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

R. Martin Conry,Bridgette A. Kanz,Romany Johnpulle,Douglas B. Johnson,Igor Puzanov,Suthee Rapisuwon,Megan H. Pollack,Zeynep Eroglu,Alicia Morgans,Leora Horn,Jeffrey A. Sosman

doi:10.1186/s40425-016-0166-5

Abstract

BackgroundAnti-PD-1 therapy is increasingly used in various advanced malignancies. Patients with baseline organ dysfunction are largely excluded from clinical trials. Therefore it is unclear whether anti-PD-1 therapy is safe or effective in this setting. Further, these patients are often not candidates for other anti-cancer therapies, highlighting their need for active treatment options.MethodsWe performed a retrospective analysis of patients from multiple centers with advanced solid tumors and baseline organ dysfunction who received anti-PD-1 therapy. Organ dysfunction was defined as cardiac (left ventricular ejection fraction ≤45 %), renal (creatinine ≥2 mg/dL or GFR ≤30 ml/min) or hepatic dysfunction (evidence of cirrhosis on imaging or AST, ALT or bilirubin ≥3x ULN). We assessed change in organ dysfunction, immune related adverse events (irAEs), response rate, progression free survival (PFS) and overall survival (OS).ResultsWe identified 27 patients eligible for inclusion with the following diseases: renal cell carcinoma (n = 8), melanoma (10), non-small cell lung cancer (3), small cell lung cancer (2) and urothelial bladder cancer (4). Baseline organ dysfunction included renal dysfunction (n = 17), hepatic dysfunction (7), cardiac dysfunction (11), including >1 organ dysfunction (8). Worsening organ dysfunction requiring hospitalization or dose delays occurred in 8 patients (30 %) although in most cases this was thought not-drug related and resolved with supportive care. Grade 3 irAEs occurred in 2 pts (7 %; hepatitis and colitis). Thirteen of 27 patients had ongoing treatment benefit (objective response or stable disease) at data collection (48 %). Eleven patients had primary progressive disease (41 %), 11 had stable disease (41 %), 4 had partial responses (15 %), and one had a complete response (4 %). Overall, median PFS was 168 days. Median OS was not reached.ConclusionsIn our experience, anti-PD-1 agents in this group of patients with cardiac, hepatic or renal dysfunction were associated with tolerable irAEs and infrequent manageable worsening of organ dysfunction. Further, objective responses and prolonged PFS were observed in a number of patients. Thus, patients with baseline organ dysfunction may be considered for anti-PD-1 therapy with appropriate clinical monitoring.

Highlights

Anti-Programmed death receptor 1 (PD-1) therapy is increasingly used in various advanced malignancies
These agents, including nivolumab and pembrolizumab, have produced objective responses, many of which are durable, in numerous solid and hematologic malignancies [1,2,3,4,5,6,7,8]. 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
Most patients were male with a median age of 69, and a majority received nivolumab as their anti-PD-1 therapy

Summary

Introduction

Patients with baseline organ dysfunction are largely excluded from clinical trials It is unclear whether anti-PD-1 therapy is safe or effective in this setting. 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 antitumor immune responses These agents, including nivolumab and pembrolizumab, have produced objective responses, many of which are durable, in numerous solid and hematologic malignancies [1,2,3,4,5,6,7,8]. Monoclonal antibodies bound to protective receptors are protected from degradation, explaining their exceptionally long half-lives [10]

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Discussion

Conclusion