Immune checkpoint–blocking drugs such as ipilimumab, pembrolizumab, and nivolumab have demonstrated clinical efficacy as anticancer agents. Through modulation of immunoregulatory molecules, these novel therapeutics can produce durable cancer remissions in a variety of tumor types. As these medications are administered to an increasing number of patients, clinicians must be able to recognize and treat the associated immune-related side effects. This review summarizes the unique mechanisms of toxicity associated with immune checkpoint–blocking drugs, appropriate steps in patient evaluation, and strategies for mitigating risk and optimizing patient outcomes. Although the management of each patient receiving immune checkpoint–blockade therapy must be individualized, a conceptual framework upon which to base a multidisciplinary approach to best practices will help oncology practitioners deliver safe and effective care.
Recent advances in the clinical application of agents that block immunoregulatory molecules have led to unprecedented optimism about the potential of these novel therapies for bringing about durable antitumor responses in patients with various advanced malignancies. However, enhancing immune responses to cancer via modulation of these immune checkpoints is associated with drug-related toxicities that are distinct from those associated with traditional chemotherapeutic agents and molecularly targeted therapies. Because the use of checkpoint blockade agents will likely be widely expanded in the near term, it is critical that healthcare practitioners caring for oncology patients have a basic familiarity with these immune-related adverse events (irAEs), their variable presentations, and recommendations regarding their evaluation and management.
To understand the mechanism of checkpoint blocker–related autoimmune toxicities, it is helpful to consider their mechanism of action. At a basic level, the role of the human immune system, and of T lymphocytes in particular, is to activate against non-self–antigens (eg, viral proteins or cancer neoantigens resulting from tumoral genetic and epigenetic alterations) and to tolerate self-antigens. Antigen recognition by a T-cell receptor is followed by interactions between a tightly regulated cadre of immunoregulatory molecules that either activate or inhibit T-cell activation. Some of the best studied of these checkpoints are cytotoxic T-lymphocyte antigen 4 (CTLA-4) and the pathway composed of programmed death 1 (PD-1) and one of its major ligands, programmed death ligand 1 (PD-L1).
When they are engaged with their respective binding partners, CTLA-4 and PD-1 promote immune tolerance via downregulation of T-cell activation.[4,5] The application of antibody antagonists of these immune checkpoints promotes T-cell activation, which can lead to tumor destruction as well as clinically relevant decreases in self-tolerance. This immune dysregulation is among the mechanisms underlying the autoimmune toxicities related to immune checkpoint blockers.
Incidence of Immune Checkpoint–Blockade Toxicities
The adverse event (AE) profiles of checkpoint-blocking drugs (ie, incidence of toxicities and organ systems most frequently affected) vary depending on agent and target. In clinical studies, toxicity severity is described using the Common Terminology Criteria for Adverse Events (CTCAE), which grades toxicities on a scale of 1 (mildest) to 5 (death related to that toxicity).
The CTLA-4 antibody ipilimumab is the most widely studied checkpoint-blocking agent. In 2011, after extensive clinical testing, it was approved by the US Food and Drug Administration (FDA) for use in patients with advanced melanoma. One seminal study that led to its approval was a phase III trial involving patients with advanced melanoma. Ipilimumab was administered at 3 mg/kg with or without a peptide vaccine to 511 patients. Grade 3 or 4 immune-related toxicities were observed in approximately 15% of patients, and 7 patient deaths were associated with irAEs. A retrospective review of safety data from 1,498 patients treated with ipilimumab on any of 14 phase I–III clinical trials found that drug-related AEs of any grade occurred in 85% of patients. About 25% of patients experienced a grade 3 or 4 drug-related toxicity, and drug-related death was observed in < 1% of patients.
Clinical trials using ipilimumab in tumor types other than melanoma have demonstrated similar AE rates. For example, in a phase III study of ipilimumab administered after patients were treated with radiotherapy for metastatic prostate cancer, 63% of patients had immune-related toxicity of any grade. Similarly, in a phase II study of ipilimumab plus chemotherapy for metastatic non–small-cell lung cancer, the rate of grade 3/4 irAEs was 15% to 20%, depending on the sequence of drug administration.
In a phase II trial of 245 patients with advanced melanoma, study participants were randomly assigned to ipilimumab plus granulocyte macrophage colony-stimulating factor (GM-CSF) or ipilimumab alone. Of note, ipilimumab was administered at 10 mg/kg, which is higher than the FDA-approved dose of 3 mg/kg. Patients who received combination therapy experienced a significantly lower rate of high-grade AEs (45% vs 58%; two-tailed P = .038). The lower rate of high-grade AEs was accompanied by significantly improved overall survival (OS) in the GM-CSF arm (median, 17.5 vs 12.7 months; hazard ratio, 0.64; P = .014), although further study is required to determine whether the increased OS is linked to improvements in AE rates.
Another CTLA-4 antibody, tremelimumab (CP-675,206; formerly ticilimumab) has been similarly studied in patients with metastatic melanoma and other advanced cancers. In a phase II clinical trial testing tremelimumab in patients with advanced melanoma, 19% of participants had a ≥ grade 3 adverse event. When tested in patients with metastatic colorectal adenocarcinoma, a similar rate of high-grade toxicities was seen, with diarrhea/colitis representing the majority of cases.
PD-1 and PD-L1 antibodies
Although clinical data are still emerging, anti–PD-1 and anti–PD-L1 agents appear to have toxicity profiles that are different from those of CTLA-4 antibodies (Table 1).
Pembrolizumab is a humanized monoclonal antibody (mAb) blocking PD-1 that was approved by the FDA in September 2014 for use in treatment-refractory unresectable or metastatic melanoma. In a phase I clinical trial involving 135 patients with advanced melanoma, grade 3/4 AEs were reported in 13% of subjects. An expansion cohort comprising patients whose disease was refractory to ipilimumab (and, if BRAF-mutant, refractory to BRAF inhibition) was reported separately. In 173 patients, at a median follow-up of 8 months, toxicity rates were similar to those in previous reports.
Nivolumab is a genetically engineered, fully human immunoglobulin (Ig) G-4 mAb specific for human PD-1. In a phase I dose-escalation study conducted in 296 patients with multiple tumor types, grade 3/4 treatment-related toxicities occurred in 41 patients (14%). Treatment-related pneumonitis was observed in 9 patients (3%), 3 cases of which were fatal. Longer-term follow-up of the entire study cohort (306 patients) demonstrated that exposure-adjusted toxicity rates were not cumulative.
BMS-936559 (MDX-1105), a PD-L1–blocking antibody, was tested in a 207-patient phase I trial. A 9% rate of grade 3/4 drug-related irAEs was reported. Similar findings were reported in 140 patients who received MPDL3280A, a human monoclonal IgG1 antibody engineered to block PD-L1 binding. Drug-related grade 3/4 AEs were observed in 14% of patients.
Preclinical evidence suggests that blockade of multiple immune checkpoints can achieve synergistic antitumor activity. Several clinical trials of combinatorial regimens are underway. In a trial of ipilimumab plus nivolumab in patients with metastatic melanoma, a 53% rate of treatment-related AEs of grade 3 or 4 was reported when the drugs were administered concurrently. When ipilimumab was followed sequentially by nivolumab, the rate dropped to 18%, which is closer to observed rates for the single agents.
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