Assessment of the Safety of Pembrolizumab in Patients With HIV and Advanced Cancer-A Phase 1 Study

Abstract

Importance: Anti-PD-1 (anti-programmed cell death 1) and anti-PD-L1 (anti-programmed cell death ligand 1) regimens are preferred therapies for many cancers, including cancers associated with HIV. However, patients with HIV were excluded from most registered trials.

Objective: The primary objective was to evaluate the safety of pembrolizumab in people with HIV and advanced cancer; the secondary objective was to evaluate tumor responses.

Design, setting, and participants: Open-label, nonrandomized, phase 1 multicenter study conducted at 7 Cancer Immunotherapy Trials Network sites. Patients with HIV and advanced cancer as well as a CD4 count greater than or equal to 100 cells/μL, antiretroviral therapy (ART) for 4 or more weeks, and an HIV viral load of less than 200 copies/mL were eligible. Exclusion criteria included uncontrolled hepatitis B or C infection, active immunosuppressive therapy, or a history of autoimmune disease requiring systemic therapy.

Interventions: Pembrolizumab, 200 mg, administered intravenously every 3 weeks for up to 35 doses in 3 CD4 count-defined cohorts. Participants continued ART.

Main outcomes and measures: Safety and tolerability were assessed using current NCI Common Terminology Criteria for Adverse Events. Immune-related adverse events grade 2 or higher were considered immune-related events of clinical interest (irECI). Tumor responses were evaluated using standard tumor-specific criteria.

Results: Thirty participants (28 men and 2 women; median [range] age, 57 [39-77] years) were enrolled from April 2016 through March 2018; 6 had Kaposi sarcoma (KS), 5 had non-Hodgkin lymphoma (NHL), and 19 had non-AIDS-defining cancers. Safety was observed over 183 cycles of treatment with pembrolizumab. Most treatment-emergent adverse events at least possibly attributed to pembrolizumab were grade 1 or 2 (n = 22), and 20% (n = 6) were grade 3. The irECI included hypothyroidism (6 participants), pneumonitis (3 participants), rash (2 participants), an elevated aminotransferase/alanine aminotransferase level (1 participant), and a musculoskeletal event (1 participant). One participant with pretreatment KS herpesvirus (KSHV) viremia developed a polyclonal KSHV-associated B-cell lymphoproliferation and died. HIV was controlled in all participants. Increases in CD4 count were not statistically significant (median increase, 19 cells/μL; P = .18). Best tumor responses included complete response (lung, 1 patient), partial response (NHL, 2 patients), stable disease for 24 weeks or more (KS, 2 patients), stable disease for less than 24 weeks (15 patients), and progressive disease (8 patients); 2 patients were not evaluable.

Conclusions and relevance: Pembrolizumab has acceptable safety in patients with cancer, HIV treated with ART, and a CD4+ T-cell count of greater than 100 cells/μL but may be associated with KSHV-associated B-cell lymphoproliferation. Clinical benefit was noted in lung cancer, NHL, and KS. Anti-PD-1 therapy is appropriate for US Food and Drug Administration-approved indications and clinical trials in this population.

Trial registration: ClinicalTrials.gov identifier: NCT02595866.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Uldrick reported other from Merck & Co during the conduct of the study; other from Celgene and Roche outside the submitted work; in addition, Dr Uldrick had a patent to the National Cancer Institute (NCI) and Celgene issued. Ms Claeys reported grants from the National Institutes of Health (NIH), NCI, and Merck Sharp & Dohme Corp during the conduct of the study. Dr Ernstoff reported grants from NCI during the conduct of the study. Dr Fling reported grants from NCI and Merck during the conduct of the study. Dr Fong reported grants from NIH during the conduct of the study; grants from Merck, Bristol-Myers Squibb, Roche/Genentech, AbbVie, and Janssen outside the submitted work. Ms Kaiser reported grants from NIH and Merck during the conduct of the study. Ms Lundgren reported grants from NIH and Merck & Co during the conduct of the study. Dr Lurain reported other from Merck during the conduct of the study; other from Celgene outside the submitted work. Dr Ramaswami reported nonfinancial support from Merck during the conduct of the study; other from Celgene Corp outside the submitted work. Dr Sznol reported personal fees from Genentech-Roche, Bristol-Myers Squibb, Astra-Zeneca/MedImmune, Pfizer, Novartis, Kyowa-Kirin, Seattle Genetics, Nektar, Pierre-Fabre, Lilly, Merck US, Theravance, Biodesix, Vaccinex, Janssen/Johnson & Johnson, Modulate Therapeutics, Baxalta-Shire, Incyte, NewLink Genetics, Lion Biotechnologies (Iovance Biotherapeutics), AgonOx, Arbutus, Celldex Therapeutics, Inovio Pharmaceuticals, Gritstone, Molecular Partners, Innate Pharma, AbbVie, Immunocore, Genmab, Almac, Hinge, Allakos, Anaeropharma, Array, Symphogen, Adaptimmune, Omniox, Pieris; other from Lycera, nonfinancial support from Amphivena, Adaptive Biotechnologies, Intensity, Actym Therapeutics; and personal fees from Torque, GI Innovation, Genocea, and Chugai-Roche outside the submitted work. Dr Wang reported grants from Bristol-Myers Squibb outside the submitted work. Dr Yarchoan reported nonfinancial support from Merck & Co during the conduct of the study; nonfinancial support and other from Celgene Corp, and nonfinancial support and other from Genentech Corp outside the submitted work; in addition, Dr Yarchoan had a patent to pomalidomide for Kaposi sarcoma-associated herpesvirus (KSHV) lymphomas issued and a patent to treatment of Kaposi sarcoma with IL-12 issued; and an immediate family member has various patents, including one to measure KSHV vIL-6. All rights, title, and interest to these patents have been or should by law be assigned to the US Department of Health and Human Services. The government conveys a portion of the royalties it receives to its employee inventors under the Federal Technology Transfer Act of 1986 (P.L. 99-502). Dr Cheever reported grants from NIH NCI during the conduct of the study; other from Merck, other from Horizon, other from Dendreon, and other from Celldex outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. CD4 and HIV Monitoring

Figure 1 shows CD4+ T-cell counts (median and range) over time on pembrolizumab (A) and the HIV RNA levels in 7 participants (B). Lines represent the 7 (23%) participants with HIV viremia detected at least once during the study. Blips were defined as a detectable HIV viral load of less than 400 copies/mL. The lower limit of detection is 20 copies/mL.

Figure 2.. Characteristics of Tumor Responses to Pembrolizumab

A, Maximum percent change of the sum of the measurements of target lesions from baseline based on tumor specific measurement criteria. B, Kinetics of change in tumor size over time. aParticipants whose best response was refined Lugano classification immune response 3. For Kaposi sarcoma, the numbers of nodular lesions were used.