Background: When resection is not an option, platinum-based chemoradiotherapy (CRT) has been the historic standard of care in non-small cell lung cancer (NSCLC). Prognosis remains poor with CRT alone. Durvalumab has shown significant improvement (versus placebo) in progression-free and overall survival in patients with unresectable stage III NSCLC without progression following CRT.
Objectives: This article aims to provide an overview of the efficacy and safety outcomes with durvalumab in patients with stage III NSCLC and identify management strategies for potential adverse events (AEs).
Methods: A review of published literature and guidelines was performed to evaluate durvalumab clinical outcomes and AE management strategies.
Findings: Durvalumab has established efficacy in patients with unresectable stage III NSCLC and is now the standard of care following CRT. Nurses need to be trained to recognize potential immune-related AEs in patients treated with immune checkpoint inhibitors.
Non-small cell lung cancer (NSCLC) accounts for about 80% of all lung cancers (Siegel et al., 2019). Surgical resection is considered the standard of care in early-stage NSCLC (National Comprehensive Cancer Network [NCCN], 2020b). Although most patients with NSCLC present with advanced disease, about 30% are diagnosed with stage III (locally advanced) disease (Siegel et al., 2019) (see Table 1). Many locally advanced NSCLC cases are not eligible for surgical resection, but patients can be treated with curative intent using chemoradiotherapy (CRT). The identification of immune checkpoints and the development of inhibitors targeting these checkpoints has altered the cancer treatment landscape for several tumor types, including NSCLC (Antonia et al., 2017; Borghaei et al., 2015; Brahmer et al., 2015; Fehrenbacher et al., 2016; Garon et al., 2015).
Immunotherapies offer significant clinical benefit, but there are risks for serious adverse events (AEs). As foundational members of an interprofessional team, nurses have unique opportunities to identify and manage these AEs early. It is vital that nurses remain informed concerning new treatment strategies and management algorithms for immune-related AEs (irAEs) (Ciccolini et al., 2017; Gordon et al., 2017). This review provides an overview of the efficacy and safety of the immune checkpoint inhibitor durvalumab and highlights patient management strategies of relevance to oncology nurses.
A key role of the immune system is to identify and remove damaged or aberrant cells. Immunotherapies enhance the immune response, allowing the immune system to identify and eradicate tumor cells that would otherwise have avoided immune detection (Pennock & Chow, 2015). The most extensively studied oncology-specific immunotherapies are immune checkpoint inhibitors, including approved antibodies against the programmed death receptor-1 (PD-1) and its ligand (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (Kyi & Postow, 2014; Meyers et al., 2018).
Durvalumab in Non-Small Cell Lung Cancer
The PACIFIC trial assessed the efficacy and safety of durvalumab in patients with unresectable stage III NSCLC whose disease did not progress following concurrent platinum-based CRT (two or more cycles) (Antonia et al., 2017). Durvalumab (an anti-PD-L1 antibody) significantly prolonged overall survival (OS), progression-free survival (PFS), and time to death or distant metastasis, with manageable safety as compared to placebo (Antonia et al., 2018). Based on these findings, durvalumab received approval from the U.S. Food and Drug Administration on February 16, 2018, and has been incorporated into the NCCN (2020b) guidelines as standard of care for patients in this setting (Brahmer, Govindan, et al., 2018).
Following CRT delivery to the patient, the healthcare provider determines if durvalumab treatment is warranted. It is important that patients understand the different phases of their treatment and potential associated side effects.
Lack of disease progression (based on diagnostic scans, patient performance, and/or clinical characteristics) should be confirmed following CRT completion and prior to initiation of durvalumab (Brahmer, Govindan, et al., 2018; NCCN, 2020a). It is essential to assess patients for potential CRT-related AEs and be cognizant of AEs that may arise later, such as radiation-induced pneumonitis (Jain & Berman, 2018). Initiation of immunotherapy may depend on adequate recovery from CRT-related AEs.
As with other immune checkpoint inhibitors, durvalumab can cause pathologic inflammation. Organ function should be assessed at baseline, and patient medical history and comorbidities should be carefully evaluated and documented prior to treatment initiation. Although there are no contraindications for durvalumab in patients with lung cancer, preexisting autoimmune conditions, history of organ transplantation, and organ damage should be documented, and risks and benefits of starting treatment should be carefully weighed (Brahmer, Govindan, et al., 2018). Patients with preexisting autoimmune conditions were excluded from the PACIFIC trial, but evidence exists that these patients may benefit from immunotherapy (Brahmer, Lacchetti, et al., 2018; Johnson et al., 2016). Careful consideration should be given to the risks and benefits of using immune checkpoint inhibitors in these patients, and close collaboration with appropriate specialists is recommended (Brahmer, Govindan, et al., 2018).
