Patient-reported symptom monitoring: using (big) data to improve supportive care at the macro-, meso-, and micro-levels.

PURPOSE: This paper aims to provide a comprehensive understanding of the need for continued development of symptom monitoring (SM) implementation, utilization, and data usage at the macro-, meso-, and micro-levels. METHODS: Discussions from a patient-reported SM workshop at the MASCC/ISSO 2022 annual meeting were analyzed using a macro-meso-micro analytical framework of cancer care delivery. The workshop categories "initiation and implementation, barriers to adoption and utilization, and data usage" were integrated for each level. RESULTS: At the macro-level, policy development could encourage data sharing and international collaboration, including the exchange of SM methods, supportive care models, and self-management modules. At the meso-level, institutions should adjust clinical workflow and service delivery and promote a thorough technical and clinical integration of SM. At the micro-level, SM should be individualized, with timely feedback for patients, and should foster trust and understanding of AI decision support tools amongst clinicians to improve supportive care. CONCLUSIONS: The workshop reached a consensus among international experts on providing guidance on SM implementation, utilization, and (big) data usage pathways in cancer survivors across the cancer continuum and on macro-meso-micro levels.

Pro-Tumorigenic and Thrombotic Activities of Platelets in Lung Cancer.

Aside from their key protective roles in hemostasis and innate immunity, platelets are now recognized as having multifaceted, adverse roles in the pathogenesis, progression and outcome of many types of human malignancy. The most consistent and compelling evidence in this context has been derived from the notable association of elevated circulating platelet counts with the onset and prognosis of various human malignancies, particularly lung cancer, which represents the primary focus of the current review. Key topics include an overview of the association of lung cancer with the circulating platelet count, as well as the mechanisms of platelet-mediated, pro-tumorigenic immunosuppression, particularly the role of transforming growth factor beta 1. These issues are followed by a discussion regarding the pro-tumorigenic role of platelet-derived microparticles (PMPs), the most abundant type of microparticles (MPs) in human blood. In this context, the presence of increased levels of PMPs in the blood of lung cancer patients has been associated with tumor growth, invasion, angiogenesis and metastasis, which correlate with disease progression and decreased survival times. The final section of the review addresses, firstly, the role of cancer-related platelet activation and thrombosis in the pathogenesis of secondary cardiovascular disorders and the associated mortality, particularly in lung cancer, which is second only to disease progression; secondly, the review addresses the potential role of antiplatelet agents in the adjunctive therapy of cancer.

GLORIA: phase III, open-label study of adagloxad simolenin/OBI-821 in patients with high-risk triple-negative breast cancer.

Triple-negative breast cancer (TNBC) has the highest rate of distant metastasis and poorest overall survival among breast cancer subtypes. In a phase II study, adagloxad simolenin (AdaSim), a synthetic Globo H conjugate vaccine administered with adjuvant OBI-821, was shown to induce IgM and IgG anti-Globo H humoral responses in patients with metastatic breast cancer overexpressing the glycosphingolipid Globo H. GLORIA is an ongoing phase III, randomized, open-label clinical trial to evaluate the safety and efficacy of AdaSim and the quality of life (QoL) of patients receiving AdaSim plus standard of care (SOC) versus SOC alone in high-risk, early-stage TNBC. The primary end point is invasive progression-free survival; secondary end points include overall survival, QoL, breast cancer-free interval, distant disease-free survival, safety, and tolerability.

Patients with triple-negative breast cancer generally do very poorly with the current available therapies. A vaccine with a totally different mechanism of action is being investigated in these patients to see how they do with this new therapy. This trial is a very early investigation and is currently ongoing. Clinical Trial Registration: NCT03562637 (ClinicalTrials.gov).

Supportive care for new cancer therapies.

