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Nivolumab in Metastatic Non–Small Cell Lung Cancer

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Nivolumab in Metastatic Non–Small Cell Lung Cancer PRESCRIBER'S CORNER Section Editors: Christopher J. Campen and Beth Eaby-Sandy Nivolumab in Metastatic Non–Small Cell Lung Cancer ANDREA DEEL, PharmD From Kingsport Hematology Oncology, ung cancer is the leading NSCLC has led to the development of Kingsport, Tennessee cause of cancer deaths in agents that target specific molecular Author’s disclosures of potential conflicts of interest are found at the end of this article. the United States (Ameri- pathways in cancer cells (Kerr et al., Correspondence to: Andrea Deel, PharmD, can Cancer Society [ACS], 2014). Targeted therapies are a signifi- Kingsport Hematology Oncology, 4485 West L2015). Non–small cell lung cancer cant step forward in treating patients Stone Drive, Suite 200, Kingsport TN 37660. (NSCLC) is one of the most common with tumors that contain specific mu- E-mail: [email protected] types of the disease and accounts tations in these pathways. doi: 10.6004/jadpro.2016.7.2.7 for 85% to 90% of lung cancer cases In the United States, several agents © 2016 Harborside Press® (ACS, 2015). Nonsquamous NSCLC have been approved to target these accounts for approximately 45% to tumors. They include erlotinib, afa- 60% of all lung cancer cases, where- tinib (Gilotrif ), and gefitinib (Iressa), as squamous NSCLC accounts for which target EGFR signaling; crizo- approximately 25% to 30% of all lung tinib (Xalkori) and ceritinib (Zykadia), cancer cases (ACS, 2015). which target ALK rearrangements; Survival rates vary depending on bevacizumab (Avastin) and ramuci- the stage and type of the cancer and rumab (Cyramza), which target vascu- when it is diagnosed. For stage IV lar endothelial growth factor (VEGF) NSCLC, the 5-year survival rate is 1% signaling. Pembrolizumab (Keytruda) (ACS, 2015). Factors that influence and nivolumab (Opdivo) target pro- treatments for an individual patient grammed cell death protein 1 (PD-1) include histology (squamous vs. non- signaling (Lexi-Comp, 2015). Nivolu- squamous), age, comorbidity, perfor- mab, one of the agents that target PD-1 mance status, and preferences and signaling, has become of particular concerns regarding treatment. The interest for its clinical activity against presence or absence of driver muta- malignant cells. tions can be another factor. Patients The PD-1 protein is an immune should have tumor tissue assessed checkpoint receptor expressed by ac- for the presence of a driver mutation, tivated T cells (Topalian et al., 2012; such as mutated epidermal growth Brahmar et al., 2012). In a normal factor receptor (EGFR) or the ana- physiologic state, this immune check- plastic lymphoma kinase (ALK) fu- point exists to protect against inflam- sion oncogene (Kerr et al., 2014). mation and autoimmunity (Robert et Ongoing research into the molecu- al., 2015). In a neoplastic state, PD-1 J Adv Pract Oncol 2016;7:220–225 lar pathways that drive malignancy in binds to its ligands PD-L1 (B7-H1) J Adv Pract Oncol 220 AdvancedPractitioner.com NIVOLUMAB IN METASTATIC NSCLC PRESCRIBER'S CORNER and PD-L2 (B7-DC), which are expressed on tu- gressed on or after platinum-based chemotherapy mor cells; this inhibits T-cell proliferation, cytokine (Bristol-Myers Squibb, 2016). Patients who have production, and cytolytic function, thereby causing genomic tumor aberrations, such as EGFR or ALK, immunosuppression and preventing the immune and are receiving an approved EGFR- or ALK- system from rejecting the tumor (Brahmer, Horn, directed therapy should have disease progres- & Antonia, 2013; Brahmer & Pardoll, 2013; Sundar, sion prior to receiving nivolumab (Bristol-Myers Soong, Cho, Brahmer, & Soo, 2014). Squibb, 2016; Rizvi et al., 2015). The overexpression of PD-L1 on CD8-positive Adult dosing is 3 mg/kg once every 2 weeks as T cells has been identified in NSCLC tumors and an infusion, mixed in 0.9% sodium chloride or 5% is associated with a poor prognosis (Hirahara et dextrose in water, to a final concentration of be- al., 2012; Konishi et al., 2004; Mu, Huang, Chen, tween 1 and 10 mg/mL. It is infused over 60 min- Chen, & Zhang, 2011). Monoclonal antibodies, in- utes using a low protein binding 0.2- to 5-µ inline cluding nivolumab, target the binding of the PD-1 filter (Bristol-Myers Squibb, 2016). receptor to one of its ligands, which disrupts the negative PD-1–receptor signaling and augments CLINICAL TRIALS the T-cell response (Robert et al., 2015). Multiple clinical trials have been conducted to examine the efficacy of nivolumab in patients PHARMACOLOGY with advanced-stage NSCLC. CheckMate 017 is a Nivolumab is a fully human immunoglobulin phase III, open-label, randomized clinical trial that G4 (IgG4) monoclonal antibody that selectively in- evaluated nivolumab and docetaxel. Patients with hibits PD-1 activity by binding to the PD-1 receptor advanced squamous cell NSCLC who had pro- to block PD-L1 and PD-L2 from binding (Bristol- gressed during or after a prior platinum-based che- Myers Squibb, 2016). The negative PD-1–receptor motherapy regimen were randomized to receive ei- signaling that regulates T-cell activation and prolif- ther nivolumab at 3 mg/kg intravenously (IV) over eration is therefore disrupted (Robert et al., 2015). 