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

Lung cancer is the second most commonly diagnosed cancer in both men and women after prostate and breast cancer, respectively [1]. Approximately 85% of all lung cancers consist of non-small cell lung cancer (NSCLC) and patients usually present with locally advanced or metastatic disease at initial diagnosis [1]. For years, the first-line standard of care treatment for advanced NSCLC consisted of platinum-based combination chemotherapies [2, 3]. Although still a mainstay therapy for many NSCLC patients [4], advances in understanding the molecular pathways driving carcinogenesis (e.g., epidermal growth factor receptor [EGFR] gene mutations and anaplastic lymphoma kinase [ALK] translocations) led to development of targeted EGFR tyrosine kinase inhibitors and ALK-directed therapies that proved superior to chemotherapies for first-line management of advanced disease in select molecularly-defined patient subgroups harboring mutations sensitive to these therapies [4, 5]. Several monoclonal antibody (MAb) therapies have also been developed for first-line treatment of advanced NSCLC [4], including bevacizumab, which targets vascular endothelial growth factor (VEGF) [6], cetuximab [7] and necitumumab [8], both of which target EGFR and, most recently, pembrolizumab, which targets the programmed death-1 (PD-1) immune checkpoint receptor on cytotoxic T-cells [9]. Additional MAbs approved for second-line therapy, but likely to soon be front-line therapy, include ramucirumab, an agent targeting VEGF receptor 2 (VEGFR2) [10], as well as the anti-PD-1 and anti-programmed death ligand-1 (PD-L1) MAbs, nivolumab [11] and atezolizumab [12]. Unlike the other MAbs mentioned above, cetuximab ultimately never achieved regulatory approval for treatment of NSCLC. However, results of phase III NSCLC studies with cetuximab in combination with platinum doublet chemotherapy did show modest improvements in clinical efficacy endpoints [13, 14], which led to National Comprehensive Cancer Network guidelines recommending treatment of NSCLC with regimens containing cetuximab in select patients [4].

BTH1677 (β(1,6)-[poly-(1,3)-D-glucopyranosyl]-poly-β-(1,3)-D-glucopyranose; Imprime PGG; Biothera Pharmaceuticals Inc., Eagan, MN), is a fungal-derived, water-soluble, 1,3–1,6 beta glucan. It is purified from the cell wall of a proprietary, non-recombinant, strain of the yeast Saccharomyces cerevisiae and consists purely of D-glucose molecules joined together via beta 1,3 and 1,6 linkages. Specifically, it consists of a backbone of 1,3 linked glucose residues with periodic branches linked to the backbone in a 1,6 configuration. Similar to the backbone, the side chains also contain multiple 1,3-linked glucose residues. No beta glucans have been approved for clinical use in the United States. However, in China and Japan, two fungal mushroom-derived 1,3–1,6 beta glucans (lentinan and schizophyllan) have been approved. The chemical structure of BTH1677 is different from that of mushroom-derived beta glucans which have a higher branching frequency and side chains that consist of only single glucose residues [15‐17].

BTH1677 functions as a pathogen-associated molecular pattern (PAMP) molecule to stimulate a coordinated innate and adaptive anti-cancer immune response in combination with anti-tumor antibody therapies. When BTH1677 enters the blood, it is bound by endogenous plasma anti-beta glucan antibodies (ABA) resulting in complement activation and opsonization with complement protein iC3b [18, 19]. The BTH1677/ABA/iC3b complex initially binds to innate immune effector cells through complement receptor 3 and Fc gamma receptor IIA (FcγIIA) [18, 19], activating innate immune cell function and enabling direct killing of antibody-targeted tumor cells [18]. BTH1677 also enables reeducation of the tumor microenvironment, shifting the normally suppressive M2-state macrophages to a more M1 (tumor attack) state [20, 21], and promoting depletion and/or maturation of myeloid-derived suppressor cells in the tumor microenvironment [22]. BTH1677 treatment additionally activates antigen-presenting cells, driving co-stimulatory marker expression on macrophages and dendritic cells, as well as dendritic cell maturation, CD4 and CD8 T-cell expansion, and production of key anti-tumor cytokines (e.g., interferon gamma) [21, 23‐26]. In murine syngeneic and xenogeneic tumor models, the administration of BTH1677 with various tumor-targeting monoclonal antibodies has resulted in greater suppression of tumor growth and longer survival than with either agent alone [27‐29]. One of these studies [28] specifically evaluated BTH1677 and cetuximab in a lung cancer model. Similar effects have been observed with BTH1677 combined with anti-angiogenic antibodies (anti-VEGF and anti-VEGFR2) [22, 30, 31] and checkpoint inhibitor antibodies [32, 33].

Clinically, in healthy subjects, BTH1677 was well tolerated after single doses up to 6 mg/kg and after 7 daily doses up to 4 mg/kg and pharmacokinetic (PK) parameters demonstrated linearity with dose [34]. Additionally, BTH1677 in combination with cetuximab, with or without irinotecan, was well tolerated with promising evidence of efficacy in a phase Ib/II study in patients with recurrent or progressive metastatic colorectal cancer (mCRC) [35‐37].

