Phase Ib/II study of imprime PGG and pembrolizumab in patients with previously treated advanced non-small cell lung cancer (NSCLC): BTCRC LUN 15-017

Introduction

Lung cancer is the second most common cancer and the leading cause of cancer-related mortality in the U.S., accounting for almost 21% of all cancer-related deaths (1). Non-small cell lung cancer (NSCLC) comprises more than 85% of all new cases of lung cancer. Nearly half of these cases have distant disease at diagnosis and exhibit 5-year survival of <10%. Approximately 65% of all NSCLC express some degree of programmed death-ligand 1 (PD-L1) protein on their cell membrane and show a relatively better prognosis with use of anti-programmed death 1 (PD-1)/PD-L1 immunotherapies. However, 35% of advanced stage NSCLC do not express PD-L1. The addition of anti-PD-1/PD-L1 immunotherapies in the treatment paradigm of this NSCLC sub-population has demonstrated only a modest impact on survival (2,3). Nevertheless, many patients who respond to initial anti-PD-1/PD-L1 therapies go on to develop resistance to these agents. Therefore, combinational treatment approaches of various immune-modulating agents may hold a better potential for immune synergy and improve treatment efficacy.

Enhanced trafficking or activation of specific effector T cells in the tumor microenvironment has remained an important strategy in targeting cancers. However, stimulating the innate arm of the immune system is now being increasingly recognized as a complimentary tool to develop effective anti-tumor immunity (4). Both endogenous danger-associated molecular patterns (DAMPs) and exogenous pathogen-associated molecular patterns (PAMPs), are detected by pattern-recognition receptors (PRR) including toll-like receptors (TLRs), nucleotide oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), C-type lectin receptors (CLRs), and absent in melanoma-2 (AIM2)-like receptors (ALRs) to orchestrate an inflammatory or anti-tumor response through members of the innate arm of the immune system (4-6). Imprime PGG (imprime) is a β-glucan isolated from a proprietary strain of yeast Saccharomyces cerevisiae and is safe to administer intravenously. It acts as a PAMP and is sensed by the PRR and orchestrates a robust innate immune response (7,8).

In preclinical models, imprime induced a widespread innate immune response in a Dectin-1-dependent manner (5). It causes production of cytokines, chemokines, and type 1 interferons, activates and enhances natural killer (NK) cell functions, reorients M2 macrophages to an M1 state, facilitates maturation of antigen-presenting dendritic cells, facilitates an anti-tumor T cell-specific response, and synergizes with anti-PD-1 antibody therapy in the murine MC38 tumor model. This makes imprime an attractive combinatorial partner with anti-PD-1/PD-L1 immunotherapies. Clinically imprime has been administered at 4 mg/kg weekly with cetuximab, carboplatin, and paclitaxel in patients with advanced stage NSCLC and found to be tolerable (8).

We present an investigator-initiated, multi-institutional, single-arm, phase Ib/II trial evaluating the combination of pembrolizumab and imprime in advanced stage NSCLC. We present this article in accordance with the TREND reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-346/rc).

Methods

Study design

Big Ten Cancer Research Consortium (BTCRC) LUN 15-017 was a multicenter, investigator-initiated, single-arm, phase Ib–II trial. Three academic medical centers, University of Illinois, Chicago, University of Iowa, and Rutgers Cancer Institute of New Jersey (RCINJ), as part of the BTCRC, participated in the trial.

Eligible patients were 18 years or older, progressed through platinum-based chemotherapy for an advanced stage, pathologically confirmed NSCLC, and naïve to anti-PD-1/PD-L1 therapies (later amended to allow receipt of prior immunotherapy; see Statistical considerations and analyses). Adequate hepatic, renal, and marrow functions were required. Patients had to have Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 and a life expectancy of at least 6 months from the time of registration. Patients with EGFR exon 19 del or L858R or ALK fusion who progressed through approved tyrosine kinase inhibitors (TKIs) were eligible. Patients enrolled in phase II were required to have measurable disease per RECISTv1.1. Participants with active central nervous system (CNS) metastases, history of solid organ or stem cell transplant, active autoimmune diseases requiring systemic immunosuppression, interstitial lung disease and active hepatitis B or C, human immunodeficiency virus (HIV), or tuberculosis infections were excluded.

