A Randomized, Controlled Trial Evaluating the Efficacy and Safety of BTH1677 in Combination with Bevacizumab, Carboplatin, and Paclitaxel in First-line Treatment of Advanced Non-small Cell Lung Cancer

Overview

Journal J Immunother Cancer

Specialties Allergy & Immunology
Oncology
Pharmacology

Date 2018 Mar 1

PMID 29486797

Citations 6

Authors

Walburga Engel-Riedel

Jamie Lowe

Paulette Mattson

J Richard Trout

Richard D Huhn

Michele Gargano

Myra L Patchen

Richard Walsh

My My Trinh

Marieve Dupuis

Folker Schneller

Affiliations

Soon will be listed here.

Abstract

Background: BTH1677, a beta-glucan pathogen-associated molecular pattern molecule, drives an anti-cancer immune response in combination with oncology antibody therapies. This phase II study explored the efficacy, pharmacokinetics (PK), and safety of BTH1677 combined with bevacizumab/carboplatin/paclitaxel in patients with untreated advanced non-small cell lung cancer (NSCLC).

Methods: Patients were randomized to the BTH1677 arm (N = 61; intravenous [IV] BTH1677, 4 mg/kg, weekly; IV bevacizumab, 15 mg/kg, once each 3-week cycle [Q3W]; IV carboplatin, 6 mg/mL/min Calvert formula area-under-the-curve, Q3W; and IV paclitaxel, 200 mg/m, Q3W) or Control arm (N = 31; bevacizumab/carboplatin/paclitaxel as above). Carboplatin/paclitaxel was discontinued after 4-6 cycles and patients who responded or remained stable received maintenance therapy with BTH1677/bevacizumab (BTH1677 arm) or bevacizumab (Control arm). Efficacy assessments, based on blinded central radiology review, included objective response rate (ORR; primary endpoint), disease control rate, duration of objective response, and progression-free survival. Overall survival and adverse events (AEs) were also assessed.

Results: ORR was higher in the BTH1677 vs Control arm but the difference between groups was not statistically significant (60.4% vs 43.5%; P = .2096). All other clinical endpoints also favored the BTH1677 arm but none statistically differed between arms. PK was consistent with previous studies. Although a higher incidence of Grade 3/4 AEs occurred in the BTH1677 vs Control arm (93.2% vs 66.7%), no unexpected AEs were observed. Serious AEs and discontinuations due to AEs were lower in the BTH1677 vs Control arm.

Conclusions: Improvements in tumor assessments and survival were observed with BTH1677/bevacizumab/carboplatin/paclitaxel compared with control treatment in patients with advanced NSCLC.

Trial Registration: ClinicalTrials.gov registration ID: NCT00874107 . Registered 2 April 2009. First participant was enrolled on 29 September 2009.

Citing Articles

Trained immunity in chronic inflammatory diseases and cancer.

Hajishengallis G, Netea M, Chavakis T Nat Rev Immunol. 2025; .

PMID: 39891000 DOI: 10.1038/s41577-025-01132-x.

The role of neutrophils in trained immunity.

Kalafati L, Hatzioannou A, Hajishengallis G, Chavakis T Immunol Rev. 2022; 314(1):142-157.

PMID: 36190144 PMC: 10050090. DOI: 10.1111/imr.13142.

Imprime PGG Enhances Anti-Tumor Effects of Tumor-Targeting, Anti-Angiogenic, and Immune Checkpoint Inhibitor Antibodies.

Chan A, Kangas T, Qiu X, Uhlik M, Fulton R, Ottoson N Front Oncol. 2022; 12:869078.

PMID: 35692755 PMC: 9178990. DOI: 10.3389/fonc.2022.869078.

Pharmacology-based ranking of anti-cancer drugs to guide clinical development of cancer immunotherapy combinations.

Lemaire V, Shemesh C, Rotte A J Exp Clin Cancer Res. 2021; 40(1):311.

PMID: 34598713 PMC: 8485537. DOI: 10.1186/s13046-021-02111-5.

Reporting quality of randomized, controlled trials evaluating immunotherapy in lung cancer.

Du J, Zhang Y, Dong Y, Duan J, Bai H, Wang J Thorac Cancer. 2021; 12(20):2732-2739.

PMID: 34432361 PMC: 8520800. DOI: 10.1111/1759-7714.14114.

References

Thomas M, Sadjadian P, Kollmeier J, Lowe J, Mattson P, Trout J . A randomized, open-label, multicenter, phase II study evaluating the efficacy and safety of BTH1677 (1,3-1,6 beta glucan; Imprime PGG) in combination with cetuximab and chemotherapy in patients with advanced non-small cell lung cancer. Invest New Drugs. 2017; 35(3):345-358. PMC: 5418307. DOI: 10.1007/s10637-017-0450-3. View

Chan A, Jonas A, Qiu X, Ottoson N, Walsh R, Gorden K . Imprime PGG-Mediated Anti-Cancer Immune Activation Requires Immune Complex Formation. PLoS One. 2016; 11(11):e0165909. PMC: 5094785. DOI: 10.1371/journal.pone.0165909. View

