blockade has shown mixed results in advanced/recurrent gynecologic malignancies. Efficacy may be improved through costimulation with OX40 and 4-1BB agonists. The authors sought to evaluate the safety and efficacy of avelumab combined with utomilumab (a 4-1BB agonist), PF-04518600 (an OX40 agonist), and radiotherapy in patients with recurrent gynecologic malignancies. METHODS: The primary end point in this six-arm, phase 1/2 trial was safety of the combination regimens. Secondary end points included the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors and immune-related Response Evaluation Criteria in Solid Tumors, the disease control rate (DCR), the duration of response, progression-free survival, and overall survival. RESULTS: Forty patients were included (35% with cervical cancer, 30% with endometrial cancer, and 35% with ovarian cancer). Most patients (n = 33; 83%) were enrolled in arms A-C (no radiation). Among 35 patients who were evaluable for efficacy, the ORR was 2.9%, and the DCR was 37.1%, with a median duration of stable disease of 5.4 months (interquartile range, 4.1-7.3 months). Patients with cervical cancer in arm A (avelumab and utomilumab; n = 9 evaluable patients) achieved an ORR of 11% and a DCR of 78%. The median progression-free survival was 2.1 months (95% CI, 1.8-3.5 months), and overall survival was 9.4 months (95% CI, 5.6-11.9 months). No dose-limiting toxicities or grade 3-5 immune-related adverse events were observed. CONCLUSIONS: The findings from this trial highlight that, in heavily pretreated patients with gynecologic cancer, even multidrug regimens targeting multiple immunologic pathways, although safe, did not produce significant responses. A DCR of 78% in patients with cervical cancer who received avelumab and utomilumab indicates that further research on this combination in select patients may be warranted.

T-cell receptor beta variable gene polymorphism predicts immune-related adverse events during checkpoint blockade immunotherapy.

BACKGROUND: Immune checkpoint inhibitors have revolutionized cancer treatment. However, they are associated with a unique spectrum of side effects, called immune-related adverse events (irAEs), which can cause significant morbidity and quickly progress to severe or life-threatening events if not treated promptly. Identifying predictive biomarkers for irAEs before immunotherapy initiation is therefore a critical area of research. Polymorphisms within the T-cell receptor beta (TCRB) variable (TRBV) gene have been implicated in autoimmune disease and may be mechanistically linked to irAEs. However, the repetitive nature of the TCRB locus and incomplete genome assembly has hampered the evaluation of TRBV polymorphisms in the past. PATIENTS AND METHODS: We used a novel method for long-amplicon next generation sequencing of rearranged TCRB chains from peripheral blood total RNA to evaluate the link between TRBV polymorphisms and irAEs in patients treated with immunotherapy for cancer. We employed multiplex PCR to create amplicons spanning the three beta chain complementarity-determining regions (CDR) regions to enable detection of polymorphism within the germline-encoded framework and CDR1 and CDR2 regions in addition to CDR3 profiling. Resultant amplicons were sequenced via the Ion Torrent and TRBV allele profiles constructed for each individual was correlated with irAE annotations to identify haplotypes associated with severe irAEs (≥ grade 3). RESULTS: Our study included 81 patients who had irAEs when treated with immunotherapy for cancer. By using principal component analysis of the 81 TRBV allele profiles followed by k-means clustering, we identified six major TRBV haplotypes. Strikingly, we found that one-third of this cohort possessed a TRBV allele haplotype that appeared to be protective against severe irAEs. CONCLUSION: The data suggest that long-amplicon TCRB repertoire sequencing can potentially identify TRBV haplotype groups that correlate with the risk of severe irAEs. Germline-encoded TRBV polymorphisms may serve as a predictive biomarker of severe irAEs.

Incidence and Risk Factors for Pneumonitis Associated With Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer: A Single Center Experience.

