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.