Preoperative PD1 checkpoint blockade and receptor activator of NFkB ligand (RANKL) inhibition in non-small cell lung cancer (NSCLC) (POPCORN).

Abstract

TPS129 Background: Preclinical studies indicate Receptor Activator of NF-κB Ligand (RANKL) blockade improves anti-tumor efficacy of immune checkpoint blockade (ICB). Clinical trials combining denosumab (anti-RANKL mAb) with ICB are underway in various cancers although the hypothesized mechanism of action of such combinations remains incomplete. RANKL and its receptor, RANK, are frequently expressed in NSCLC (tumor and immune cells). Denosumab demonstrated survival advantage over bisphosphonate in metastatic NSCLC (mNSCLC) to bone; a recent retrospective case series suggests a relationship between concurrent ICB and denosumab duration and survival in mNSCLC. Neoadjuvant nivolumab recently showed encouraging pathologic response rates in resectable NSCLC; neoadjuvant trials lend themselves to translational research. Methods: POPCORN is a multicenter phase 1b/2 study to determine the mechanism of action, activity and safety of neoadjuvant nivolumab plus denosumab versus nivolumab alone. 30 patients with resectable stage 1A (tumor > 2cm) – 3A NSCLC will be randomized 1:1 to two arms (Table). Exclusion criteria include uncontrolled autoimmune disease, steroid contraindications, and unhealed dental disease. Tumor tissue at baseline, surgery and relapse, and peripheral blood at various timepoints (including on-therapy) will be collected. The primary endpoint is to define pharmacodynamic correlates of the two arms through investigations including T-cell receptor clonality, RNA/transcription profile changes (tumor and peripheral blood), and expression of tumor/immune markers of interest via multiplex immunohistochemistry, compared between groups. Secondary endpoints include pathologic response rates, toxicity, R0 resection, and PFS/OS (exploratory). Statistical analysis will be primarily descriptive on the intention-to-treat population. The trial is sponsored by Metro North Hospital and Health Service (Queensland, Australia) with funding from AMGEN, Inc. Clinical trial information: ACTRN12618001121257. [Table: see text]

Development of an Immune-Related Risk Signature for Predicting Prognosis in Lung Squamous Cell Carcinoma

“…Some immunotherapies have been utilized to leverage the immune system to fight tumors (Kobold et al, 2018;Popovic et al, 2018). Immune checkpoint inhibitors (ICIs), such as anti-PD-1/PD-L1, have emerged as an effective therapeutic selection for advanced breast cancer, metastatic melanoma and NSCLC (Wang et al, 2018;Ahern et al, 2019;Liu D. et al, 2019). NSCLC is characterized by several mutations in the immune system, making it possible that these patients may benefit from immunotherapy.…”

Denosumab as an immune modulator in HER2-negative early breast cancer: results of the window-of-opportunity D-BIOMARK clinical trial.

“…The safety of the combination in clinical practice was reported in the CHARLI trial, a phase I/II study of the effect of denosumab with nivolumab (an anti-PD-1), with or without ipilimumab (anti-CTLA4), in patients with metastatic melanoma, which showed that the combination is safe and with at least interesting response rates (42). Pembrolizumab and denosumab have also been tested in clear cell renal cell carcinoma, a phase II trial (KeyPAD trial) with response rates close to 31% (43), and there are other ongoing trials with ICI in different tumors such as in lung cancer (Popcorn Trial) (44). Testing the combination in BC will be of interest, although we recognize that more data are required.…”

Biologically interpretable deep learning to predict response to immunotherapy in advanced melanoma using mutations and copy number variations

“…Among the remaining genes, Chen et al [40] found that CCNB2 could serve as a marker to predict response to anti-PD-1 therapy in NSCLC patients, suggesting that CCNB2 might also be a predictor of response to anti-PD-1 treatment in melanoma. For another important gene TNFRSF11A, also named RANK, a clinical trial combining its monoclonal antibody and Immune checkpoint inhibitors for the treatment of melanoma were already underway [41]. The other genes such as IFNA13, ACTG1 and PPP2R1B all involved in immune-regulatory activities, playing distinctive roles in melanoma cells' focal adhesion and motility [42][43][44][45].…”