60 minutes every 2 weeks vs. docetaxel at 75 mg/ This releases PD-1 pathway–mediated inhibition of m2 IV administered every 3 weeks. The trial includ- the immune response, including the antitumor im- ed patients regardless of their PD-L1 expression mune response (Bristol-Myers Squibb, 2016). status (Bristol-Myers Squibb, 2016). The primary endpoint was overall survival (OS), and secondary INDICATION AND DOSING endpoints included progression-free survival (PFS) Nivolumab is approved in the United States for and objective response rate (ORR; Brahmer et al., the treatment of unresectable or metastatic mela- 2015; Bristol-Myers Squibb, 2016). noma as a single agent in patients with disease The results of the trial showed an OS benefit, progression following ipilimumab (Yervoy) and, if with an estimated 28% of patients alive at 18 months positive for BRAF V600 mutation, a BRAF inhibi- for nivolumab vs. 13% for docetaxel. The median tor. It is also used in combination with ipilimumab OS for the nivolumab arm was 9.2 months and 6.0 in patients with BRAF V600 wild-type unresect- months for docetaxel (hazard ratio [HR]: 0.62; 95% able or metastatic melanoma (Postow et al., 2015; confidence interval [CI] = 0.48–0.81; p = .0004; Brah- Larkin et al., 2015). Nivolumab is indicated for mer et al., 2015; Bristol-Myers Squibb, 2016). treatment of advanced metastatic renal cell carci- The PFS rate at 18 months was 17% for the noma in patients who have received prior therapy nivolumab arm vs. 2.7% for docetaxel. Median (Bristol-Myers Squibb, 2016). Clinical trials have PFS was 3.5 months for patients administered shown the efficacy of nivolumab in treating pa- nivolumab vs. 2.8 months for docetaxel (HR: 0.63; tients with NSCLC, which lead to its approval for 95% CI = 0.48–0.83; p = .0008). The ORR was 20% this disease by the US Food and Drug Administra- for the nivolumab arm vs. 9% for docetaxel, for an tion (FDA) in 2015 (Bristol-Myers Squibb, 2016). estimated odds ratio of 2.6 (95% CI = 1.3–5.5; p = The indication includes the treatment of .0083), with a continued ongoing response seen in metastatic NSCLC, for both advanced squamous 63% of patients treated with nivolumab (Brahmer NSCLC and nonsquamous NSCLC, that has pro- et al., 2015; Bristol-Myers Squibb, 2016). AdvancedPractitioner.com 221 Vol 7 . No 2 . Mar 2016 PRESCRIBER'S CORNER DEEL Adverse effects occurred less frequently with musculoskeletal pain (36%), decreased appe- nivolumab (131 patients) with any grade, 59%, and tite (35%), cough (32%), nausea (29%), constipa- grade 3 or more, 8%. In 129 patients treated with tion (24%), and rash (21%; Bristol-Myers Squibb, docetaxel, adverse effects for any grade were 87% 2016). Other adverse events may include edema; and for grade 3 or greater, 58% (Brahmer et al., chest pain; and electrolyte imbalances including 2015; Bristol-Myers Squibb, 2016). These results hyponatremia, hypokalemia, hyperkalemia, hy- included both hematologic and nonhematologic perglycemia, hypomagnesemia, hypocalcemia, toxicities (Bristol-Myers Squibb, 2016). and hypercalcemia (Lexi-Comp, 2015). Another clinical trial, CheckMate 057, a phase Severe infusion reactions have been reported in III, open-label, randomized clinical trial that < 1% of patients in clinical trials of nivolumab as a evaluated patients with metastatic nonsquamous single agent. Infusions should be interrupted or the NSCLC who had experienced disease progression rate of infusion slowed in patients with grade 1 or 2 during or after one prior platinum-based chemo- reactions and discontinued in patients with grade therapy regimen. This study included patients re- 3 or 4 infusion reactions (Table 1). Immune-medi- gardless of their PD-L1 expression status. Patients ated adverse events included pneumonitis, colitis, were randomized to receive either nivolumab at 3 rash, adrenal insufficiency, hypophysitis, thyroid mg/kg administered IV every 2 weeks or docetax- dysfunction, encephalitis, and hepatitis (Bristol- el at 75 mg/m2 administered IV every 3 weeks Myers Squibb, 2016). (Borghaei et al., 2015; Bristol-Myers Squibb, 2016). Baseline and periodic hepatic and renal func- The primary endpoint of this trial was over- tion tests should be monitored (Lexi-Comp, all survival, which was 12.2 months in the nivolu- 2015). Serum blood glucose levels should be as- mab arm (95% CI = 9.7–15.0) and 9.4 months in sessed prior to each treatment and throughout the docetaxel arm (95% CI = 8.0–10.7). The HR therapy for patients at risk for hyperglycemia and resulted with 0.73 (95% CI = 0.60–0.89; p = .0015; patients with diabetes. Monitoring for signs and Borghaei et al., 2015; Bristol-Myers Squibb, 2016).
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