In addition to medical history, a list of concomitant medications should be collected and monitored because of possible interaction with the immunogenic potential of durvalumab and potential side effects. Identifying the need for steroids or other immunosuppressants is particularly important. There is a risk for reduced durvalumab efficacy if an ongoing daily high-dose steroid regimen is administered prior to or during therapy (Arbour et al., 2018). Therefore, steroid doses equivalent to greater than 10 mg per day of prednisone should be avoided. However, single doses of steroids do not seem to have a deleterious effect on the immune checkpoint inhibitor antitumor response (Langer et al., 2016).
Nurses have a crucial role in providing patient and caregiver education regarding pertinent safety information, including the incidence and symptoms of irAEs (Ciccolini et al., 2017; Davies & Duffield, 2017; Dine et al., 2017) (see Table 2). Teaching resources are available to help reinforce patient education (Wood et al., 2019). Re-education is particularly important for patients receiving immune checkpoint inhibitors because AEs may develop at any point and are not predictable. Patients and caregivers should be encouraged to maintain communication with the interprofessional team and to report any new or progressing symptoms. The emergence of AEs may not necessitate immediate treatment discontinuation; AE management strategies are available that may allow patients to remain on therapy. Reassurance may be provided that, in most cases of irAEs, there is typically a concordant antitumor effect taking place.
The recommended dose of durvalumab is 10 mg/kg every two weeks until disease progression, unacceptable toxicity, completion of 12 months of therapy, or 26 doses are administered. Durvalumab should be administered via IV over 60 minutes; no other drugs should be coadministered using the same infusion line (AstraZeneca, 2018). There is no dose reduction for durvalumab. As with other immune checkpoint inhibitors, it is either administered at the full dose or held if treatment parameters are not met (Davies & Duffield, 2017).
Data on the potential biohazards of immune checkpoint inhibitors are limited. The Oncology Nursing Society (ONS) has published the Chemotherapy and Immunotherapy Guidelines that includes guidance on safe handling of durvalumab (Olsen et al., 2019; Wiley et al., 2017).
Regular assessments are required throughout treatment to monitor tumor response and irAEs (Brahmer, Govindan, et al., 2018). Blood tests should be performed at baseline and throughout treatment to monitor organ function; recommended laboratory tests prior to each dose include a complete blood cell count, complete metabolic panel, and baseline thyroid hormone levels.
Nurses should be particularly aware of serious or potentially fatal AEs that may arise during and after treatment with immune checkpoint inhibitors (Davies & Duffield, 2017). Standardized nursing documentation templates can facilitate detailed assessment and communication of AEs with all members of the interprofessional team (Reimschissel et al., 2017). It is important to constantly assess for any AEs and ensure that they are treated quickly.
In the PACIFIC trial, the most frequent AEs were cough, fatigue, dyspnea, and pneumonitis/radiation pneumonitis. The most common grade 3 or 4 AE was pneumonia, occurring at a similar rate in both treatment arms (Antonia et al., 2017, 2018). The most frequent AEs leading to discontinuation were pneumonitis, radiation pneumonitis, and pneumonia. Fatal AEs occurred in 4.4% and 6.4% of patients who received durvalumab and placebo, respectively (Antonia et al., 2018).
Management of Immune-Related Adverse Events
Clinical practice guidelines have been published by the American Society of Clinical Oncology, NCCN, and AIM with Immunotherapy regarding the management of irAEs (Brahmer, Lacchetti, et al., 2018; Davies, 2019; NCCN, 2020a; Puzanov et al., 2017). AE grading described in the current article is based on the Common Terminology Criteria for Adverse Events (U.S. Department of Health and Human Services, 2018). For suspected moderate or severe irAEs, it is important to withhold therapy and exclude other causes. Corticosteroids should be initiated as clinically indicated. Permanent discontinuation of durvalumab is recommended for patients with grade 4 irAEs. Once initiated, corticosteroid dosing continues until the irAE improves to grade 1, followed by taper over at least four weeks. Steroid-refractory irAEs may require higher steroid doses or additional immunosuppressive therapeutics.