Study treatment plan

Dose escalation during phase Ib was planned according to 3+3 design. The initial dose for imprime with pembrolizumab was 2 mg/kg on days 1, 8 and 15 of every 21-day cycle for 4 cycles and then on day 1 of cycles 5 through 16. Three to six patients were to be initially enrolled at 2 mg/kg (dose level 1). If none of the first three patients experienced a dose-limiting toxicity (DLT) during the first cycle, then an additional three patients were to be enrolled at dose level 2 (4 mg/kg). If at most 1 of 3 patients in dose level 2 complete the first cycle of therapy without DLT, then three additional patients were to be enrolled to ensure at most one of six patients had a DLT. No further dose escalation was planned and if tolerable, this dose was considered as the maximum-tolerated dose (MTD). Treatment was continued for up to 16 cycles, until progression, significant toxicity, or withdrawal, whichever occurred first. Patients were monitored for progression every 2 cycles.

Statistical considerations and analyses

The primary objective of phase Ib was to establish the MTD of imprime in combination with pembrolizumab. The primary objective of phase II was to evaluate preliminary evidence of anti-tumor activity of imprime in combination with pembrolizumab by testing the null hypothesis that the median progression-free survival (PFS) is less than a historic estimate of 3.2 months in the immunotherapy naïve patient population in the second-line setting (9,10) versus the alternative that it is 6.3 months or greater. The trial was originally designed to have 90% power to detect a 3.1-month increase in median PFS with two-sided statistical testing performed at the 5% level with a sample size of 24 patients. With the Food and Drug Administration (FDA) approval of anti-PD-1/PD-L1 immunotherapy in the frontline setting for advanced stage NSCLC, inclusion criteria for the trial were modified between phases Ib and II to include patients who had received prior anti-PD-1/PD-L1 immunotherapy with platinum-based chemotherapy or as monotherapy. Thus, comparisons to the historic estimate are no longer considered clinically relevant, and formal statistical testing of the phase II primary endpoint was not performed.

The incidence of treatment-emergent adverse events was summarized by type of adverse event, grade, and attribution, with the most severe grade per patient being reported. The objective response rate was defined as the proportion of patients with a confirmed complete response (CR) or partial response (PR) per RECIST v1.1. The clinical benefit rate was defined as the proportion of patients with a CR, PR, or stable disease (SD). PFS was defined as the time from treatment initiation to the date of first documentation of disease progression or death due to any cause. Otherwise, patients were censored at date of last radiographic assessment. Overall survival (OS) was defined as the time from treatment initiation to death due to any cause. Patients still alive were censored at the last date known to be alive. Survival probabilities were estimated and plotted using the Kaplan-Meier method. Estimates along with 95% pointwise confidence intervals (CIs) are reported. Cox regression models were utilized to estimate the effect of baseline characteristics on PFS and OS. Estimated covariate effects are reported as hazard ratios (HRs) along with 95% CI. All tests were two-sided and assessed for significance at the 5% level using SAS v9.4 (SAS Institute, Cary, NC, USA).

Study oversight

The protocol was submitted to the U.S. FDA under Investigational New Drug 131052 and registered to ClinicalTrials.gov prior to enrollment of the first patient (NCT03003468) (supplementary file 1 available at https://cdn.amegroups.cn/static/public/tlcr-24-346-1.pdf). Participating sites include University of Illinois Chicago Cancer Center (UICCC), Holder Comprehensive Cancer Center (HCCC) University of Iowa and RCINJ. Each participating center’s institutional review board approved the study prior to enrolling patients (UIC IRB # 2016-1085, University of Iowa Hawk IRB # 201703873, Rutgers eIRB Pro20170000733) (supplementary file 2 available at https://cdn.amegroups.cn/static/public/tlcr-24-346-2.pdf). Informed written consent was obtained from each patient before participating in the study. The trial was conducted according to the Belmont Report, the United States Common Rule (45CFR§46), and the International Council on Harmonisation-Good Clinical Practice (GCP) as adopted by U.S. federal law. All investigators were GCP trained. The University of Illinois, Chicago Cancer Center’s Data and Safety Monitoring Committee (DSMC) reviewed all data for compliance to protocol and participant safety. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Safety and annual reports regarding this trial were submitted as required (21CFR§312.23, §312.32).