PURPOSE OF REVIEW: The past decade has witnessed unprecedented delivery to the clinical arena of a range of novel, innovative, and effective targeted anticancer therapies. These include immunotherapies, most prominently immune checkpoint inhibitors, as well as agents that target growth factors and cancer-related mutations. Many of these new cancer therapies are, however, associated with an array of toxicities, necessitating insight and vigilance on the part of attending physicians to achieve high-quality supportive care alongside toxicity management. In this review, we consider some of the key supportive care issues in toxicity management. RECENT FINDINGS: Although both supportive care and targeted therapies have brought significant benefits to cancer care, the management of novel cancer therapy toxicities is nevertheless often complex. This is due in large part to the fact that target organs differ widely, particularly in the case of checkpoint inhibitors, with minor dermatological disorders being most common, while others, such as pneumonitis, are more severe and potentially life threatening. Accordingly, efficient management of these immune-related adverse events requires collaboration between multiple medical specialists. SUMMARY: Supportive care is a key component in the management of new cancer therapy toxicities and needs to be incorporated into treatment pathways.

Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients receiving moderately emetogenic chemotherapy regimens: a subgroup analysis from a randomized clinical trial of response in subjects by cancer type.

BACKGROUND: Results from a phase III, randomized, double-blind, active comparator-controlled, parallel-group trial evaluating fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) found that a single-day, triple-antiemetic fosaprepitant regimen resulted in a significantly higher proportion of patients achieving a complete response (CR; no vomiting or rescue medication use) in the delayed phase (25-120 h after chemotherapy initiation), compared with a 3-day control regimen ( ClinicalTrials.gov , NCT01594749). As the risk for CINV is dependent on chemotherapy regimen and generally guided by tumor type, this post hoc analysis evaluated the efficacy and safety of this regimen by cancer subpopulations (gastrointestinal [GI] or colorectal, lung, breast, and gynecologic cancers). METHODS: Subjects with confirmed cancer who were naive to highly and moderately emetogenic chemotherapy (HEC and MEC) and were scheduled to receive intravenous (IV) anthracycline-cyclophosphamide (AC)-based MEC on the first day of chemotherapy were randomly assigned to receive oral ondansetron and oral dexamethasone plus either a single IV dose of fosaprepitant 150 mg (fosaprepitant regimen) or placebo (control regimen). The primary efficacy end point was the proportion of subjects achieving CR in the delayed phase. CR rates in the overall and acute phases (0-120 h and 0-24 h after MEC initiation, respectively) were assessed as secondary end points. Safety and tolerability were also assessed. RESULTS: CR rates in the delayed phase favored the fosaprepitant regimen over the control regimen across the GI/colorectal, lung, breast, and gynecologic cancer subgroups (range, 6.2-22%); similar findings were observed for CR in the overall phase. CR in the acute phase was high for all groups (≥87%). The fosaprepitant regimen was well tolerated in all cancer subgroups. CONCLUSIONS: This post hoc analysis indicated that a single-day fosaprepitant regimen was effective in preventing CINV in patients receiving MEC, regardless of cancer type. TRIAL REGISTRATION: ClinicalTrials.gov NCT01594749 , registered May 9, 2012.

Cancer immunotherapy-related adverse events: causes and challenges.

Despite the success and ongoing promise of monoclonal antibody-targeted immune checkpoint inhibitor immunotherapy of advanced malignancies, in particular, antibodies directed against CTLA-4 and PD-1/PD-L1, the development of immune-related adverse events (irAEs) remains a constraint of this type of therapy. Although rarely fatal, the occurrence of irAEs may necessitate discontinuation of immunotherapy, as well as administration of corticosteroids or other immunosuppressive therapies that may not only compromise efficacy but also predispose for development of opportunistic infection. Clearly, retention of efficacy of immune checkpoint-targeted therapies with concurrent attenuation of immune-mediated toxicity represents a formidable challenge. In this context, the current brief review examines mechanistic relationships between these events, as well as recent insights into immunopathogenesis, and strategies which may contribute to resolving this issue. These sections are preceded by brief overviews of the discovery and functions of CTLA-4 and PD-1, as well as the chronology of the development of immunotherapeutic monoclonal antibodies which target these immune checkpoint inhibitors.

Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of immune-related adverse events: pulmonary toxicity.