Prophylactic medications should be prescribed along with a steroid regimen, including proton pump inhibitors to prevent gastritis and antibiotics to prevent opportunistic infections. Prophylactic medications may be discontinued when patients are taking less than 10 mg prednisone daily. Long-term steroid dosing may increase the risk for osteoporosis, requiring prescription of vitamin D and calcium supplements and assessment of bone density (Brahmer, Lacchetti, et al., 2018; Puzanov et al., 2017).
Immune-Mediated Dermatologic Reactions
Dermatologic irAEs include maculopapular rash, psoriasiform rash, pruritus, and vitiligo, as well as more severe forms, such as bullous dermatitis and Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN).
A total body skin examination (including mucosa) and assessment of prior inflammatory dermatologic diseases is recommended for patients with rash or pruritus. Biopsy should be considered for patients with unusual rash features. Patients with grade 1 rash may continue durvalumab, incorporating supportive care with topical emollient, low- to moderate-potency topical steroid, and oral antihistamine if needed for pruritus (Fazer, 2019). For grade 2 rash, consider withholding durvalumab, and initiate supportive care along with high-potency topical steroids and/or prednisone (0.5–1 mg/kg per day). Withhold durvalumab for grade 3 or 4 rash, and initiate treatment with high-potency topical steroids and/or prednisone (1–2 mg/kg per day). For severe rash, obtain an urgent dermatology consultation, and consider inpatient care if the rash is progressing or not improving within 24–48 hours. GABA agonists can be considered for patients with grade 3 pruritus, and aprepitant or omalizumab may be indicated in refractory cases (Brahmer, Lacchetti, et al., 2018; NCCN, 2020a; Puzanov et al., 2017).
Bullous dermatitis and SJS/TEN are rare, serious, and potentially life-threatening complications of durvalumab. In the event of this severe dermatologic toxicity, durvalumab should be permanently discontinued and prednisone/methylprednisolone (1–2 mg/kg per day) initiated; these patients require inpatient care, as well as urgent dermatology, ophthalmology, urology, infectious disease, and pain/palliative consultations (NCCN, 2020a; Puzanov et al., 2017).
Colitis may present with diarrhea, cramping, abdominal pain, or fever. Infection should be ruled out with a stool evaluation. Abdominal/pelvic imaging and gastrointestinal consultation are recommended, with a colonoscopy to diagnose the underlying pathology in severe cases.
Medical management for grade 1 or 2 diarrhea or colitis includes supportive care (e.g., loperamide, diphenoxylate/atropine) and monitoring for dehydration and electrolyte abnormalities (Wood, 2019). Consider withholding durvalumab in patients with grade 2 colitis. Permanently discontinue durvalumab at higher grades and initiate corticosteroids (prednisone 2 mg/kg or less per day). IV steroids or infliximab are recommended if there is no response to oral steroids in two to three days, with vedolizumab reserved for infliximab-refractory cases. Patients with grade 3 or 4 symptoms may require inpatient care (Brahmer, Lacchetti, et al., 2018; NCCN, 2020a; Puzanov et al., 2017).
Patients with pneumonitis typically present with cough, dyspnea, and hypoxia. Oxygen saturation (at rest and with ambulation) should be evaluated before and during treatment because modest changes may be a sign of evolving pneumonitis (Davies, 2019). For patients whose respiratory status declines, it is prudent to perform a chest computed tomography (CT) scan to evaluate all potential causes of respiratory compromise. A bronchoscopy and biopsy should be considered if CT scan results are equivocal to exclude other causes, such as disease progression or infection.
Grade 1 pneumonitis is asymptomatic and identified by radiographic imaging. Although no intervention is indicated for grade 1 pneumonitis, patients should be closely monitored for clinical and radiologic changes indicative of worsening pneumonitis. Durvalumab may be tentatively continued, but withholding therapy should be considered. For grade 2 pneumonitis, withhold durvalumab and administer corticosteroids until reduction in severity or resolution of symptoms. Reintroduction of durvalumab following resolution of grade 2 pneumonitis may be cautiously considered. Patients with grade 3 or 4 pneumonitis should permanently discontinue durvalumab and be treated with high-dose steroids (1–2 mg/kg per day of prednisone or equivalent). If symptoms do not improve within 48 hours, infliximab, mycophenolate mofetil, or IV immunoglobulin should be considered (Brahmer, Lacchetti, et al., 2018; NCCN, 2020a; Puzanov et al., 2017). Inpatient care with pulmonary and infectious disease consultations is recommended for patients demonstrating new supplemental oxygen requirement and those needing additional immunosuppressants.
