Pilot study of bempegaldesleukin in combination with nivolumab in patients with metastatic sarcoma

Abstract

PD-1 blockade (nivolumab) efficacy remains modest for metastatic sarcoma. In this paper, we present an open-label, non-randomized, non-comparative pilot study of bempegaldesleukin, a CD122-preferential interleukin-2 pathway agonist, with nivolumab in refractory sarcoma at Memorial Sloan Kettering/MD Anderson Cancer Centers (NCT03282344). We report on the primary outcome of objective response rate (ORR) and secondary endpoints of toxicity, clinical benefit, progression-free survival, overall survival, and durations of response/treatment. In 84 patients in 9 histotype cohorts, all patients experienced ≥1 adverse event and treatment-related adverse event; 1 death was possibly treatment-related. ORR was highest in angiosarcoma (3/8) and undifferentiated pleomorphic sarcoma (2/10), meeting predefined endpoints. Results of our exploratory investigation of predictive biomarkers show: CD8 + T cell infiltrates and PD-1 expression correlate with improved ORR; upregulation of immune-related pathways correlate with improved efficacy; Hedgehog pathway expression correlate with resistance. Exploration of this combination in selected sarcomas, and of Hedgehog signaling as a predictive biomarker, warrants further study in larger cohorts.

Conflict of interest statement

S.P.D. reports consulting or advisory roles at EMD Serono, Amgen, Nektar, Immune Design, GlaxoSmithKline, Incyte, Merck, Adaptimmune, and Immunocore. She reports research funding from EMD Serono, Amgen, Merck, Incyte, Nektar, Bristol-Meyers Squibb, and Deciphera, as well as travel expenses from Adaptimmune, EMD Serono, and Nektar. She also reports participation on a Data Safety Monitoring Board or Advisory Board for GlaxoSmithKline, Nektar, Adaptimmune, and Merck. A.P.C. reports research funding from Chordoma Foundation/Cancer Research Institute, Chordoma Foundation, Lilly Pharmaceuticals, Roche Pharmaceuticals/Ignyta, NantPharma, and Bavarian Nordic, as well as consulting fees from Deciphera, Inhbrx, Bayer Pharmaceuticals, and NovellusDX. He has received honoraria from Medscape and Onclive. M.G. reports consulting fees from pharmaceutical companies: Ayala, Bayer, Boehringer Ingelheim, Daiichi, Epizyme, Karyopharm, Springworks, Tracon and TYME; consultation fees from: Flatiron Health, Guidepoint, GLG, Medscape, More Health, Physicians Education Resource and touchIME; royalty fees from UpToDate; patents with MSKCC (GODDESS PRO); uncompensated research with Foundation Medicine, Rain and Athenex. Grants from Food and Drug Administration (R01 FD005105) and the National Cancer Institute, National Institutes of Health (P30CA008748)—core grant (CCSG shared resources and core facility). C.K. reports consulting fees from Exicure and that her spouse is employed at Daiichi Sankyo. S.M. reports research funding from Ascentage Pharmaand Hutchinson MediPharma Limited. K.T. is on the advisory board at GSK. B.N. reports uncompensated provision of services to Delphi Diagnostics, QuadW Foundation, and Rapafusyn Pharmaceuticals. J.E.C. reports research support from Cytek. T.A. reports stock options for BAYRY, CPRX, GSK, TAK, PFE and JNJ. S.P. reports research funding from Blueprint Medicines and Hutchison MediPharma, as well as consultant fees/honoraria from Deciphera, Daichi Sankyo, Dova Pharmaceuticals, and Epizyme. J.A.L. reports research funding from REPARE Therapeutics, Roche/Genentech, Exelixis, Osteosarcoma Institute and CPRIT, as well as consulting fees from ITM and honoraria from Onclive. He is a NCCN Adolescent and Young Adult Oncology Guidelines Committee Member. W.D.T. reports personal fees from Eli Lilly, personal fees from EMD Serono, personal fees from Mundipharma, personal fees from C4 Therapeutics, personal fees from Daiichi Sankyo, personal fees from Blueprint, personal fees from GlaxoSmithKline, personal fees from Agios Pharmaceuticals, personal fees from NanoCarrier, personal fees from Deciphera, personal fees from Adcendo, personal fees from Ayala Pharmaceuticals, personal fees from Kowa, personal fees from Servier, personal fees from AbMaxBio, outside the submitted work; In addition, Dr. Tap has a patent Companion Diagnostic for CDK4 inhibitors - 14/854,329 pending to MSKCC/SKI, and a patent Enigma and CDH18 as companion Diagnostics for CDK4 inhibition – SKI2016-021-03 pending to MSKCC/SKI and Scientific Advisory Board - Certis Oncology Solutions, Stock Ownership. He is Co-Founder at Atropos Therapeutics with Stock Ownership and on the Scientific Advisory Board at Innova Therapeutics. All other authors declare no potential conflicts.