The immune checkpoints associated with the CTLA-4 and PD-1 pathways are critical modulators of immune activation. These pathways dampen the immune response by providing brakes on activated T cells, thereby ensuring more uniform and controlled immune reactions and avoiding immune hyper-responsiveness and autoimmunity. Cancer cells often exploit these regulatory controls through a variety of immune subversion mechanisms, which facilitate immune escape and tumor survival. Immune checkpoint inhibitors (ICI) effectively block negative regulatory signals, thereby augmenting immune attack and tumor killing. This process is a double-edged sword in which release of regulatory controls is felt to be responsible for both the therapeutic efficacy of ICI therapy and the driver of immune-related adverse events (IrAEs). These adverse immune reactions are common, typically low-grade and may affect virtually every organ system. In the early clinical trials, lung IrAEs were rarely described. However, with ever-expanding clinical applications and more complex ICI-containing regimens, lung events, in particular, pneumonitis, have become increasingly recognized. ICI-related lung injury is clinically distinct from other types of lung toxicity and may lead to death in advanced stage disease. Thus, knowledge regarding the key characteristics and optimal treatment of lung-IrAEs is critical to good outcomes. This review provides an overview of lung-IrAEs, including risk factors and epidemiology, as well as clinical, radiologic, and histopathologic features of ICI-related lung injury. Management principles for ICI-related lung injury, including current consensus on steroid refractory pneumonitis and the use of other immune modulating agents in this setting are also highlighted.

Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of severe gastrointestinal and hepatic toxicities from checkpoint inhibitors.

Immune-related adverse events (IrAEs) affecting the gastrointestinal (GI) tract and liver are among the most frequent and most severe inflammatory toxicities from contemporary immunotherapy. Inflammation of the colon and or small intestines (entero)colitis is the single most common GI IrAE and is an important cause of delay of discontinuation of immunotherapy. The severity of these GI IrAEs can range from manageable with symptomatic treatment alone to life-threatening complications, including perforation and liver failure. The frequency and severity of GI IrAEs is dependent on the specific immunotherapy given, with cytotoxic T lymphocyte antigen (CTLA)-4 blockade more likely to induce severe GI IrAEs than blockade of either programmed cell death protein 1 (PD-1) or PD-1 ligand (PD-L1), and combination therapy showing the highest rate of GI IrAEs, particularly in the liver. To date, we have minimal prospective data on the appropriate diagnosis and management of GI IrAEs, and recommendations are based largely on retrospective data and expert opinion. Although clinical diagnoses of GI IrAEs are common, biopsy is the gold standard for diagnosis of both immunotherapy-induced enterocolitis and hepatitis and can play an important role in excluding competing, though less common, diagnoses and ensuring optimal management. GI IrAEs typically respond to high-dose corticosteroids, though a significant fraction of patients requires secondary immune suppression. For colitis, both TNF-α blockade with infliximab and integrin inhibition with vedolizumab have proved highly effective in corticosteroid-refractory cases. Detailed guidelines have been published for the management of low-grade GI IrAEs. In the setting of more severe toxicities, involvement of a GI specialist is generally recommended. The purpose of this review is to survey the available literature and provide management recommendations focused on the GI specialist.

Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of severe dermatological toxicities from checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) frequently result in cutaneous immune-related adverse events (IrAEs). Although the majority of these events are mild-to-moderate in severity, up to 5% are severe, which may lead to morbidity and dose interruption or discontinuation of ICI therapy. In addition, up to 25% of dermatologic IrAEs are corticosteroid-refractory or corticosteroid-dependent. These 2020 MASCC recommendations cover the diagnosis and management of cutaneous IrAEs with a focus on moderate-to-severe and corticosteroid-resistant events. Although the usage of immune-suppressive therapy has been advocated in this setting, there is a lack of randomized clinical trial data to provide a compelling level of evidence of its therapeutic benefit.

Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of immune-mediated cardiovascular, rheumatic, and renal toxicities from checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have emerged as the newest pillar of cancer treatment. Immune-mediated toxicities, stemming from increased activity within the T cell lineage, range from asymptomatic or mild complications to those that are fulminant and potentially fatal. Although they are of variable occurrence, cardiovascular, rheumatic, and renal immune-mediated toxicities are among the most serious of these adverse events. We present MASCC recommendations with respect to the workup and management of cardiovascular, rheumatic, and renal immune-mediated toxicities with a focus on presentations that require treatment with immunomodulating agents.

Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of immune checkpoint inhibitor endocrinopathies and the role of advanced practice providers in the management of immune-mediated toxicities.

Immune checkpoint inhibitors (ICIs) have emerged as the newest pillar of cancer treatment, transforming outcomes in melanoma and showing benefit in a range of malignancies. Immune-mediated toxicities, stemming from increased activity within the T cell lineage, range from asymptomatic or mild complications to those that are fulminant and potentially fatal. Immune-mediated endocrinopathies include hypophysitis, thyroiditis, and insulin-dependent diabetes mellitus. These presentations, which may be vague and non-specific, can be life-threatening if not diagnosed and treated appropriately. This review considers the work-up and management of immune-mediated endocrinopathies and also considers the role of advanced practice practitioners in the management of immune-mediated toxicities. These state-of-the-art MASCC recommendations represent a comprehensive overview of the management and clinical work-up in those in whom the diagnosis should be considered.

Role of the Neutrophil in the Pathogenesis of Advanced Cancer and Impaired Responsiveness to Therapy.

Notwithstanding the well-recognized involvement of chronic neutrophilic inflammation in the initiation phase of many types of epithelial cancers, a growing body of evidence has also implicated these cells in the pathogenesis of the later phases of cancer development, specifically progression and spread. In this setting, established tumors have a propensity to induce myelopoiesis and to recruit neutrophils to the tumor microenvironment (TME), where these cells undergo reprogramming and transitioning to myeloid-derived suppressor cells (MDSCs) with a pro-tumorigenic phenotype. In the TME, these MDSCs, via the production of a broad range of mediators, not only attenuate the anti-tumor activity of tumor-infiltrating lymphocytes, but also exclude these cells from the TME. Realization of the pro-tumorigenic activities of MDSCs of neutrophilic origin has resulted in the development of a range of adjunctive strategies targeting the recruitment of these cells and/or the harmful activities of their mediators of immunosuppression. Most of these are in the pre-clinical or very early clinical stages of evaluation. Notable exceptions, however, are several pharmacologic, allosteric inhibitors of neutrophil/MDSC CXCR1/2 receptors. These agents have entered late-stage clinical assessment as adjuncts to either chemotherapy or inhibitory immune checkpoint-targeted therapy in patients with various types of advanced malignancy. The current review updates the origins and identities of MDSCs of neutrophilic origin and their spectrum of immunosuppressive mediators, as well as current and pipeline MDSC-targeted strategies as potential adjuncts to cancer therapies. These sections are preceded by a consideration of the carcinogenic potential of neutrophils.

Realizing the Clinical Potential of Immunogenic Cell Death in Cancer Chemotherapy and Radiotherapy.

Immunogenic cell death (ICD), which is triggered by exposure of tumor cells to a limited range of anticancer drugs, radiotherapy, and photodynamic therapy, represents a recent innovation in the revitalized and burgeoning field of oncoimmunnotherapy. ICD results in the cellular redistribution and extracellular release of damage-associated molecular patterns (DAMPs), which have the potential to activate and restore tumor-targeted immune responses. Although a convincing body of evidence exists with respect to the antitumor efficacy of ICD in various experimental systems, especially murine models of experimental anticancer immunotherapy, evidence for the existence of ICD in the clinical setting is less compelling. Following overviews of hallmark developments, which have sparked the revival of interest in the field of oncoimmunotherapy, types of tumor cell death and the various DAMPs most prominently involved in the activation of antitumor immune responses, the remainder of this review is focused on strategies which may potentiate ICD in the clinical setting. These include identification of tumor- and host-related factors predictive of the efficacy of ICD, the clinical utility of combinatorial immunotherapeutic strategies, novel small molecule inducers of ICD, novel and repurposed small molecule immunostimulants, as well as the critical requirement for validated biomarkers in predicting the efficacy of ICD.

Neurokinin 1 receptor antagonists in the prevention of chemotherapy-induced nausea and vomiting: focus on fosaprepitant.