Based on the preclinical efficacy observed in vivo in murine lung cancer models with BTH1677 combined with either cetuximab [28] or bevacizumab [31], parallel studies were designed to evaluate these BTH1677 combinations in NSCLC patients. Here we report results of the randomized, open-label, multicenter, phase II study (NCT00874848) designed to evaluate the antitumor activity, safety, and PK profile of BTH1677 when combined with cetuximab and concomitant carboplatin and paclitaxel therapy in patients with previously untreated, advanced NSCLC. Exploratory evaluation of the potential use of baseline ABA levels as a measure of a patient’s ability to respond to BTH1677 is also presented. At the time this study was initiated, cetuximab was undergoing regulatory review for first-line use in late-stage NSCLC patients, with approval anticipated. This anticipation, along with our preclinical and clinical mCRC data demonstrating enhanced antitumor effects with BTH1677 combined with cetuximab therapy prompted us to evaluate this combination in NSCLC. Although cetuximab was ultimately not approved and is not currently a standard therapy for NSCLC, the results of this study nevertheless support the concept of improved efficacy with the addition of BTH1677 to antitumor antibody therapy.

BTH1677 is a novel PAMP being developed for the treatment of cancer in combination with tumor-targeted antibodies, as well as anti-angiogenic and checkpoint inhibitor antibodies. A previous phase Ib/II study in second- to third-line mCRC patients evaluated BTH1677 combined with cetuximab and showed good tolerability with promising efficacy [34‐37]. This randomized, open-label, phase II study demonstrated that BTH1677 in combination with cetuximab, carboplatin, and paclitaxel numerically improved the ORR in patients with previously untreated, advanced NSCLC by 13% (p = 0.2895; central review) to 24% (p = 0.0468; investigator review) beyond the ORR observed in Control patients. No meaningful changes were observed in other tumor-associated assessments or survival. Subject numbers were small for time-to-event assessments and not all randomized subjects were included in the primary efficacy populations. Furthermore, large differences in the percentage of patients censored for some of these assessments in the investigator (~20%) vs central (~50%) reviews no doubt further clouded an ability to see consistent meaningful changes.

The population enrolled in this study was similar to the large BMS099 study (N = 676) evaluating cetuximab and carboplatin/taxane vs carboplatin/taxane alone as first-line treatment in advanced NSCLC patients that were not selected for EGFR expression or KRAS gene status [13]. Our Control ORRs of 23.1% (both investigator and central reviews) compare similarly to the ORRs of 27.5% (investigator review) and 25.7% (central review) in the BMS099 cetuximab and carboplatin/taxane arm. In light of our Control ORR responding as expected, the improved 47.8% (investigator review) and 36.6% (central review) ORRs observed with the addition of BTH1677 to the backbone therapy does suggest further benefit from the addition of BTH1677. However, whether improved ORR will translate into benefit in more clinically relevant endpoints such as PFS or OS would require larger studies powered for such endpoints. Even in the large BMS099 study, improved ORR did not translate into improved PFS or OS. In the larger FLEX study (N = 1125), evaluating cetuximab and cisplatin/vinorelbine vs cisplatin/vinorelbine alone as first-line treatment in selected EGFR-expressing advanced NSCLC patients [14], the slight improvement in ORR (36% vs 29%) was associated with a statistically significant improvement in OS, but the effect was very modest (11.3 vs 10.1 months; HR 0.871; p = 0.044).

Interestingly, our findings indicated that ABA level may be useful as a predictive biomarker for response to BTH1677. BTH1677 biomarker-positive patients exhibited better OS than biomarker-negative patients. However, no serum was available from Control patients for ABA analysis and, therefore, key comparisons of BTH1677 biomarker-positive and biomarker-negative responses to Control biomarker-positive and biomarker-negative responses could not be performed. Hence, the possibility that ABA level may be prognostic for better responders vs predictive of a BTH1677-specific effect cannot be ruled out. Given the critical role of ABA in facilitating the binding of BTH1677 to immune cells [18‐22, 39‐42] the former seems unlikely; however, controlled studies are needed to further assess the true contribution of ABA in response to BTH1677, as well as to refine the most appropriate ABA thresholds for defining biomarker-positive and biomarker-negative patients in the cancer population.

In terms of safety, BTH1677 combination therapy was well tolerated among patients, which was consistent with previous experience using BTH1677 in combination with cetuximab in mCRC patients [34‐37]. Overall, most AEs were mild or moderate in severity. Only skin fissures occurred at a 10% greater incidence in the BTH1677 arm than in the Control arm (18.6% vs 6.9%).

PK parameters were consistent with those previously observed in healthy volunteers [34], suggesting that neither cetuximab nor the carboplatin and paclitaxel therapy affected the PK of BTH1677.

In conclusion, BTH1677 in combination with cetuximab and concomitant carboplatin and paclitaxel improved ORR and was well tolerated in patients with previously untreated, advanced NSCLC. At the time this study was initiated, cetuximab was undergoing regulatory review for first-line use in late-stage NSCLC patients, but ultimately never received approval. Hence, although the treatment regimen used here will not proceed to further evaluation, the results of this study support the concept of improved efficacy with the addition of BTH1677 to antibody therapy. The NSCLC study run in parallel with this study, that evaluated BTH1677 combined with bevacizumab/carboplatin/paclitaxel in non-squamous late-stage NSCLC patients, also demonstrated promising results [43], and a NSCLC study of BTH1677 in combination with pembrolizumab is ongoing (ClinicalTrials.​gov NCT03003468). This novel therapeutic also continues to be investigated in combination with antibody therapies in additional oncology clinical trials that also include further investigation into the possible role of ABA as a predictive biomarker for response to BTH1677.