© 2022. The Author(s).

Figures

Fig. 1. Response to the combination of nivolumab and bempegaldesleukin in patients with metastatic sarcoma.

A CONSORT diagram. B Waterfall plot of overall best response (% change in sum of length measurements) of target lesions/nodes (RECIST v1.1; n = 77 patients evaluable for efficacy). Horizontal line represent cutoff for partial response (PR). Dot indicates achievement of response according to radiographic assessments despite classification as PD in non-target lesions (per RECIST v1.1). Two patients with progressive disease had target lesions that were not evaluable by RECIST. C Progression-free survival (PFS) for each patient (n = 77 patients). PFS is listed for patients without progression longer than 1 year and for patients who did not yet reach progression (indicated by + ). Dashed line indicates 24 weeks. ASPS alveolar soft part sarcoma, UPS undifferentiated pleomorphic sarcoma, MFS myxofibrosarcoma. Source data are provided as a Source Data file.

Fig. 2. Immune cell content in on-treatment samples differentiates response.

A–C Percent (A) PD-1-positive cells (Baseline n = 5 patients [PR], 12 [SD], 31 [PD]; On-Treatment n = 3 [PR], 7 [SD], 23 [PD]), (B) CD8-positive T cells (Baseline n = 4 patients [PR], 11 [SD], 32 [PD]; On-Treatment n = 3 [PR], 7 [SD], 22 [PD]), (C) change in PD-1-positive cells (n = 2 patients [PR], 6 [SD], 20 [PD]), as determined by IHC and categorized by best response and sample time point. A–C Colors indicate trial cohort. ASPS alveolar soft part sarcoma, UPS undifferentiated pleomorphic sarcoma, MFS myxofibrosarcoma. P values are nominal and derived from linear model of positive cells with ORR including sarcoma subtype as a covariate. Boxplot shows the median with hinges at 25th and 75th percentile with whiskers extending to smallest or largest value, no more than 1.5 times interquartile range from the hinges. All values are shown with points. D, F Immune markers in baseline (n = 41 patients) and on-treatment samples (n = 38 patients), respectively, clustered using Manhattan distance and Ward D clustering on the immune populations from RNA-seq (bottom heatmap), with color coding for best response (top row), quartile of percent positive cells for 5 immune markers as detected using IHC, and immune clusters according to the dendrogram. E, G Kaplan–Meier plot of progression-free survival of 3 and 2 immune clusters defined in D and F, respectively. Logrank p values shown for significant comparisons (Baseline n = 8 patients [A], 6 patients [B], n = 27 [C], On-Treatment n = 9 patients [A], On-Treatment n = 29 [C]). Source data are provided as a Source Data file.

Fig. 3. Differentially expressed pathways in partial responders.

A Volcano plot of differential expression between partial responders (n = 7 patients) and non-responders (n = 41 patients). Model included trial cohort, patient, purity, and sample time point as covariates. Points represent genes. Genes in Hallmark hedgehog pathway are highlighted in red. B Top 10 upregulated and all 5 downregulated Hallmark pathways between partial responders (n = 7 patients) and non-responders (n = 41 patients). Analysis performed using fgsea in R. All pathways are significantly enriched (BH adjusted p < 0.05). C Heatmap of ssGSEA scores of baseline (n = 41 patients) and on-treatment (n = 38 patients) expression in individual patients for top enriched pathways in (B) using the leading-edge genes from the fgsea analysis. D, E. Kaplan–Meier plot of progression-free survival of patients divided into four groups depending on the amount CD8 + T cells and ssGSEA score of hedgehog pathway enrichment across cohort (high versus low, split by median). Scores derived from expression at baseline in (D) and on-treatment samples in (E). Note, cross-validation analysis does not output p values. Source data are provided as a Source Data file.