Results

Between Feb 2017 to Sep 2020, a total of 35 patients were registered; 1 patient withdrew consent prior to initiating treatment, and 1 patient was deemed ineligible (no measurable lesions) after initiating treatment. The remaining 33 patients were included in the reported safety analysis. Participant demographics and baseline disease characteristics are described in Table 1. No DLT was observed in the phase Ib cohorts at both 2 and 4 mg/kg dose with pembrolizumab. The imprime dose of 4 mg/kg was determined as the MTD. Thirty of 33 patients received imprime at the MTD (phase Ib, 6; phase II, 24) and were included in the efficacy analysis. At the time of data cutoff, the median length of follow-up was 10.8 months (range, 0.0 to 52.8 months). Of the efficacy population, 21 patients were deceased, while 5 patients were alive and had not progressed at the time of data cutoff (Figure 1).

Figure 1 Flow of participant through the trial.

Reasons for coming off treatment were as follows: disease progression (n=18), adverse events (n=5), completed protocol defined treatment (n=4), death (n=1), withdrew consent (n=1), reason unspecified (n=1). In the efficacy analysis, the confirmed objective response rate was 10% (95% CI: 2–27%), with one CR and two PRs. The clinical benefit rate was 47% (95% CI: 23–67%). Thirteen patients (43.3%) developed PD as their best overall response, while three patients (10%) were not evaluable for response. Figures 2A,2B demonstrate patients’ disease course and correlates their responses with disease-related factors and outcomes.

Figure 2 Changes in target disease per RECIST v1.1. (A) Spider plot; (B) waterfall plot along with disease characteristics and patient outcomes. CR, complete response; PR, partial response; SD, stable disease; PD, disease progression; Immuno, immunotherapy; PD-L1, program death ligand-1; PFS, progression-free survival; N, no or negative; Y, yes; L, low; H, high.

In the safety population (n=33), a total of 10 patients experienced serious adverse events (SAE). Three (10%) SAEs were treatment related. Adverse events related to imprime are summarized in Table 2 and treatment-emergent adverse event occurring with frequency of ≥5% are reported in Table 3.

Median PFS was 2.6 months (95% CI: 1.4–7.0), and 6-month and 12-month PFS rates were 37% (95% CI: 20–55%) and 17% (95% CI: 5–34%), respectively (Figure 3A). Median OS of 11.1 months was observed, and 6-month and 12-month OS rates were 75% (95% CI: 55–87%) and 46% (95% CI: 28–63%), respectively (Figure 3B). We assessed the influence of factors including age, sex, race, disease-stage, level of PD-L1 expression and receipt of prior anti-PD-1/PD-L1 immunotherapy on PFS and OS. Of these, receipt of prior immunotherapy negatively influenced the outcomes (Figure 3C,3D) and was statistically significant for OS. Univariate analysis for PFS and OS are shown in Table 4.

Figure 3 Kaplan-Meier curves. (A) PFS; (B) OS; (C) PFS by receipt of prior immunotherapy; (D) OS by receipt of prior immunotherapy. CI, confidence interval; PFS, progression-free survival; OS, overall survival.

Discussion

This study was initially designed to explore the safety and the efficacy of the combination of imprime and pembrolizumab in advanced stage NSCLC in the second line setting after progression on platinum-based chemotherapy. However, shortly after the completion of phase Ib, anti-PD-1/PD-L1 agents received FDA approval and were moved to the first-line setting in advanced stage NSCLC after demonstrating a survival benefit both as monotherapy and in combination with platinum-based chemotherapy (11-15). The study protocol was amended to allow the receipt of anti-PD-1/PD-L1 prior to enrolling in the study. This development after initiation of the trial explains why patients who did not receive anti-PD-1/PD-L1 therapies prior to participating in this study did better. In the overall patient population, median PFS was 2.6 months, which is no better than docetaxel, an FDA approved second-line chemotherapy. However, patients who were immunotherapy naïve, had a relatively longer PFS and OS. In CheckMate 057 and 017 studies, the median PFS of patients who received docetaxel, was 4.2 and 2.8 months respectively while median OS was 9.4 and 6.0 months respectively (9,10).

Improving clinical outcomes for patients with NSCLC after progression on combination of platinum-based chemotherapy and anti-PD-1/PD-L1 immunotherapies continues to remain a major challenge. Nivolumab, atezolizumab and pembrolizumab have been shown to improve 1-year PFS and OS over docetaxel (9,10,16,17). However, since these agents moved to the first-line setting, docetaxel with or without ramucirumab continues as the standard second-line option for these patients. Three different classes of agents are currently under investigation to improve NSCLC outcomes in the second-line setting: (I) drugs invigorating the innate arm of the immune system against NSCLC; (II) agents enhancing the adaptive arm of the immune system; and (III) antibody drug conjugates (ADC).

