Safety and efficacy of anti-PD-1 in patients with baseline cardiac, renal, or hepatic dysfunction

Agents that block the interaction between programmed death-1 receptor and its ligand (PD-1/PD-L1) inhibit this negative immune regulator and thereby unleash anti-tumor immune responses. These agents, including nivolumab and pembrolizumab, have produced objective responses, many of which are durable, in numerous solid and hematologic malignancies [1–8]. As these agents are incorporated into standard treatment algorithms, questions have arisen regarding their use in patient populations excluded from clinical trials, including those with organ dysfunction.

Advanced malignancies have traditionally been treated with cytotoxic chemotherapy. Unfortunately, many patients have limited baseline organ function and/or performance status and are unable to receive optimal chemotherapy regimens. As such, they may have extremely limited therapeutic options. Due to their pharmacokinetic and pharmacodynamic properties, cytotoxic chemotherapies frequently result in bone marrow suppression, kidney and liver dysfunction, and cardiac toxicity. In patients that are further limited by baseline organ dysfunction, chemotherapy may exacerbate existing organ injury or result in decreased clearance or metabolism, increasing toxicities. By contrast, monoclonal antibodies are metabolized to peptides and amino acids by circulating phagocytic cells or by their target antigen-containing cells, rather than through the liver and kidneys [9]. Monoclonal antibodies bound to protective receptors are protected from degradation, explaining their exceptionally long half-lives [10].

These pharmacologic and immune properties result in a distinct toxicity profile specific to immunotherapies. These idiosyncratic adverse events, termed immune related adverse events (irAEs), include colitis, pneumonitis, hepatitis, nephritis, and endocrinopathies [11]. Although usually manageable with corticosteroids, irAEs represent a significant cause of morbidity and rarely mortality.

The effects of anti-PD-1 in patients with baseline organ dysfunction have not been explored. We hypothesized that, based on their pharmacokinetics and mechanism of action, anti-PD-1 therapies would not induce worsening organ dysfunction or high rates of irAEs in this population. To address, we performed a retrospective analysis of patients from four centers with pre-existing organ dysfunction treated with anti-PD-1 agents. We assessed safety endpoints, including irAEs and worsening organ dysfunction, and efficacy endpoints.