Management of Immunotherapy-Related Toxicities, Version 1.2019.

The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions and ASCO, consisting of medical and hematologic oncologists with expertise in a wide array of disease sites, and experts from the fields of dermatology, gastroenterology, neuro-oncology, nephrology, emergency medicine, cardiology, oncology nursing, and patient advocacy. Several panel representatives are members of the Society for Immunotherapy of Cancer (SITC). The initial version of the NCCN Guidelines was designed in general alignment with recommendations published by ASCO and SITC. The content featured in this issue is an excerpt of the recommendations for managing toxicity related to immune checkpoint blockade and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to chimeric antigen receptor T-cell therapy, visit NCCN.org.

Long-Term Follow-Up of Desmoid Fibromatosis Treated with PF-03084014, an Oral Gamma Secretase Inhibitor.

BACKGROUND: Desmoid fibromatosis is a fibroblastic neoplasm driven by aberrations within the WNT pathway, exhibiting mutations in ß-catenin or APC. We review the long-term follow-up of patients in a phase I study treated with an oral gamma secretase inhibitor, PF-03084014. METHODS: PF-03084014 was administered orally at doses ranging from 20 to 330 mg twice daily. Tumor assessments were performed using computed tomography/magnetic resonance imaging (CT/MRI) within 4 weeks of study entry, and every other cycle through cycle 9. After cycle 9, patients were evaluated as clinically indicated. RESULTS: Seven patients with desmoid fibromatosis were treated between December 2009 and December 2016 at the University of Colorado. Five patients (71.4%, 95% confidence interval [CI] 29.0-96.3%) achieved a partial response (PR), with a mean time to achieving response of 11.9 months (95% CI 2.5-21.4 months). All patients who achieved a PR continue to maintain responses between 47.9 and 73+ months. Four patients stopped treatment yet remain free of progression between 11 and 53+ months. One patient had PFS of 42+ months, with a 17% decrease in the target lesion. A biopsy performed at the end of the study showed decreased tumoral cellularity compared with previous biopsies. Effective treatment doses ranged from 80 to 330 mg administered orally twice daily. CONCLUSIONS: PF-03084014 was effective in treating desmoid tumors, with an objective response rate of 71.4% (95% CI 29.0-96.3%) in this small cohort of patients. PF-03084014 exhibits promising activity, even at relatively low doses (80 mg twice daily), with high tolerability leading to prolonged disease control even after therapy discontinuation.

Oncolytic immunotherapy: unlocking the potential of viruses to help target cancer.

Oncolytic immunotherapy is a research area of cancer immunotherapy investigating the use of modified viruses to target cancer cells. A variety of different viral backbones (e.g., adenovirus, reovirus) with a diverse range of genetic modifications are currently being investigated for the treatment of a variety of cancers. The oncolytic virus that has advanced the furthest in clinical development is talimogene laherparepvec, a recombinant HSV-1 virus expressing granulocyte-macrophage colony-stimulating factor (GM-CSF). In a phase 3 study in patients with unresectable metastatic melanoma, intralesional talimogene laherparepvec treatment resulted in a higher durable response rate compared with subcutaneous GM-CSF treatment (16.3 versus 2.1%; P < 0.001). Notably, responses were observed at uninjected lesions including visceral lesions, indicating a systemic antitumor response had occurred. Studies evaluating combination treatments involving oncolytic viruses and immunologic agents are ongoing. This review focuses on the mechanisms of action for oncolytic viruses and highlights select agents and combinations currently in development.

Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma.

