Background High-dose IL2 therapy has shown clinical benefit in metastatic melanoma and renal cell carcinoma, however only in a select subset of patients. Bempegaldesleukin (BEMPEG), a novel CD122-preferential IL2 pathway agonist, preferentially binds the heterodimeric IL2βγR predominantly expressed on NK and CD8 T cells and minimizes binding to the IL2αR expressed on immunosuppressive Tregs. BEMPEG monotherapy in Phase I clinical trials induced proliferation and activation of NK cells in the blood and tumor microenvironment.¹ NK activation is dependent on the balance of inhibitory and excitatory signals transmitted by NK receptors, including Fc-gamma receptors (FCγRs) and killer immunoglobulin-like receptors (KIRs) along with their KIR-ligands. The repertoire of KIRs/KIR-ligands an individual inherits and the single-nucleotide polymorphisms (SNPs) of FCγRs can influence NK cell function and affect responses to immunotherapies.^2–4 Thus, we sought to investigate whether distinct immunogenotypes are associated with clinical response of patients enrolled in PIVOT-02, a Phase II study of BEMPEG plus nivolumab.

Methods 200 patients with advanced solid tumors enrolled in PIVOT-02 who were not previously treated with immunotherapy (immunotherapy-naïve, ‘IO’) had DNA available for genotyping and clinical data for correlative analyses. All patients received 0.006mg/kg BEMPEG plus 360mg nivolumab every 3 weeks.⁵ KIR/KIR-ligand gene status was assessed by real-time SYBR green PCR melt-curve analyses and PCR-SSP. FCγR SNP status was determined using Taqman primers/probes for FCγR2A, and FCγR3A and FCγR2C were determined using RNaseH primers/probes.⁶ Clinical outcome parameters included objective response rate (ORR), progression-free survival (PFS), and tumor shrinkage (TS, defined as best objective response <0% by RECIST). Preliminary statistical analyses were done using a chi-square test, log-rank test, and Wilcoxon rank-sum test, respectively.

Results KIR2DL2+/C1+ IO patients observed significantly greater TS (p=0.015) and a trend towards improved ORR (p=0.060) and increased PFS (p=0.058) compared to IO patients who were not KIR2DL2+/C1+. IO patients who were KIR2DL2+/C1+/KIR3DL1+/Bw4+ showed significantly improved ORR (p=0.014) and greater TS (p=0.044) compared to IO patients who were not KIR2DL2+/C1+/KIR3DL1+/Bw4+, with no significance found for PFS in these patients. FCγR polymorphisms did not influence ORR/PFS/TS.

Conclusions NK cells may play an important role in the anti-tumor efficacy of BEMPEG plus nivolumab, and NK activation is influenced by certain immunogenotypes. Similar to previous findings,^2–4 the status of KIR2DL2+/C1+ and KIR2DL2+/C1+/KIR3DL1+/Bw4+ was associated with the response to BEMPEG plus nivolumab treatment in the PIVOT-02 trial. The potential to utilize these genotypes in clinical decision-making for immunotherapy treatment requires further investigation.

ClinicalTrials gov NCT02983045

References

1. Bentebibel S-E, et al. A first-in-human study and biomarker analysis of NKTR-214, a Novel IL2βγ-Biased cytokine, in patients with advanced or metastatic solid tumors. Cancer Discov 2019;9:711–21.

2. Erbe AK, et al. Follicular lymphoma patients with KIR2DL2 and KIR3DL1 and their ligands (HLA-C1 and HLA-Bw4) show improved outcome when receiving rituximab. J Immunother Cancer 2019;7(1):70.

3. Erbe AK, et al. Neuroblastoma patients’ KIR and KIR-Ligand genotypes influence clinical outcome for dinutuximab-based immunotherapy: A report from the Children’s Oncology Group. Clin Cancer Res 2018;24(1):189–96.

4. Erbe AK, et al. FCGR polymorphisms influence response to IL2 in metastatic renal cell carcinoma. Clin Cancer Res 2017;23(9):2159–68.

5. Diab A, et al. Bempegaldesleukin (NKTR-214) plus nivolumab in patients with advanced solid tumors: Phase I dose-escalation study of safety, efficacy, and immune activation (PIVOT-02). Cancer Discov 2020;10:1–16.

6. Erbe AK, et al. Genotyping single nucleotide polymorphisms and copy number variability of the FCGRs expressed on NK cells. Methods Mol Biol 2016;1441:43–56.

Ethics Approval The study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. The Protocol (online only) was approved by independent ethics committees and the relevant institutional review board at each site. All patients provided written informed consent.