INTRODUCTION: Immune checkpoint inhibitor (ICI) pneumonitis causes substantial morbidity and mortality. Estimates of real-world incidence and reported risk factors vary substantially. METHODS: We conducted a retrospective review of 419 patients with advanced non-small cell lung cancer (NSCLC) who were treated with anti-PD-(L)1 with or without anti-CTLA-4 therapy. Clinical, imaging, and microbiological data were evaluated by multidisciplinary adjudication teams. The primary outcome of interest was grade ≥2 (CTCAEv5) pneumonitis. Clinicopathologic variables, tobacco use, cancer therapies, and preexisting lung disease were assessed for univariate effects using Cox proportional hazards models. We created multivariate Cox proportional hazards models to assess risk factors for pneumonitis and mortality. Pneumonitis, pneumonia, and progression were modeled as time-dependent variables in mortality models. RESULTS: We evaluated 419 patients between 2013 and 2021. The cumulative incidence of pneumonitis was 9.5% (40/419). In a multivariate model, pneumonitis increased the risk for mortality (HR 1.6, 95% CI, 1.0-2.5), after adjustment for disease progression (HR 1.6, 95% CI, 1.4-1.8) and baseline shortness of breath (HR 1.5, 95% CI, 1.2-2.0). Incomplete resolution was more common with more severe pneumonitis. Interstitial lung disease was associated with higher risk for pneumonitis (HR 5.4, 95% CI, 1.1-26.6), particularly in never smokers (HR 26.9, 95% CI, 2.8-259.0). CONCLUSION: Pneumonitis occurred at a high rate and significantly increased mortality. Interstitial lung disease, particularly in never smokers, increased the risk for pneumonitis.

Role of Abdominal and Pelvic CT Scans in Diagnosis of Patients with Immunotherapy-Induced Colitis.

Introduction: Colitis is one of the most common immune-related adverse events in patients receiving immune checkpoint inhibitors. Although radiographic changes on computed tomography (CT), such as mild diffuse bowel thickening, mesenteric fat stranding, and mucosal enhancement, have been reported, the utility of CT in diagnosis of patients with suspected immune-related colitis is not well documented. The aim of this retrospective study was to determine the value of CT scans in diagnosis of immunotherapy-induced colitis. Methods: CT scans of the abdomen and pelvis of 34 patients receiving immunotherapy who had a clinical diagnosis of immunotherapy-induced colitis and 19 patients receiving immunotherapy without clinical symptoms of colitis (controls) were evaluated. Segments of the colon (rectum, sigmoid, descending, transverse, ascending, and cecum) were assessed independently by two abdominal imaging specialists, blinded to the clinical diagnosis. Each segment was assessed for radiographic signs such as mucosal enhancement, wall thickening, distension, and periserosal fat stranding. The presence of any of the signs was considered radiographic evidence of colitis. Results: CT findings suggestive of colitis was seen in 20 of 34 patients with symptoms of colitis and in 5 of 19 patients without symptoms of colitis. The sensitivity, specificity, positive predictive value, and negative predictive value for colitis on CT were 58.8%, 73.7%, 80%, and 50%, respectively. Conclusions: We found that CT had a low sensitivity, specificity, and negative predictive value for the diagnosis of immunotherapy-induced colitis. We therefore conclude that CT has a limited role in the diagnosis of patients with suspected uncomplicated immune-related colitis.

Pneumonitis after immune checkpoint inhibitor therapies in patients with acute myeloid leukemia: A retrospective cohort study.