In most cases, immune-related endocrinopathies will require lifetime hormone replacement because organ function rarely recovers (even upon completion or discontinuation of treatment). Nurses must counsel patients that they will need to continue with hormone replacement therapy and maintain close follow-up with their endocrinologist.
Thyroid disorders: Patients with grade 1 hyperthyroidism may be mildly symptomatic or asymptomatic with changes in thyroid test values. These patients may safely continue durvalumab without interruption with thyroid function monitoring. For grade 2 or greater hyperthyroidism, withhold durvalumab until symptoms resolve. A beta blocker is recommended for symptomatic relief, with an endocrine consultation considered (Brahmer, Lacchetti, et al., 2018; NCCN, 2020a; Puzanov et al., 2017). It is important to monitor patients who develop hyperthyroidism for transition to hypothyroidism because thyroid inflammation will often cause damage resulting in decreased thyroid activity (Frazer, 2019).
For patients who develop moderate or severe hypothyroidism (grades 2–4), durvalumab should be withheld, and hormone replacement should be initiated (Brahmer, Lacchetti, et al., 2018; NCCN, 2020a; Puzanov et al., 2017). Durvalumab may be safely resumed once the patient is clinically stable and symptoms have improved or resolved.
Adrenal insufficiency: In cases of adrenal insufficiency, testing for serum cortisol, a comprehensive metabolic panel, adrenocorticotropic hormone, and renin levels should be performed. Hormone repletion with corticosteroids is recommended and, for patients with grade 2 or greater adrenal insufficiency, durvalumab should be held until patients become clinically stable. Endocrinology consultations are recommended, and sick-day guidelines should be followed for steroid dosing (National Institutes of Health, n.d.; NCCN, 2020a; Puzanov et al., 2017).
Type 1 diabetes mellitus: Blood glucose should be regularly monitored for patients on durvalumab. Insulin therapy may be required for patients who develop diabetes. Withhold durvalumab for grades 2–4 type 1 diabetes mellitus, and resume when clinically stable. Endocrine consultation is recommended, along with appropriate diet and lifestyle modifications (Brahmer, Lacchetti, et al., 2018; Davies, 2019; NCCN, 2020a; Puzanov et al., 2017).
Hypophysitis: If hypophysitis and associated hypopituitarism, leading to secondary adrenal insufficiency and/or diabetes insipidus, is suspected, evaluation includes a brain magnetic resonance imaging scan and a full endocrine panel (Davies, 2019). Durvalumab should be withheld, steroid treatment initiated, and hormone supplementation provided as needed. An endocrine consultation is recommended (Brahmer, Lacchetti, et al., 2018; NCCN, 2020a; Puzanov et al., 2017).
Immune-related hepatitis: Autoimmune and drug-induced hepatitis may be difficult to distinguish based on symptoms and laboratory values, with imaging and biopsy necessary to differentiate by histologic features (Cramer & Bresalier, 2017). Patients should be monitored for signs of hepatitis (elevated transaminases and/or bilirubin levels). Use of hepatotoxic agents (e.g., acetaminophen, dietary supplements, alcohol) should be minimized (Frazer, 2019; NCCN, 2020a). Steroids, at an initial prednisone dose of 1–2 mg/kg per day, are recommended. Withhold durvalumab in patients with grade 2 symptoms, and permanently discontinue for grade 3 or 4 (Brahmer, Lacchetti, et al., 2018; Puzanov et al., 2017).
Immune-related nephritis: Patients with nephritis, characterized by increased serum creatinine level, should be assessed for other possible causes (e.g., nephrotoxic agents). Management includes hydration and close monitoring of renal function (Wood, 2019). For grade 2 or greater nephritis, durvalumab should be withheld and steroids (1–2 mg/kg per day of prednisone) initiated. Permanent discontinuation of durvalumab is recommended if creatinine rises to three times or greater upper limits of normal, with initiation of steroids (1–2 mg/kg per day of prednisone) and nephrology consultation (Brahmer, Lacchetti, et al., 2018; NCCN, 2020a; Puzanov et al., 2017).
Other Adverse Events
Infections, infusion-related reactions, and other AEs also may occur following durvalumab treatment (AstraZeneca, 2018). Patients should be regularly monitored for signs of infection and treated with antibiotics and supportive care. If patients develop grade 3 or 4 infections, durvalumab should be withheld until clinically stable. Infusion-related reactions can be managed by slowing or interrupting the rate of infusion, with permanent discontinuation of immunotherapy for grade 3 or 4 reactions (NCCN, 2020a; Puzanov et al., 2017).