IMPORTANCE: The programmed death 1 (PD-1) pathway limits immune responses to melanoma and can be blocked with the humanized anti-PD-1 monoclonal antibody pembrolizumab. OBJECTIVE: To characterize the association of pembrolizumab with tumor response and overall survival among patients with advanced melanoma. DESIGN, SETTINGS, AND PARTICIPANTS: Open-label, multicohort, phase 1b clinical trials (enrollment, December 2011-September 2013). Median duration of follow-up was 21 months. The study was performed in academic medical centers in Australia, Canada, France, and the United States. Eligible patients were aged 18 years and older and had advanced or metastatic melanoma. Data were pooled from 655 enrolled patients (135 from a nonrandomized cohort [n = 87 ipilimumab naive; n = 48 ipilimumab treated] and 520 from randomized cohorts [n = 226 ipilimumab naive; n = 294 ipilimumab treated]). Cutoff dates were April 18, 2014, for safety analyses and October 18, 2014, for efficacy analyses. EXPOSURES: Pembrolizumab 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks continued until disease progression, intolerable toxicity, or investigator decision. MAIN OUTCOMES AND MEASURES: The primary end point was confirmed objective response rate (best overall response of complete response or partial response) in patients with measurable disease at baseline per independent central review. Secondary end points included toxicity, duration of response, progression-free survival, and overall survival. RESULTS: Among the 655 patients (median [range] age, 61 [18-94] years; 405 [62%] men), 581 had measurable disease at baseline. An objective response was reported in 194 of 581 patients (33% [95% CI, 30%-37%]) and in 60 of 133 treatment-naive patients (45% [95% CI, 36% to 54%]). Overall, 74% (152/205) of responses were ongoing at the time of data cutoff; 44% (90/205) of patients had response duration for at least 1 year and 79% (162/205) had response duration for at least 6 months. Twelve-month progression-free survival rates were 35% (95% CI, 31%-39%) in the total population and 52% (95% CI, 43%-60%) among treatment-naive patients. Median overall survival in the total population was 23 months (95% CI, 20-29) with a 12-month survival rate of 66% (95% CI, 62%-69%) and a 24-month survival rate of 49% (95% CI, 44%-53%). In treatment-naive patients, median overall survival was 31 months (95% CI, 24 to not reached) with a 12-month survival rate of 73% (95% CI, 65%-79%) and a 24-month survival rate of 60% (95% CI, 51%-68%). Ninety-two of 655 patients (14%) experienced at least 1 treatment-related grade 3 or 4 adverse event (AE) and 27 of 655 (4%) patients discontinued treatment because of a treatment-related AE. Treatment-related serious AEs were reported in 59 patients (9%). There were no drug-related deaths. CONCLUSIONS AND RELEVANCE: Among patients with advanced melanoma, pembrolizumab administration was associated with an overall objective response rate of 33%, 12-month progression-free survival rate of 35%, and median overall survival of 23 months; grade 3 or 4 treatment-related AEs occurred in 14%. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01295827.

Hepatic hemorrhage as a consequence of rapid response to combined targeted therapy in metastatic melanoma.

A middle-aged female with metastatic melanoma was found to have hemoperitoneum after starting systemic therapy with the BRAF and MEK inhibitors dabrafenib and trametinib. Etiology proved to be bleeding from a known hepatic metastasis. The patient was managed conservatively and eventually resumed systemic therapy with ongoing response. This case serves to illustrate the possible deleterious effects of rapid tumor response after initiation of targeted systemic therapy in patients with metastatic melanoma.

Programmed death 1 immune checkpoint inhibitors.

Programmed death 1 (PD-1) is an immune checkpoint that provides inhibitory signals to the immune system in order to modulate the activity of T cells in peripheral tissues and maintain self-tolerance in the setting of infection and inflammation. In cancer, the immune checkpoints are exploited so that the tumor cells are able to evade the immune system. Immune checkpoint inhibitors are a type of cancer immunotherapy that targets pathways such as PD-1 in order to reinvigorate and enhance the immune response against tumor cells. The US Food and Drug Administration (FDA) has approved 2 PD-1 inhibitors, nivolumab and pembrolizumab, and several others are under investigation. Although PD-1 inhibitors have demonstrated activity in many different types of malignancies, FDA approval has been granted only in melanoma and in non-small cell lung cancer (NSCLC). Identifying biomarkers that can predict response to PD-1 inhibitors is critical to maximizing the benefit of these agents. Future directions for PD-1 inhibitors include investigation of combination therapies, use in malignancies other than melanoma and NSCLC, and refinement of biomarkers.

Investigating the Salience of Clinical Meaningfulness and Clinically Meaningful Outcomes in Metastatic Breast Cancer Care Delivery.