BACKGROUND: Immune checkpoint inhibitors (ICI), combined with hypomethylating agents, can be used to treat acute myeloid leukemia (AML), but this strategy results in a high rate of pneumonitis. The authors sought to determine risk factors for pneumonitis development and whether pneumonitis increased mortality. METHODS: The authors conducted a retrospective review of 258 AML patients who received ICI-containing regimens from 2016 to 2018. A multidisciplinary adjudication committee diagnosed pneumonia and pneumonitis by reviewing symptoms, imaging, microbiology, and response to therapies. To measure risk factors for pneumonitis and mortality, multivariate Cox proportional hazards models were constructed. Pneumonia, pneumonitis, and disease progression were modeled as a time-dependent variable and incorporated a standard risk set modifying variables into the models. RESULTS: Thirty patients developed pneumonitis (12%). Of these, 17 had partial or complete resolution, whereas 13 patients died from pneumonitis. Increasing age (hazard ratio [HR], 1.04 per year; 95% confidence interval [CI], 1.00-1.08), and baseline shortness of breath increased pneumonitis risk (HR, 2.51; 95% CI, 1.13-5.55). Female sex (HR, 0.33; 95% CI, 0.15-0.70) and increasing platelet count (HR, 0.52 per log-unit increase; 95% CI, 0.30-0.92) decreased pneumonitis risk. In adjusted models, ICI-related pneumonitis significantly increased mortality (HR, 2.84; 95% CI, 1.84-4.37). CONCLUSIONS: ICI-related pneumonitis occurs at a high rate in AML patients and increases mortality. LAY SUMMARY: Immune checkpoint inhibitors (ICIs) remove inhibitory signals that reduce T-cell function and allow T-cells to better attack cancer cells. In acute myeloid leukemia (AML), the effectiveness of ICIs is limited in part by inflammation of the lung, called pneumonitis. This study reviewed 258 patients with AML who received ICIs and identified 30 patients who developed pneumonitis, nearly half of whom died. Older age and baseline shortness of breath increased pneumonitis risk, whereas female sex and higher baseline platelet counts decreased pneumonitis risk. Pneumonitis increased mortality by nearly 3-fold. This work highlights the significant harm imposed by pneumonitis after ICI therapies.

Supportive care for the prevention of nausea, vomiting and anorexia in a phase 1B study of selinexor in advanced cancer patients: an exploratory study.

INTRODUCTION: Clinical observations of cancer patients treated with selinexor have reported high incidence of nausea and anorexia. The study objective was to investigate the adoption of prophylactic olanzapine for the prevention of nausea, vomiting and anorexia in cancer patients receiving selinexor and standard chemotherapy. METHODS: We retrospectively reviewed supportive care interventions in patients receiving selinexor and recorded frequency of adverse events (NCI-CTAE). Association between categorical variables were analyzed using Fisher's exact tests; repeated measures analysis was performed to assess weight changes over time. RESULTS: Of 124 evaluable patients, 83 (66.9%) were female, 93 were white (75.0%), and the most common cancer was ovarian (N = 30, 24.2%). One hundred and four patients (83.9%) received olanzapine, of which 93 (89.4%) were prophylactically treated, the majority (86.5%) receiving low 2.5 mg daily dose. Other anti-emetics included ondansetron in 90 patients (72.6%), dexamethasone prescribed in 50 patients (40.3%) and metoclopramide in 49 patients (39.5%), while aprepitant/fosaprepitant (N = 2, 1.6%) were prescribed infrequently. Cancer patients receiving prophylactic olanzapine (N = 93) compared to patients who never received olanzapine (N = 20) had more Grade 1 + anorexia (31.2% vs 20.0%), less nausea (53.8% vs 70.0%), less vomiting (33.3% vs 40.0%), and increased hyperglycemia (29.0% vs 10.0%), but differences were non-statistically significant. In addition, there was minimal weight loss over time in both groups and no statistically significant differences in weight loss between groups. CONCLUSION: Prophylactic olanzapine decreased nausea, vomiting and maintained weight over 3 months but did not prevent anorexia in patients receiving selinexor and chemotherapy. Low dose olanzapine was well tolerated but associated with hyperglycemia.

Cardiac Toxicities Associated with Immune Checkpoints Inhibitors: Mechanisms, Manifestations and Management.

Immune checkpoint inhibitor (ICI) associated cardiovascular adverse events (CVAE) have become more frequent with the growing use of cancer immunotherapy. CVAEs include a wide spectrum of diseases such as myocarditis, pericarditis, heart failure, arrhythmias, coronary artery disease, and hypertension. The induction of cardiovascular side effects by ICI use is hypothesized to occur due to inflammation and immune dysregulation of normal tissue in response to immunotherapy. Management of ICI-associated CVAEs mitigates an overactive immune response by utilizing steroids, immunomodulatory drugs and hemodynamic stabilization. However, few controlled studies on the cardiovascular safety of ICIs exist and treatment of their side effects are mostly from limited case series. Our review seeks to provide the most recent understanding of ICI-associated CVAEs and their management.