Chemotherapy-induced nausea and vomiting (CINV) remains a challenge in cancer care. Improved understanding of CINV pathophysiology has triggered the development of new antiemetic therapeutic options, such as selective neurokinin-1 (NK1) receptor antagonists (RAs), which effectively prevent CINV when added to a standard antiemetic regimen (serotonin-3 RA and dexamethasone). Aprepitant and its water-soluble prodrug, fosaprepitant dimeglumine, are the most widely used NK1 RAs, with extensive clinical use worldwide. Recently, a Phase III trial prospectively evaluated fosaprepitant-based antiemetic therapy for CINV prevention in a large, well-defined nonanthracycline- and cyclophosphamide-based moderately emetogenic chemotherapy population. Fosaprepitant demonstrated significantly improved efficacy outcomes compared with a control regimen and was generally well tolerated, indicating that NK1 RAs are a valuable therapeutic option in this setting.

Evaluation of factors contributing to the response to fosaprepitant in a heterogeneous, moderately emetogenic chemotherapy population: an exploratory analysis of a randomized phase III trial.

PURPOSE: Fosaprepitant improved prevention of chemotherapy-induced nausea and vomiting (CINV) in a randomized, double-blind phase III trial (PN031). This post hoc analysis explored factors that may have influenced response. METHODS: Adult subjects (N = 1000) scheduled to receive non-anthracycline and cyclophosphamide (AC) moderately emetogenic chemotherapy (MEC) on day 1 were randomly assigned 1:1 to a single-dose, 150-mg intravenous fosaprepitant regimen or a control regimen. Both regimens included dexamethasone and ondansetron on day 1, with ondansetron continuing through day 3 in the control arm only. Complete response (CR; no vomiting and no rescue medication) rates in the acute, delayed, and overall phases (0-25, 25-120, and 0-120 h, respectively) were analyzed by chemotherapy type (carboplatin-based vs non-carboplatin-based), chemotherapy duration (single-day vs multiple-day), and baseline characteristics. RESULTS: Most subjects received single-day chemotherapeutic regimens (70.6%), which were mainly carboplatin-based (67.6%). CR with fosaprepitant was consistent (76-80%) during the delayed and overall phases in carboplatin-based and non-carboplatin-based subgroups and in subgroups receiving single-day or multiple-day MEC regimens. Treatment effects favored fosaprepitant for the carboplatin-based versus the non-carboplatin-based group during the delayed phase (14.1 vs 6.5%; p = 0.06), and for the single-day versus the multiple-day subgroup during the delayed (13.2 vs 3.2%; p = 0.02) and overall phases (12.8 vs 4.0%; p = 0.06). CONCLUSIONS: This exploratory analysis confirms that single-dose fosaprepitant is effective for the prevention of CINV in subjects receiving carboplatin or non-carboplatin in both single- and multiple-day non-AC MEC chemotherapy regimens. This trial is registered at ClinicalTrials.gov , number NCT01594749.

Rolapitant for the treatment of chemotherapy-induced nausea and vomiting: a review of the clinical evidence.

Chemotherapy-induced nausea and vomiting (CINV), both acute and delayed, has a dramatic effect on the well-being and quality of life of patients with cancer. Improved understanding of the mechanisms involved in CINV has led to the development of agents targeting the 5-HT3 receptor as well as the NK-1 receptor. Antiemetic prophylaxis given to patients receiving highly emetogenic chemotherapy combines agents blocking the 5-HT3 and NK-1 receptors along with corticosteroids given regularly and repeatedly. Rolapitant is a long-acting NK-1 receptor antagonist with proven efficacy in controlling CINV as part of the prophylaxis regimen. This review will detail the clinical efficacy and safety of rolapitant in the treatment of patients with cancer receiving highly or moderately emetogenic chemotherapy.

Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide regimens in patients with cancer: a randomised, active-controlled, double-blind, phase 3 trial.