PURPOSE: As metastatic breast cancer (mBC) treatment evolves, there is a need to understand how clinical meaningfulness, or a meaningful change in a patient's daily life, and clinically meaningful outcomes inform patient-centered care. Partnering with key stakeholders ensures patient-centered research incorporates the knowledge and expertise of advisors with lived experience. We describe a multistakeholder engagement approach to examine how people living with mBC (PLWmBC), caregivers, and health care providers interpret clinical meaningfulness and clinically meaningful outcomes and their influence on mBC treatment decision making and care. METHODS: Qualitative focus groups with PLWmBC, caregivers, and health care providers were conducted and analyzed along three overarching themes: interpretations of clinical meaningfulness and clinically meaningful outcomes; treatment recommendations, preferences, and decisions; and implications for clinical practice. Patient-led and professional organizations served as research partners in study design, implementation, and interpretation of findings. RESULTS: Partnerships were established with four patient-led and three professional organizations representing diverse constituencies throughout the United States. Twenty-two focus groups were conducted with 50 PLWmBC, 24 caregivers, and 41 health care providers (oncologists, n = 11; advanced practice providers, n = 13; oncology nurses, n = 17) between March and June 2023. PLWmBC and caregivers were unfamiliar with the concepts of clinical meaningfulness and clinically meaningful outcomes. Although health care providers were familiar, they did not use the terms when discussing treatment with PLWmBC. Across groups, participants emphasized the importance of meaningful outcomes beyond overall survival, including quality of life and improvement in symptoms and functioning. Participants noted that outcomes considered meaningful are individualized and dynamic. CONCLUSION: This study offers insight into how partnering with patient advocacy and professional organizations can enhance research quality and aid translation of findings to clinical practice, thereby supporting patient-centered care.

What Does Dobbs v. Jackson Mean for Oncology Patients and Providers? Current Considerations for Pregnancy and Fertility in the Oncology Setting.

The incidence of cancers such as colorectal cancer, head and neck cancer, and melanoma has increased in younger patients. The number of cancer survivors is also increasing in the US. Pairing these facts together, there are many people with cancer for whom pregnancy and fertility concerns are crucial aspects of their oncologic and survivorship care. For these patients, understanding and having access to fertility preservation options is an essential part of their care. At JADPRO Live 2022, a panel of experts from diverse professions provided perspectives on the consequences for the treatment landscape after the Dobbs v. Jackson decision.

"Entering a Clinical Trial: Is it Right for You?": a randomized study of The Clinical Trials Video and its impact on the informed consent process.

PURPOSE: This randomized study was designed to assess the utility of an educational video in preparing cancer patients for decisions about clinical trial participation. The study assessed the effect of the video on patients' understanding and perceptions of clinical trials, its impact on decision making and patient-provider communication, and patients' satisfaction with the video. METHODS: Ninety adults considering cancer clinical trials were randomized to receive (n = 45) or not receive (n = 45) the video. Using the validated Quality of Informed Consent (QuIC), respondents' knowledge about clinical trial participation was assessed. All subjects completed additional questions about satisfaction with the video, decision making, and patient-provider communication. Data were analyzed using the Wilcoxon rank-sum test, regression model, and descriptive statistics. RESULTS: Although intent-to-treat analysis found no significant group differences in objective understanding between those randomized to view or not view the video, the majority of participants reported favorable experiences with regard to watching the video: 85% found the video was an important source of information about clinical trials; 81% felt better prepared to discuss the trial with their physician; 89% of those who watched the video with family indicated that it helped family better understand clinical trials; and 73% indicated it helped family accept their decision about participation. CONCLUSIONS: Although the video did not measurably improve patients' knowledge about clinical trials, it was an important source of information, helped educate families, and enhanced patient communication with their oncology providers.

A Call to Action: The Role of the Oncology AP in Equitable Cancer Care.

The COVID-19 pandemic has only further brought to light how racism, bias, and lack of equity can result in social injustice, morbidity, and mortality. A panel of four advanced practitioners convened at JADPRO Live Virtual 2021 to examine oncology advanced practitioners' capacity for enhancing equitable cancer care in the domains of care coordination and communication, clinical trials, and acknowledging and mitigating bias.

Role of Oncology Advanced Practitioners to Enhance Clinical Research.

Background: Oncology advanced practitioners (APs), including nurse practitioners, clinical nurse specialists, physician assistants, and clinical pharmacists contribute significantly to quality cancer care. Advanced practitioners enhance value across the spectrum of cancer care. Research is an underdeveloped component of quality care, as well as an underdeveloped component of AP practice. Understanding research-related attitudes and roles of APs could lead to enhanced clinical trial accrual, conduct, and protocol development. Methods: A nationwide survey addressing attitudes, beliefs, and roles of APs regarding clinical research was distributed by the Association of Community Cancer Centers (ACCC) and Harborside in early 2020. Results: 408 oncology APs completed the survey. Thirty-five percent practice in an academic setting and 62% in the community. Nearly all respondents believe clinical trials are important to improve care, and over 90% report clinical trials are available at their practice. About 80% report being comfortable discussing the topic of clinical trials with patients and are involved in the care of trial participants. Sixty percent are comfortable discussing available trials, and 38% routinely explore available trials with patients. While 70% report approaching eligible patients about trials, only 20% report doing so "a great deal" or "a lot." Ninety percent report that APs should play a role in clinical research, and 73% want to be more involved. Barriers identified to greater AP clinical trial involvement include lack of time, inadequate awareness of trial specifics, and a lack of a formal role in protocol development and leadership. Conclusions: Advanced practitioners are engaged and interested in clinical trials and believe clinical research is important to improve cancer care. Multidisciplinary team integration, trials-related education, and policy change are needed to employ APs to their full potential within cancer clinical trials.