Selinexor in combination with topotecan in patients with advanced or metastatic solid tumors: Results of an open-label, single-center, multi-arm phase Ib study.

Background Selinexor, a first-in-class, oral selective inhibitor of nuclear export (SINE) compound inhibits Exportin-1(XPO1), had demonstrated synergistic activity with many chemotherapies and conferred in vivo antitumor efficacy in hematologic as well as solid tumors. Methods This open-label, single-center, multi-arm phase 1b study used a standard 3 + 3 design and a "basket type" expansion. Selinexor with intravenous topotecan was given in one of the 13 parallel arms. Patients with advanced or metastatic relapsed/refractory solid tumors following prior systemic therapy, or in whom the addition of selinexor to standard chemotherapy deemed appropriate, were eligible. Results Fourteen patients with the median age of 61 years (range, 22-68years) were treated, and the most common cancer types were gynecological cancers; ovarian (n = 5), endometrial (n = 2), and 1 each with fallopian tube and vaginal cancers. Of the 14 patients treated, 12 (86 %) had at least one treatment-related adverse event (TRAE). The most common TRAEs were anemia (71 %), thrombocytopenia (57 %), hyponatremia (57 %), vomiting (57 %), fatigue (50 %), nausea (50 %), and neutropenia (36 %). Two patients had dose limiting toxicities. One patient dosed at selinexor 80 mg had grade 3 nausea and vomiting and one patient dosed at selinexor 60 mg experienced grade 4 neutropenia and thrombocytopenia. Of the 13 efficacy evaluable patients, one (8 %) with endometrial cancer achieved unconfirmed partial response (uPR) and the time-to-treatment failure (TTF) was 48 weeks, whereas 6 of the 13 (46 %) patients had stable disease (SD) contributing to the clinical benefit rate of 46 %. The median TTF for all patients was 9 weeks (range, 2-48weeks). Conclusions Once weekly selinexor in combination with topotecan was viable and showed some preliminary tumor efficacy. The recommend phase 2 dose of selinexor was 60 mg once weekly in combination with IV topotecan.Trial registration: NCT02419495. Registered 14 April 2015, https://clinicaltrials.gov/ct2/show/NCT02419495.

Associations between the gut microbiome and fatigue in cancer patients.

Fatigue is the most prevalent symptom of cancer and its treatments. Changes in the intestinal microbiome have been identified in chronic fatigue syndrome and other neuropsychiatric disorders, and cancer patients. However, the association between intestinal microbiome and fatigue in patients with advanced cancers has not been evaluated. Understanding the connection between intestinal microbiome and fatigue will provide interventional and therapeutic opportunities to manipulate the microbiome to improve fatigue and other patients' reported outcomes. In this project, we aimed to identify associations between microbiome composition and fatigue in advanced cancer patients. In this cross-sectional observational study at a tertiary cancer care center, we included 88 patients with advanced, metastatic, unresectable cancers who were in a washout period from chemotherapy. We measured fatigue using the MD Anderson Symptom Inventory-Immunotherapy fatigue score, and used 16srRNA to analyze intestinal microbiome. Using correlation analysis we found that Eubacterium hallii was negatively associated with fatigue severity scores (r = - 0.30, p = 0.005), whereas Cosenzaea was positively associated with fatigue scores (r = 0.33, p = 0.0002). We identified microbial species that exhibit distinct composition between high-fatigued and low-fatigued cancer patients. Further studies are warranted to investigate whether modulating the microbiome reduces cancer patients' fatigue severity and improves their quality of life.

Effects of glutamine for prevention of radiation-induced esophagitis: a double-blind placebo-controlled trial.