BACKGROUND: Chemotherapy-induced nausea and vomiting is a common side-effect of many antineoplastic regimens and can occur for several days after treatment. We aimed to assess the neurokinin-1 receptor antagonist rolapitant, in combination with a serotonin (5-HT3) receptor antagonist and dexamethasone, for the prevention of chemotherapy-induced nausea and vomiting in patients with cancer after administration of moderately emetogenic chemotherapy or regimens containing an anthracycline and cyclophosphamide. METHODS: We conducted a global, randomised, double-blind, active-controlled, phase 3 study at 170 cancer centres in 23 countries. We included patients with cancer aged 18 years or older, who had not received moderately or highly emetogenic chemotherapy before, with a Karnofsky performance score of 60 or higher, and a predicted life expectancy of 4 months or longer. We used an interactive web-based randomisation system to randomly allocate patients to receive either oral rolapitant (one 180 mg dose; rolapitant group) or a placebo that was identical in appearance (active control group) 1-2 h before administration of moderately emetogenic chemotherapy. Patients were stratified by sex. All patients also received granisetron (2 mg orally) and dexamethasone (20 mg orally) on day 1 (except for patients receiving taxanes as part of moderately emetogenic chemotherapy, who received dexamethasone according to the package insert) and granisetron (2 mg orally) on days 2-3. Every cycle was a minimum of 14 days. In up to five subsequent cycles, patients received the same study drug they were assigned in cycle 1, unless they chose to leave the study or were removed at the treating clinician's discretion. Efficacy analysis was done in the modified intention-to-treat population (comprising all patients who received at least one dose of study drug at a study site compliant with Good Clinical Practice [GCP]). The primary endpoint was the proportion of patients achieving a complete response (defined as no emesis or use of rescue medication) in the delayed phase (>24-120 h after initiation of chemotherapy) in cycle 1. This study is registered with ClinicalTrials.gov, number NCT01500226. The study has been completed. FINDINGS: Between March 5, 2012, and Sept 6, 2013, 1369 patients were randomised to receive either rolapitant (n=684) or active control (n=685). 666 patients in each group received at least one dose of study drug at a GCP-compliant site and were included in the modified intention-to-treat population. A significantly greater proportion of patients receiving rolapitant had complete responses in the delayed phase than did those receiving active control (475 [71%] vs 410 [62%]; odds ratio 1·6, 95% CI 1·2-2·0; p=0·0002). The incidence of adverse events was similar in the rolapitant and control groups, with the most frequently reported treatment-related treatment-emergent adverse events being fatigue, constipation, and headache. For cycle 1, the most common grade 3-4 adverse event in the rolapitant versus active control groups was neutropenia (32 [5%] vs 23 [3%] patients). No serious adverse event was treatment-related, and no treatment-related treatment-emergent adverse event resulted in death. INTERPRETATION: Rolapitant in combination with a 5-HT3 receptor antagonist and dexamethasone is well tolerated and shows superiority over active control for the prevention of chemotherapy-induced nausea and vomiting during the 5-day (0-120 h) at-risk period after administration of moderately emetogenic chemotherapy or regimens containing an anthracycline and cyclophosphamide. FUNDING: TESARO, Inc.

Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: two randomised, active-controlled, double-blind, phase 3 trials.