Toxicity management with combination chemotherapy and programmed death 1/programmed death ligand 1 inhibitor therapy in advanced lung cancer.

PURPOSE: The combination of an anti-programmed death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) monoclonal antibody with platinum-based chemotherapy can improve outcomes for patients with advanced non-small-cell lung cancer (NSCLC) or small-cell lung cancer (SCLC) compared with chemotherapy alone. For patients receiving these new treatment regimens, it is important that toxicities be managed effectively. A particular challenge can be determining the etiology of an event, especially when there are overlapping symptoms that can be attributed to either immunotherapy or to platinum-based chemotherapy. Here, we evaluate adverse events (AEs) reported in clinical trials of combination therapy with an anti-PD-1 or anti-PD-L1 (anti-PD-[L]1) immunotherapy and chemotherapy to provide information on toxicity management. METHODS: We performed a systematic review of the literature focused on randomized controlled trials of anti-PD-(L)1 therapy combined with platinum-based chemotherapy for advanced/metastatic NSCLC and SCLC. RESULTS: Eleven reports from 9 randomized studies evaluating pembrolizumab, nivolumab, and atezolizumab combined with platinum-based chemotherapy in patients with advanced lung cancer were identified. Immune-mediated AEs and infusion reactions occurred more commonly in patients who received anti-PD-(L)1 immunotherapy with platinum-based chemotherapy compared with chemotherapy alone; however, there was no evidence of unexpected or unanticipated toxicity with these combinations. CONCLUSION: Combinations of anti-PD-(L)1 immunotherapy with platinum-based chemotherapy regimens improve outcomes for patients with NSCLC and SCLC, and toxicity is generally manageable. Strategies for appropriate workup of AEs to allow clinicians to make informed decisions regarding causality and treatment modifications when appropriate are an important element of management of patients receiving an anti-PD-(L)1 agent combined with platinum-based chemotherapy.

Meeting the Challenge of Immune-Related Adverse Events With Optimized Telephone Triage and Dedicated Oncology Acute Care.

Immune checkpoint inhibitors (ICIs) have improved outcomes for many patients with advanced cancers. However, managing the immune-related adverse events (irAEs) associated with these agents is challenging. Late recognition and/or inadequate irAE management can result in ICI discontinuation or termination, negatively impacting patient outcomes and increasing unplanned emergency department visits, hospital admissions, and costs of care. Improved clinician training and infrastructure development are needed to adequately address irAEs and maximize the potential benefits of ICIs. Advanced practice providers (APPs) are well positioned to drive these improvements. Two aspects of care may reduce the burden of irAE management: improved telephone triage and the implementation of dedicated oncology acute care services. Evidence-based protocols should be used for telephone triage. Protocol development may benefit from an evaluation of current irAE management guidelines together with resources from the Melanoma Nursing Initiative and Immuno-Oncology Essentials. Patients and their caregivers must be educated to recognize and report early symptoms suggestive of an irAE, thereby supporting triage efforts. Advanced practice providers should also advocate for the development of dedicated oncology acute care facilities staffed with clinicians well trained to recognize, grade, and manage irAEs. This manuscript reviews multiple existing models of telephone triage and dedicated oncology acute care. Oncology APPs are poised to lead the staffing, infrastructure, and educational changes necessary to reduce the burden of irAEs in patients receiving ICI therapy.

The Advanced Practice Provider Perspective: Treating Patients With Immuno-Oncology Combination Therapy Across Tumor Types.