Purpose Acute radiation-induced esophagitis (ARIE) leads to treatment delays, decreased quality of life (QOL), and secondary adverse events such as weight loss. Grade 3 ARIE occurs in 15%-30% of patients undergoing radiotherapy to the esophagus, leading to disruption or discontinuation of treatment. The purpose of this study was to assess the effects of glutamine, a common nutritional supplement, on ARIE in patients with thoracic malignancies. Patients and methods This double-blind, placebo-controlled trial enrolled patients with advanced thoracic malignancies receiving concurrent chemotherapy/radiotherapy or radiotherapy alone, with radiation doses to the esophagus ≥45 Gy. Patients were randomized (1:1) to receive 4 g of glutamine or glycine placebo twice daily. The primary objective was to determine whether glutamine decreases the severity of ARIE in these patients. Secondary objectives included assessment of the effects of glutamine on other measures of ARIE, weight, symptom burden measure assessed by the MD Anderson Symptom Inventory (MDASI-HN) questionnaire and the toxicity profile of glutamine. Results At the time of interim analysis, 53 patients were enrolled: 27 in the glutamine arm and 26 in the placebo arm. There was no difference in the incidence of esophagitis in the first 6 weeks of radiotherapy between the glutamine and placebo arms (74% versus 68%; P = 1.00). There were no significant differences between the two arms for time to onset of esophagitis. The duration of ARIE was shorter (6.3 versus 7.1 weeks; P = 0.54) and median weight loss was lower (0.9 kg versus 2.8 kg; p = 0.83) in the glutamine arm versus the placebo arm. The groups differ significantly in core symptom severity (2.1 vs 1.5, p < .03) but not in head and neck specific symptom severity (1.2 vs 1.1, p < .60) nor in symptom interference (2.1 vs 1.7, p < .22). There was no grade 3 or higher adverse event at least possibly related to glutamine. The study was terminated for futility following interim analysis. Conclusion Oral glutamine was not associated with significant improvement in severity of ARIE, weight loss, head and neck specific symptoms or symptom interference compared with placebo in patients with advanced thoracic malignancies receiving radiotherapy to the esophagus.Clinical trial information. NCT01952847, and date of registration is September 30, 2013.

Implementation of a Novel Web-Based Lesion Selection Tool to Improve Acquisition of Tumor Biopsy Specimens.

Introduction: For maximum utility of molecular characterization by next-generation sequencing (NGS) and better understanding of tumor microenvironment with immune correlates analysis, biopsy specimens must yield adequate tumor tissue, and sequential biopsy specimens should sample a consistent site. We developed a web-based lesion selection tool (LST) that enables management and tracking of the biopsy specimen collections. Methods: Of 145 patients, the LST was used for 88 patients; the other 57 served as controls. We evaluated consistency of the lesion biopsied in longitudinal collections, number of cores obtained, and cores with adequate tumor cellularity for NGS. The Fisher exact test and Wilcoxon rank sum test were used to identify differences between the groups. Results: The analysis included 30 of 88 (34%) patients in the LST group and 52 of 57 (91%) in the control group. The LST workflow ensured 100% consistency in the lesions biopsied compared with 75% in the control group in longitudinal collections and increased the proportion of patients in whom at least five cores were collected per biopsy. Conclusions: The novel LST platform facilitates coordination, performance, and management of longitudinal biopsy specimens. Use of the LST enables sampling of the designated lesion consistently, which is likely to accurately inform us the effect of the treatment on tumor microenvironment and evolution of resistant pathways. Such studies are important translational component of any clinical trials and research as they guide the development of next line of therapy, which has significant effect on clinical utility. However, validation of this approach in a larger study is warranted.

Immune Checkpoint Inhibitor (ICI)-Related Cardiotoxicity.

The growing success of immune checkpoint inhibitors (ICIs) has led to improved outcomes in several types of cancers with studies looking for expanding their indications and use. However immune-related adverse events have been recognized of which myocarditis is associated with a high mortality. Other cardiac events such as arrhythmias, pericardial disease, and coronary atherosclerosis have been observed in patients on ICI therapy. These cardiac toxicities are thought to be the result of increased inflammatory responses after inhibition of specific checkpoint proteins on T cells. Although cardiotoxicities related to immunotherapy are reportedly rare, they can be severe and associated with life-threatening conditions such as fulminant myocarditis, hemodynamic instability, and cardiac arrest. We will review the most commonly reported cardiovascular toxicities associated with ICIs and their management.

Evaluating the psychometric properties of the Immunotherapy module of the MD Anderson Symptom Inventory.

