Management of Treatment-Related Adverse Events Associated with Nivolumab and Ipilimumab Combination Therapy in Patients with Metastatic Melanoma, NSCLC, and RCC

Conference Correspondent  - ONS 2017 - Immunotherapy, Conference Correspondent

Cancer immunotherapy modulates the body’s immune system to promote tumor destruction. These therapeutic agents target immune checkpoint molecules dysregulated by tumors, and augment specific CD4+ and CD8+ T-cell responses.

Immune checkpoints, crucial for self-tolerance and mitigating tissue damage, can be dysregulated by tumors as an important immune resistance mechanism. Cancer cells can upregulate inhibitory immune checkpoint proteins, including cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and PD-1 to avoid immune surveillance and destruction. Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor on T-cells, inhibits T-cell proliferation and cytokine production.

Nivolumab is a human immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor, blocking its interaction with PD-L1 and PD-L2. Blockade of this inhibitory checkpoint molecule removes the constraints on T-cell activation, amplifies antigen-specific T-cell responses, and encourages powerful antitumor responses. Ipilimumab is a monoclonal antibody that binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80 and CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor-infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function which may contribute to a general increase in T-cell responsiveness, including the antitumor immune response.

Dual blockade of PD-1 and CTLA-4 with nivolumab and ipilimumab results in enhanced T-cell function greater than either antibody alone, and increased antitumor activity. In clinical studies with patients with metastatic melanoma (MEL), non–small-cell lung cancer (NSCLC), and renal-cell carcinoma (RCC), nivolumab in combination with ipilimumab resulted in higher tumor response and longer progression-free survival than either monotherapy.

Retrospective analysis of the safety profile in 3 MEL studies (CA209-004, n = 41, CheckMate-069, n = 94, and CheckMate-067, n = 313; nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks x 4, followed by nivolumab 3 mg/kg every 2 weeks), 1 NSCLC study (CheckMate-012, n = 39; nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks), and 1 RCC study (CheckMate-016; nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks x 4 [nivolumab 3 plus ipilimumab 1, n = 47], or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks x 4 [nivolumab 1 plus ipilimumab 3, n = 47]) revealed that combination therapy resulted in grade 3 and 4 immune-related adverse events (irAEs) in 41.5% of patients with MEL, 5.1% of patients with NSCLC, 6.4% of patients with RCC (nivolumab 3 plus ipilimumab 1), and 23.4% of patients with RCC (nivolumab 1 plus ipilimumab 3). The most commonly reported irAEs were gastrointestinal (16% MEL, 5.1% NSCLC, 4.3% RCC [nivolumab 3 plus ipilimumab 1], and 23.4% RCC [nivolumab 1 plus ipilimumab 3]) and hepatic (17% MEL, 5.1% NSCLC, 6.4% RCC [nivolumab 3 plus ipilimumab 1], and 21.3% RCC [nivolumab 1 plus ipilimumab 3]).

In the MEL studies, 329 (73%) patients discontinued treatment, most commonly because of study drug toxicity (40%) or disease progression (21%). Treatment-related AEs of any grade were reported in 95% of patients, and 55% of patients reported a grade 3 or 4 treatment-related AE in the MEL studies. Thirty-six percent of patients in the MEL studies had any-grade treatment-related AEs leading to discontinuation, including colitis (8%), diarrhea (7%), and increased alanine aminotransferase (5%). Median time to onset and resolution of treatment-related grade 3 and 4 irAEs in the MEL studies ranged from 3.1 weeks to 16.3 weeks and 1.9 weeks to 15.1 weeks, respectively. Excluding endocrinopathies that may require long-term hormone replacement therapy, 81.8% to 100% of MEL patients experienced irAE resolution. The most commonly used immune-mediated management in the MEL studies were systemic corticosteroids (65%) and topical corticosteroids (29%). Infliximab was used to treat 6% of patients with MEL who had gastrointestinal AEs, and mycophenolic acid was used to treat 1% of patients with MEL who had hepatic AEs.

Clinical trials with combination nivolumab and ipilimumab reveal a higher incidence and more rapid onset of irAEs than monotherapy. When administering immunotherapy, it is critical to collect a detailed medical history to establish a baseline, guide vigilant monitoring, and determine the etiology of symptoms. Oncology nurses play a critical role in educating patients and caregivers about irAE monitoring to ensure patient safety. IrAEs associated with combination therapy are manageable if recognized and treated promptly.

Kannan R, et al. ONS Abstract IS-12.

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Last modified: May 5, 2017