A number of immune checkpoint inhibitors (ICIs) have been approved by the U.S. Food and Drug Administration (FDA) as immuno-oncology (IO) monotherapy for multiple solid and hematologic tumor types across various lines of therapy. Furthermore, evidence shows some patients may derive additional benefit from IO combination therapy. Three IO combination regimens, nivolumab plus ipilimumab, and pembrolizumab or atezolizumab plus chemotherapy, are approved by the FDA as of April 2019. Because peripheral immune surveillance via T-cell activity is increased to attack malignant cells, the antitumor effects of ICIs may be accompanied by immune-mediated adverse reactions (IMARs). Although potentially more efficacious than monotherapy, IO combination therapies are associated with increased incidences of IMARs vs. IO monotherapy. Advanced practice providers (APPs) are uniquely placed within the multidisciplinary team to counsel patients with cancer on their IO treatment and educate them about identifying manifestations of IMARs. Advanced practice providers should be aware of the presentation and time to onset of IMARs, appropriate management to reduce risk of organ dysfunction, and guidelines for treating these patients. This article reviews IO/IO and IO/chemotherapy combination regimens with respect to clinical efficacy and safety, and discusses the role of the APP in managing IMARs associated with IO combination therapy.

Caring for Patients Treated With Checkpoint Inhibitors for the Treatment of Metastatic Merkel Cell Carcinoma.

OBJECTIVE: To provide an overview for oncology nurses about Merkel cell carcinoma and its management with immunotherapy. DATA SOURCES: A literature search was conducted from 2013 to the present using search terms including "Merkel cell carcinoma," "avelumab," "pembrolizumab," "immune-mediated adverse events," and "infusion-related reactions." Clinical experience of the authors was also considered. CONCLUSION: Oncology nurses can expect to manage an increasing number of patients with Merkel cell carcinoma because of increased incidence of the disease, as well as evolving immunotherapy treatment paradigms. Both avelumab and pembrolizumab possess favorable safety profiles but are associated with immune-mediated and infusion-related reactions. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses need to understand Merkel cell carcinoma and be able to recognize the signs and symptoms of immune-mediated adverse events and infusion-related reactions associated with treatment to provide early intervention.

Trametinib: A Targeted Therapy in Metastatic Melanoma.

Trametinib is a MEK inhibitor approved both as a single agent and in combination with dabrafenib for the treatment of BRAF V600E or V600K mutated melanoma. It is a once-daily oral medication that was approved based on progression-free survival and overall survival advantage compared to chemotherapy. Most common side effects include rash, diarrhea, peripheral edema, and fatigue. When used in combination with dabrafenib, pyrexia and nausea are also common. Most side effects can be managed effectively with dose interruptions, supportive care, and/or dose reductions. Ongoing trials are investigating the use of targeted therapy in combination with immunotherapy for cutaneous melanoma and other malignancies. The treatment landscape for metastatic melanoma continues to evolve. However, targeted therapy with trametinib remains a fast-acting and efficacious option, particularly when used in combination with dabrafenib.

Targeted Therapies in the Treatment of Sarcomas.

About 50% of sarcomas have specific pathology-defining molecular alterations including mutations, fusion genes, and gene amplifications. Some of these alterations appear to be oncogenic drivers, and a subset can be utilized as targets for standard or experimental molecularly targeted agents in the clinic. In addition, immunotherapies may have a growing role in the treatment of sarcomas in the future.

Ipilimumab-Based
 Therapy: Consensus Statement From the Faculty of the Melanoma Nursing Initiative on Managing Adverse Events With Ipilimumab Monotherapy and Combination Therapy With Nivolumab.

BACKGROUND: Ipilimumab (Yervoy®) therapy improves outcomes in patients with resected stage III melanoma, and ipilimumab alone or combined with nivolumab (Opdivo®) does so in those with unresectable or metastatic melanoma. These immunotherapies are associated with immune-related adverse events (irAEs). With prompt recognition and appropriate management, serious sequelae or unnecessary treatment discontinuation can be prevented.
. OBJECTIVES: This article presents consensus statements to guide oncology nurses in the recognition and management of irAEs associated with ipilimumab and nivolumab. 
. METHODS: Members of the Melanoma Nursing Initiative reviewed the current literature and clinical experience regarding nursing interventions related to irAEs associated with ipilimumab or ipilimumab and nivolumab therapy.
. FINDINGS: The care step pathways provided represent a proactive, evidence-based, and comprehensive plan to support optimal patient outcomes.

Management of Patients With Skin Cancers: Basal Cell Carcinoma and Melanoma.

Novel therapies are changing the treatment paradigm for both melanoma and advanced/metastatic basal cell carcinoma. While immunotherapies are increasing survival benefits in melanoma, they are associated with unique immune-related adverse events.