In a phase I study combining nivolumab with an engineered IL-2 targeting the medium-affinity IL-2 receptor IL2βγR, Diab, Tanner, and Bentebibel et al. report on safety and clinical activity across 3 tumor types in immunotherapy-naive patients. The maximum tolerated dose and recommended Phase II dose were identified. The overall response rate was nearly 60%, including 7 complete responses among 37 evaluated patients. Responses deepened over time and were independent of initial PD-L1 status. Significant increases in peripheral blood mobilization and activation of lymphocytes and intratumoral CD8+ T cells, but not intratumoral Tregs, were observed.
Contributed by Ed Fritsch
ABSTRACT: This single-arm, phase I dose-escalation trial (NCT02983045) evaluated bempeg-a-ldesleukin (NKTR-214/BEMPEG), a CD122-preferential IL2 pathway agonist, plus nivolumab in 38 patients with selected immunotherapy-naive advanced solid tumors (melanoma, renal cell carcinoma, and non-small cell lung cancer). Three dose-limiting toxicities were reported in 2 of 17 patients during dose escalation [hypotension (n = 1), hyperglycemia (n = 1), metabolic acidosis (n = 1)]. The most common treatment-related adverse events (TRAE) were flu-like symptoms (86.8%), rash (78.9%), fatigue (73.7%), and pruritus (52.6%). Eight patients (21.1%) experienced grade 3/4 TRAEs; there were no treatment-related deaths. Total objective response rate across tumor types and dose cohorts was 59.5% (22/37), with 7 complete responses (18.9%). Cellular and gene expression analysis of longitudinal tumor biopsies revealed increased infiltration, activation, and cytotoxicity of CD8(+) T cells, without regulatory T-cell enhancement. At the recommended phase II dose, BEMPEG 0.006 mg/kg plus nivolumab 360 mg every 3 weeks, the combination was well tolerated and demonstrated encouraging clinical activity irrespective of baseline PD-L1 status. SIGNIFICANCE: These data show that BEMPEG can be successfully combined with a checkpoint inhibitor as dual immunotherapy for a range of advanced solid tumors. Efficacy was observed regardless of baseline PD-L1 status and baseline levels of tumor-infiltrating lymphocytes, suggesting therapeutic potential for patients with poor prognostic risk factors for response to PD-1/PD-L1 blockade.
Author Info: (1) The University of Texas MD Anderson Cancer Center, Houston, Texas. adiab@mdanderson.org. (2) The University of Texas MD Anderson Cancer Center, Houston, Texas. (3) The Universi
Author Info: (1) The University of Texas MD Anderson Cancer Center, Houston, Texas. adiab@mdanderson.org. (2) The University of Texas MD Anderson Cancer Center, Houston, Texas. (3) The University of Texas MD Anderson Cancer Center, Houston, Texas. (4) The University of Texas MD Anderson Cancer Center, Houston, Texas. (5) The University of Texas MD Anderson Cancer Center, Houston, Texas. (6) The University of Texas MD Anderson Cancer Center, Houston, Texas. (7) Yale School of Medicine, New Haven, Connecticut. (8) Yale School of Medicine, New Haven, Connecticut. (9) Yale School of Medicine, New Haven, Connecticut. (10) University of Washington and Fred Hutchinson Cancer Research Center, Seattle, Washington. (11) Providence Cancer Center and Earle A. Chiles Research Institute, Portland, Oregon. (12) Nektar Therapeutics, San Francisco, California. (13) Nektar Therapeutics, San Francisco, California. (14) Nektar Therapeutics, San Francisco, California. (15) Nektar Therapeutics, San Francisco, California. (16) Nektar Therapeutics, San Francisco, California. (17) Nektar Therapeutics, San Francisco, California. (18) Nektar Therapeutics, San Francisco, California. (19) Nektar Therapeutics, San Francisco, California. (20) Nektar Therapeutics, San Francisco, California. (21) The University of Texas MD Anderson Cancer Center, Houston, Texas. (22) Yale School of Medicine, New Haven, Connecticut. (23) Perlmutter Cancer Center at NYU Langone Medical Center, New York, New York.