Durvalumab Case Study
J.C., a 58-year-old man with a 60 pack-year smoking history presented with a mass in the right upper lobe. The biopsy was positive for NSCLC, and staging scans showed no distant metastases. He was diagnosed with stage IIIA lung adenocarcinoma.
A decision was reached by J.C. and his healthcare team to pursue CRT followed by durvalumab at a dose of 10 mg/kg via IV every two weeks. J.C. completed CRT with mild fatigue and minimal esophagitis. Restaging CT scan showed response to treatment, and durvalumab maintenance therapy was initiated.
Three months later, the patient reported increased shortness of breath and dry cough. The triage nurse was concerned that his symptoms could represent pneumonitis and arranged for the patient to be evaluated. Vitals showed decreased oxygen saturation. He was coughing and visibly short of breath.
The nurse practitioner evaluated the patient and shared the triage nurse’s concern for pneumonitis. CT angiography of the chest showed continued response, with evolving postradiation changes in the right upper lobe, now sharply demarcated and fibrotic. The changes conformed to the radiation field, representing radiation-induced pneumonitis.
Durvalumab was held, and the nurse explained the plan for a high-dose steroid regimen, as well as prophylactic medications to J.C. Symptoms resolved, and the prednisone dose was tapered over six weeks with no recurrence of pneumonitis symptoms. Durvalumab therapy was resumed at the same dose and schedule, with the plan to complete the remainder of the 26 scheduled doses.
Implications for Nursing
The treatment journey of patients with NSCLC encompasses various providers, including nurses, nurse practitioners, oncologists, and subspecialists, all of whom are essential to support patients and their families (Davies & Duffield, 2017). Nurses play a paramount role in monitoring and managing toxicities and AEs associated with immune checkpoint inhibitors (Ciccolini et al., 2017; Davies, 2019). This includes face-to-face evaluations in clinic, as well as telephone triage to monitor irAEs remotely (Hoffner & Rubin, 2019). Nursing assessment and management of irAEs may minimize treatment delays and enhance patient quality of life during treatment (Dine et al., 2017).
Nurse practitioners can enhance overall patient care by managing the diverse array of potential AEs based on interprofessional irAE practice guidelines, coordinating care by interprofessional subspecialists, and developing care delivery models (Davies, 2019; Hoffner & Rubin, 2019). Because irAEs can occur long after completion of therapy, nurses and nurse practitioners must incorporate the monitoring for and management of latent irAEs into patient survivorship care plans (Brahmer, Lacchetti, et al., 2018; Wood et al., 2019).
In the PACIFIC trial, durvalumab therapy showed significant clinical benefits (including improved OS and PFS versus placebo) in patients with unresectable stage III NSCLC who had not progressed following CRT. Although typically well tolerated, side effects from durvalumab can have serious consequences if not identified and managed appropriately. Careful assessment and management of potential AEs associated with durvalumab are critical responsibilities of the interprofessional team.
Nurses play a vital role in the durvalumab treatment journey by providing education, identifying side effects and toxicities, and giving psychological support to the patient and family. Nurses are a core facet of the interprofessional approach to treatment and are essential to maximizing patient benefit from this promising new therapy. Given the results immunotherapy has demonstrated in the stage III NSCLC patient population, data from additional studies investigating the efficacy and safety of durvalumab across the spectrum of NSCLC diagnoses are highly anticipated.
About the Author(s)
Marianne Davies, DNP, ACNP, AOCNP®, is an oncology nurse practitioner in the Department of Medical Oncology at Yale Comprehensive Cancer Center and in the Department of Nursing at Smilow Cancer Hospital at Yale–New Haven Hospital and an associate professor at Yale School of Nursing, and Emily Duffield, APRN, MPH, is a thoracic advanced practice RN in the Department of Nursing at Smilow Cancer Hospital at Yale–New Haven Hospital, all in New Haven, CT. The authors take full responsibility for this content. Davies has received speaker honoraria from AstraZeneca. Duffield has received speakers bureau compensation from AstraZeneca. Medical writing support, which was in accordance with Good Publication Practice guidelines, was provided by Hashem Dbouk, PhD, of Cirrus Communications and was funded by AstraZeneca. The article has been reviewed by independent peer reviewers to ensure that it is objective and free from bias. Davies can be reached at email@example.com, with copy to CJONEditor@ons.org. (Submitted November 2019. Accepted December 23, 2019.)
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