INTRODUCTION: Immunotherapies have revolutionized the treatment of various cancers, but little is known about their symptomatic toxicity. Assessing these symptoms is best accomplished by asking the patients themselves. However, such reports are subjective and may face challenges as bonafide scientific data. Demonstrating the validity of symptom assessment tools, mainly through the reduction of measurement errors, has the potential to improve patient care if these tools are widely adopted. To that end, we present herein the psychometric properties of the Immunotherapy for Early-Phase Trials module of the MD Anderson Symptom Inventory (MDASI-Immunotherapy EPT) in patients receiving various immunotherapies in early phase trials at a major cancer center. METHODS: One hundred forty-five patients completed the inventory at baseline, with 85 of them also doing so after 9 weeks of treatment. The mean (±SD) age of the patients was 57.0±12.9 years. Also, 56% of the patients were women, 79% identified as white, and 49% had at least some college education. RESULTS: The internal consistency reliability of the MDASI-Immunotherapy EPT was excellent, as the Cronbach's alphas for all of its subscales were at least 0.88 (range 0.88-0.95). Known-group validity based on Eastern Cooperative Oncology Group performance status groupings was excellent at 9 weeks after the start of an immunotherapy trial for the MDASI-Immunotherapy EPT severity (effect size, 0.96) and interference (effect size, 0.82) subscales. We found substantial changes in the symptom items difficulty remembering (effect size, -0.85), fever and/or chills (effect size, -0.63), disturbed sleep (effect size, -0.52), diarrhea (effect size, -0.42), and swelling of hands, legs, or feet (effect size, -0.39). CONCLUSIONS: In conclusion, the MDASI-Immunotherapy EPT is a valid, reliable, and sensitive tool for measuring symptomatic toxicity.

Phase II study of pembrolizumab efficacy and safety in women with recurrent small cell neuroendocrine carcinoma of the lower genital tract.

OBJECTIVE: To investigate the efficacy and safety of pembrolizumab in women with recurrent small cell neuroendocrine tumors of the lower genital tract. METHODS: We conducted an open-label, investigator-initiated phase II basket trial of pembrolizumab 200 mg intravenously every 3 weeks in patients with rare tumors (ClinicalTrials.gov: NCT02721732). The trial had prespecified cohorts, including small cell malignancies of extrapulmonary origin. Eligibility criteria included disease progression during standard treatment in the 6 months before study enrollment. Patients were enrolled from February 2017 to February 2019. The primary endpoint was the proportion of patients alive without progression at 27 weeks. Response to pembrolizumab was evaluated every 9 weeks (3 cycles) with radiographic imaging. RESULTS: Seven women with gynecologic extrapulmonary small cell carcinoma were enrolled, 6 with cervical and 1 with vulvar carcinoma. No patient was progression free at 27 weeks. At first radiologic assessment, 1 patient had stable disease, while 6 had progression. The single patient with stable disease at 6 weeks had disease progression at 14 weeks. The median progression-free interval was 2.1 months (range 0.8-3.3 months). Severe treatment-related adverse events (≥grade 3) were seen in 2 of 7 patients (29%); 1 patient had grade 3 asymptomatic elevation of serum alkaline phosphatase, and 1 had grade 3 asymptomatic elevation of serum alanine aminotransferase. CONCLUSIONS: Pembrolizumab alone showed minimal activity in women with recurrent small cell neuroendocrine tumors of the lower genital tract. Treatment was well tolerated in the majority of study participants, and the rate of severe adverse events was low.

Immune Checkpoint Inhibitors (ICIs)-Related Cardiotoxicity.

The growing success of immune checkpoint inhibitors (ICIs) has led to effectively treating several types of cancers. Even though their use has been associated with the development of cardiac adverse effects, which may decrease the overall survival in cancer patients. These cardiac toxicities are thought to be the result of targeting specific checkpoint proteins on normal myocardial cells leading to over stimulation of the immune system as well as secondary downstream off-target effects on normal tissue.Although cardiotoxicities related to immunotherapy are reportedly rare, they can be severe and associated with life-threatening conditions such as fulminant myocarditis, hemodynamic instability, and cardiac arrest.We will review the most commonly reported cardiovascular toxicities associated with ICIs and their management.

