Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02)

Abstract

This single-arm, phase I dose-escalation trial (NCT02983045) evaluated bempega ldesleukin (NKTR-214/BEMPEG), a CD122-preferential IL2 pathway agonist, plus nivolumab in 38 patients with selected immunotherapy-naïve 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 fl u-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 infi ltration, 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. Effi cacy was observed regardless of baseline PD-L1 status and baseline levels of tumor-infi ltrating lymphocytes, suggesting therapeutic potential for patients with poor prognostic risk factors for response to PD-1/PD-L1 blockade.

Mobilization of pre-existing polyclonal T cells specific to neoantigens but not self-antigens during treatment of a patient with melanoma with bempegaldesleukin and nivolumab

“…Staging showed multiple lung nodules and mediastinal lymphadenopathy, without a detectable primary skin lesion. The patient was enrolled in a phase I clinical trial combining nivolumab 360 mg and bempegaldesleukin 0.06 mg/kg 16 intravenously every 3 weeks. A CT scan at 4.5 months showed a partial response by RECIST V.1.1 (figure 1A,B) and positron emission tomography showed no Fluorodeoxyglucose (FDG) avid disease after 13 months of therapy.…”

<p>Immunotherapeutic Targets and Therapy for Renal Cell Carcinoma</p>

“…Overall, 21.1% of patients experienced G3/4 toxicities. 91 Promising activity was observed with the HIF-2α inhibitor in treatment-naïve patients with VHL-associated tumor, with a favorable safety profile. 92 Data of a randomized trial evaluating HIF-2α inhibitor vs everolimus are awaited to assess the efficacy of this emerging molecule in the ICIs pretreated setting.…”

Engineering IL-2 to Give New Life to T Cell Immunotherapy

“…To this end, the PIVOT-02 trial of bempegaldesleukin and nivolumab in patients with locally advanced/metastatic solid tumors established the recommended phase II dose as 0.006 mg/kg bempegaldesleukin every 3 weeks plus nivolumab 360 mg every 3 weeks (46). Data have also been reported for patients with melanoma (47), RCC (48), triple-negative breast cancer (49), urothelial cancer (UC) (50), and NSCLC (48).…”