Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates

J Clin Oncol. 2010 Jul 1;28(19):3167-75. doi: 10.1200/JCO.2009.26.7609. Epub 2010 Jun 1.

Abstract

Purpose: Programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, may suppress antitumor immunity. This phase I study sought to determine the safety and tolerability of anti-PD-1 blockade in patients with treatment-refractory solid tumors and to preliminarily assess antitumor activity, pharmacodynamics, and immunologic correlates.

Patients and methods: Thirty-nine patients with advanced metastatic melanoma, colorectal cancer (CRC), castrate-resistant prostate cancer, non-small-cell lung cancer (NSCLC), or renal cell carcinoma (RCC) received a single intravenous infusion of anti-PD-1 (MDX-1106) in dose-escalating six-patient cohorts at 0.3, 1, 3, or 10 mg/kg, followed by a 15-patient expansion cohort at 10 mg/kg. Patients with evidence of clinical benefit at 3 months were eligible for repeated therapy.

Results: Anti-PD-1 was well tolerated: one serious adverse event, inflammatory colitis, was observed in a patient with melanoma who received five doses at 1 mg/kg. One durable complete response (CRC) and two partial responses (PRs; melanoma, RCC) were seen. Two additional patients (melanoma, NSCLC) had significant lesional tumor regressions not meeting PR criteria. The serum half-life of anti-PD-1 was 12 to 20 days. However, pharmacodynamics indicated a sustained mean occupancy of > 70% of PD-1 molecules on circulating T cells > or = 2 months following infusion, regardless of dose. In nine patients examined, tumor cell surface B7-H1 expression appeared to correlate with the likelihood of response to treatment.

Conclusion: Blocking the PD-1 immune checkpoint with intermittent antibody dosing is well tolerated and associated with evidence of antitumor activity. Exploration of alternative dosing regimens and combinatorial therapies with vaccines, targeted therapies, and/or other checkpoint inhibitors is warranted.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal / pharmacokinetics
  • Antibodies, Monoclonal / therapeutic use*
  • Antigens, CD / immunology*
  • Apoptosis Regulatory Proteins / immunology*
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Renal Cell / drug therapy
  • Carcinoma, Renal Cell / pathology
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / pathology
  • Dose-Response Relationship, Drug
  • Fatigue / chemically induced
  • Female
  • Humans
  • Kidney Neoplasms / drug therapy
  • Kidney Neoplasms / pathology
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / pathology
  • Lymphopenia / chemically induced
  • Male
  • Melanoma / drug therapy
  • Melanoma / pathology
  • Middle Aged
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Nivolumab
  • Programmed Cell Death 1 Receptor
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / pathology
  • Treatment Outcome

Substances

  • Antibodies, Monoclonal
  • Antigens, CD
  • Apoptosis Regulatory Proteins
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Nivolumab