Li B, Allendorf D, Hansen R, Marroquin J, Cramer D, Harris C . Combined yeast {beta}-glucan and antitumor monoclonal antibody therapy requires C5a-mediated neutrophil chemotaxis via regulation of decay-accelerating factor CD55. Cancer Res. 2007; 67(15):7421-30. PMC: 1933500. DOI: 10.1158/0008-5472.CAN-07-1465. View

Zhong W, Hansen R, Li B, Cai Y, Salvador C, Moore G . Effect of yeast-derived beta-glucan in conjunction with bevacizumab for the treatment of human lung adenocarcinoma in subcutaneous and orthotopic xenograft models. J Immunother. 2009; 32(7):703-12. DOI: 10.1097/CJI.0b013e3181ad3fcf. View

Vesely M, Kershaw M, Schreiber R, Smyth M . Natural innate and adaptive immunity to cancer. Annu Rev Immunol. 2011; 29:235-71. DOI: 10.1146/annurev-immunol-031210-101324. View

Manegold C, Dingemans A, Gray J, Nakagawa K, Nicolson M, Peters S . The Potential of Combined Immunotherapy and Antiangiogenesis for the Synergistic Treatment of Advanced NSCLC. J Thorac Oncol. 2016; 12(2):194-207. DOI: 10.1016/j.jtho.2016.10.003. View

Qi C, Cai Y, Gunn L, Ding C, Li B, Kloecker G . Differential pathways regulating innate and adaptive antitumor immune responses by particulate and soluble yeast-derived β-glucans. Blood. 2011; 117(25):6825-36. PMC: 3128477. DOI: 10.1182/blood-2011-02-339812. View

Salvador C, Li B, Hansen R, Cramer D, Kong M, Yan J . Yeast-derived beta-glucan augments the therapeutic efficacy mediated by anti-vascular endothelial growth factor monoclonal antibody in human carcinoma xenograft models. Clin Cancer Res. 2008; 14(4):1239-47. PMC: 2394864. DOI: 10.1158/1078-0432.CCR-07-1669. View

Brahmer J . Harnessing the immune system for the treatment of non-small-cell lung cancer. J Clin Oncol. 2013; 31(8):1021-8. DOI: 10.1200/JCO.2012.45.8703. View

10.

Halstenson C, Shamp T, Gargano M, Walsh R, Patchen M . Two randomized, double-blind, placebo-controlled, dose-escalation phase 1 studies evaluating BTH1677, a 1, 3-1,6 beta glucan pathogen associated molecular pattern, in healthy volunteer subjects. Invest New Drugs. 2016; 34(2):202-15. PMC: 4786610. DOI: 10.1007/s10637-016-0325-z. View

11.

Shepherd F, Douillard J, Blumenschein Jr G . Immunotherapy for non-small cell lung cancer: novel approaches to improve patient outcome. J Thorac Oncol. 2011; 6(10):1763-73. DOI: 10.1097/JTO.0b013e31822e28fc. View

12.

Li B, Allendorf D, Hansen R, Marroquin J, Ding C, Cramer D . Yeast beta-glucan amplifies phagocyte killing of iC3b-opsonized tumor cells via complement receptor 3-Syk-phosphatidylinositol 3-kinase pathway. J Immunol. 2006; 177(3):1661-9. DOI: 10.4049/jimmunol.177.3.1661. View

13.

Bose N, Chan A, Guerrero F, Maristany C, Qiu X, Walsh R . Binding of Soluble Yeast β-Glucan to Human Neutrophils and Monocytes is Complement-Dependent. Front Immunol. 2013; 4:230. PMC: 3740326. DOI: 10.3389/fimmu.2013.00230. View

14.

Ferrara N, Hillan K, Gerber H, Novotny W . Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004; 3(5):391-400. DOI: 10.1038/nrd1381. View

15.

Carbone D, Gandara D, Antonia S, Zielinski C, Paz-Ares L . Non-Small-Cell Lung Cancer: Role of the Immune System and Potential for Immunotherapy. J Thorac Oncol. 2015; 10(7):974-84. PMC: 4618296. DOI: 10.1097/JTO.0000000000000551. View

16.

Jain R . Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell. 2014; 26(5):605-22. PMC: 4269830. DOI: 10.1016/j.ccell.2014.10.006. View

17.

Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V . Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009; 27(8):1227-34. DOI: 10.1200/JCO.2007.14.5466. View

18.

Ettinger D, Wood D, Akerley W, Bazhenova L, Borghaei H, Camidge D . NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 4.2016. J Natl Compr Canc Netw. 2016; 14(3):255-64. PMC: 10181272. DOI: 10.6004/jnccn.2016.0031. View

19.

Ohm J, Carbone D . VEGF as a mediator of tumor-associated immunodeficiency. Immunol Res. 2001; 23(2-3):263-72. DOI: 10.1385/IR:23:2-3:263. View

20.

Masters G, Temin S, Azzoli C, Giaccone G, Baker Jr S, Brahmer J . Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2015; 33(30):3488-515. PMC: 5019421. DOI: 10.1200/JCO.2015.62.1342. View