BACKGROUND: Highly emetogenic chemotherapy induces emesis in almost all patients in the absence of prophylaxis. Guidelines recommend use of a neurokinin-1 (NK-1) receptor antagonist in conjunction with a 5-HT3 receptor antagonist and corticosteroid in patients receiving highly emetogenic chemotherapy. We aimed to assess rolapitant, an NK-1 receptor antagonist, for prevention of chemotherapy-induced nausea and vomiting in patients with cancer after administration of cisplatin-based highly emetogenic chemotherapy. METHODS: We conducted two global, randomised, double-blind, active-controlled, phase 3 trials (HEC-1 and HEC-2) at 155 cancer centres (76 in HEC-1 and 79 in HEC-2) in 26 countries (17 in HEC-1 and 14 in HEC-2). We enrolled patients with cancer aged 18 years or older, who had not previously been treated with cisplatin, with a Karnofsky performance score of 60 or higher, and a predicted life expectancy of 4 months or longer. We used an interactive web-based randomisation system to randomly assign patients to treatment. Patients were stratified by sex and randomly allocated to either oral rolapitant (180 mg dose; rolapitant group) or a placebo that was identical in appearance (active control group) about 1-2 h before administration of highly emetogenic chemotherapy. All patients received granisetron (10 µg/kg intravenously) and dexamethasone (20 mg orally) on day 1, and dexamethasone (8 mg orally) twice daily on days 2-4. Every cycle was a minimum of 14 days. In up to five subsequent cycles, patients were allowed to receive the same study drug they were assigned in cycle 1, unless removed at the clinician's discretion. Patients could also choose to leave the study at any point. Efficacy analysis was done in the modified intention-to-treat population (comprising all patients who received at least one dose of study drug at a cancer centre compliant with Good Clinical Practice [GCP]). The primary endpoint was the proportion of patients achieving a complete response (no emesis or use of rescue medication) in the delayed phase (>24-120 h after initiation of chemotherapy) in cycle 1. These studies are registered with ClinicalTrials.gov, numbers NCT01499849 and NCT01500213. Both studies have been completed. FINDINGS: Between Feb 21, 2012, and March 12, 2014, 532 patients in HEC-1 and 555 patients in HEC-2 were randomly assigned to treatment. 526 patients in HEC-1 (264 rolapitant and 262 active control) and 544 in HEC-2 (271 rolapitant and 273 active control) received at least one dose of study drug at a GCP-compliant site and were included in the modified intention-to-treat population. A significantly greater proportion of patients in the rolapitant group had complete responses in the delayed phase than did patients in the active control group (HEC-1: 192 [73%] vs 153 [58%]; odds ratio 1·9, 95% CI 1·3-2·7; p=0·0006; HEC-2: 190 [70%] vs 169 [62%]; 1·4, 1·0-2·1; p=0·0426; pooled studies: 382 [71%] vs 322 [60%]; 1·6, 1·3-2·1; p=0·0001). The incidence of adverse events was similar across treatment groups. The most commonly reported treatment-related treatment-emergent adverse events in the rolapitant versus active control groups were headache (three [<1%] vs two [<1%]), hiccups (three [<1%] vs four [<1%]), constipation (two [<1%] vs three [<1%]), and dyspepsia (two [<1%] vs three [<1%]). For cycle 1, the most common grade 3-5 adverse events in patients allocated rolapitant versus active control were neutropenia (HEC-1: nine [3%] vs 14 [5%]; HEC-2: 16 [6%] vs 14 [5%]), anaemia (HEC-1: one [<1%] vs one [<1%]; HEC-2: seven [3%] vs two [<1%]), and leucopenia (HEC-1: six [2%] vs two [<1%]; HEC-2: two [<1%] vs two [<1%]). No serious treatment-emergent adverse events were treatment related, and no treatment-related treatment-emergent adverse events resulted in death. INTERPRETATION: Rolapitant in combination with a 5-HT3 receptor antagonist and dexamethasone is well-tolerated and shows superiority over active control for the prevention of chemotherapy-induced nausea and vomiting during the at-risk period (120 h) after administration of highly emetogenic cisplatin-based chemotherapy. FUNDING: TESARO, Inc.

Aprepitant and fosaprepitant: a 10-year review of efficacy and safety.

Chemotherapy-induced nausea and vomiting (CINV) is a common adverse event associated with anticancer treatment that can have a significant adverse impact on patient health-related quality of life and that can potentially undermine the effectiveness of chemotherapy. Traditional regimens to prevent CINV generally involved a combination of a corticosteroid plus a 5-hydroxytryptamine (5HT3) receptor antagonist (RA). In the past 10 years, antiemetic treatment has greatly advanced with the availability of the neurokinin-1 receptor antagonist (NK1 RA) aprepitant and its prodrug fosaprepitant. NK1 RAs have a different mechanism of action in CINV than corticosteroids and 5HT3 RAs, thus their use can complement traditional antiemetic drugs and can enhance control of CINV. This review examined accumulated data regarding the safety and efficacy of aprepitant and fosaprepitant over the decade since the first regulatory approval. Data from key studies of aprepitant and fosaprepitant in the prevention of CINV in patients receiving moderately and highly emetogenic chemotherapy were explored, as were recommendations in currently available guidelines for their use. In addition, their use as antiemetic therapy in special patient populations was highlighted. Future perspectives on potential uses of aprepitant and fosaprepitant for indications other than CINV are presented.