Phase II clinical trial of pembrolizumab efficacy and safety in advanced adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare malignancy without good treatment options. There are limited data about the use of immunotherapy in ACC. We investigated the efficacy and safety of pembrolizumab in patients with metastatic ACC. METHODS: This is a pre-specified cohort of a single-center, investigator-initiated, phase II clinical trial using pembrolizumab monotherapy in patients with rare malignancies. Patients must have had prior treatment fail in the past 6 months before study enrollment. Patients were enrolled from August 2016 to October 2018. Follow-up data were updated as of March 26, 2019. Patients received 200 mg pembrolizumab intravenously every 3 weeks without concomitant oncologic therapy. The primary endpoint was non-progression rate (NPR) at 27 weeks. Other endpoints included adverse events, tumor responses measured independently by objective radiologic criteria, and select immunological markers. RESULTS: Sixteen patients with ACC (including eight women [50%]) were included in this cohort. Ten patients (63%) had evidence of hormonal overproduction (seven had cortisol-producing ACC). Non-progression rate at 27 weeks was evaluable in 14 patients, one patient was lost to follow-up, and one patient left the study because of an adverse event. Five of 14 patients were alive and progression-free at 27 weeks (non-progression rate at 27 weeks was 36, 95% confidence interval 13-65%). Of the 14 patients evaluable for imaging response by immune-related Response Evaluation Criteria in Solid Tumors, two had a partial response (including one with cortisol-producing ACC), seven had stable disease (including three with cortisol-producing ACC), and five had progressive disease, representing an objective response rate of 14% (95% confidence interval 2-43%). Of those who had stable disease, six had disease stabilization that lasted ≥4 months. Severe treatment-related adverse events (≥grade 3) were seen in 2 of 16 patients (13%) and resulted in one patient discontinuing study participation. All studied tumor specimens (14/14) were negative for programmed cell death ligand-1 expression. Thirteen of 14 tumor specimens (93%) were microsatellite-stable. Eight of 14 patients (57%) had a high tumor-infiltrating lymphocyte score on immunohistochemistry staining. CONCLUSIONS: Single-agent pembrolizumab has modest efficacy as a salvage therapy in ACC regardless of the tumor's hormonal function, microsatellite instability status, or programmed cell death ligand-1 status. Treatment was well tolerated in most study participants, with a low rate of severe adverse events. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02721732 , Registered March 29, 2016.

Cardiac toxicities of anticancer treatments: chemotherapy, targeted therapy and immunotherapy.

PURPOSE OF REVIEW: Current oncologic treatments have shown improvement in overall survival in cancer patients. However, the cardiac toxicities of cancer therapeutics, particularly chemotherapy, targeted therapy and immunotherapy can have life-threatening side effects. RECENT FINDINGS: A MEDLINE search for cardiovascular toxicities associated with Federal Drug Administration (FDA)-approved cancer treatments including chemotherapy, targeted therapy and immunotherapy was performed. We included comprehensive articles and research articles establishing the incidence, diagnosis, monitoring and management of cardiovascular toxicities related to cancer treatments until January 2019.This review highlights the mechanisms and epidemiology of cardiotoxicity associated with some cancer treatments. The most common cardiovascular side-effects are discussed at an introductory level with emphasis on those related with the development of heart failure. SUMMARY: Cardiovascular side effects of cancer treatments are common and might affect the survival in cancer patients. Recognition and management of these side effects require understanding of their mechanisms and their clinical manifestations. A multidisciplinary approach with understanding of both the cardiovascular and oncologic risks is necessary in order to provide well tolerated and effective cardio-oncology care.

The Role of Cardiovascular Imaging and Serum Biomarkers in Identifying Cardiotoxicity Related to Cancer Therapeutics.

Innovations and discoveries in cancer therapeutics have improved survival rates in patients with various types of malignancies. At the same time, physicians are identifying an increased number of patients with treatment-related cardiotoxicity. It is imperative that physicians recognize early treatment-related adverse effects to determine the safest therapeutic options for patients with cancer. This manuscript evaluates the role of cardiovascular imaging and biomarkers in identifying cardiotoxicity trigged by various chemotherapeutic agents and summarizes expert consensus statements regarding cardiotoxicity monitoring.