Several mechanisms to harness anti-tumor innate immunity, such as TLR, STING, and CD40 agonists, indoleamine 2,3-dioxygenase (IDO) inhibitors, inhibitory antibodies to KIR and NKG2A, and adoptive NK cell transfer are being evaluated in clinical trials (18). Similarly, multiple early phase studies have shown encouraging results with anti-TIM3, anti-TIGIT, anti-LAG3, OX-40 agonist, and 41BB agonist (19-24). Drugs employing adaptive immune system checkpoints are further along in clinical development than agents orchestrating the innate arm of the immune system.

While ADC are even further along in development, these drugs are relatively toxic compared to immunotherapies. Datopotamab deruxtecan (Dato-DXd) is a TROP2 ADC. It has recently demonstrated a statistically significant improvement in PFS over docetaxel (25). Other ADCs, such as BL-B01D1 (EGFRxHER3 bispecific ADC), patritumab deruxtecan (HER3-DXd), and tusamitamab ravtansine (anti-CEACM5 ADC), are currently in phase I/II trials and showing promising results in select patient populations (26-28).

There are a few limitations to our study. The study enrollment period was relatively long and the change in the standard of care for first- and second-line therapy for advanced stage NSCLC during the study period affected the study design, accrual, and interpretation of results. In addition, it was a small signal seeking study evaluating the synergistic activity of the combination of pembrolizumab and imprime.

Conclusions

The combination of imprime and pembrolizumab is tolerable; however, it did not improve advanced stage NSCLC outcomes in patients who were previously treated with anti-PD-1/PD-L1 immunotherapies. Further investigation is needed to determine the effects of therapeutic PAMPs and to discover approaches for harnessing the anti-tumor innate immune system.

Acknowledgments

We acknowledge the work of BTCRC staff in providing the project management and logistical support, and Kristina K. Greiner who assisted with editing and proofreading of the manuscript.

Funding: This work was funded by Merck and HiberCell (previously Biothera Pharm.). HiberCell provided imprime PGG for participants of the trial.

Footnote

Reporting Checklist: The authors have completed the TREND reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-346/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-346/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-346/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-346/coif). M.F. serves as an unpaid editorial board member of Translational Lung Cancer Research from October 2023 to September 2025. All authors report that they had received institutional research funding from Merck and HiberCell to conduct the study. M.F. received institutional research funding from Amgen, Abbvie, Elicio, Incyte, Genmab, Merck, GSK, Pfizer, Astellas, BMS, Beigene, AZ, Seattle Genetics, Mirati, Genentech, Immunocore, Fate therapeutics, and Poseida; received speaker honoraria from ASCO, Iowa Oncology Society and OncLive and serves on the Pfizer, Mirati, Abbvie, Immunocore, AstraZeneca, Jazz, Immunocore advisory board. J.M. received institutional research funding from Biohaven, Daiichi-Sankyo, BMS, Beyond Spring Pharma, Celldex; serves as a consultant or on the advisory board of Janssen, BMS, Bioatla, AZ, Tekeda, Abbvie, Daiichi-Sankyo, Regernron, Sanofi, Jazz Pharma, and Mirati; and received honoraria for educational events from Tempus. A.S. received institutional research funding from Hutchison MediPharma, Merck, Inhibrx, Verastem Oncology, Turning Point Therapeutics, Gritstone, Bolt Therapeutics, BMS, Pfizer, Astellas, Oncologie, Macrogenics, Seattle Genetics, Amgen, Daiichi, Lilly, Jacobio. A.S. serves as a consultant or on the advisory board for Regeneron/Sanofi, Pfizer, guardant, Catalyst Pharmaceuticals and KLJ Associates. A.S. received honoraria for educational events from OncLive, OSCO/ASCO Direct, ACPMP, Cholangiocarcinoma Summit, Cholangiocarcinoma Foundation, and ASCO. She also participates in ACPMP Think Tank. M.M.P. serves as consultant for Center for Business Models in HealthCare and Prevent Cancer through MMP Consulting Services and received institutional research support from Coleman Foundation and American Lung Association. M.M.P. received travel grant from GO2 Foundation and participate in Prevent Cancer and NLCRT. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Each participating center’s Institutional Review Board approved the study prior to enrolling patients (UIC IRB # 2016-1085, University of Iowa Hawk IRB # 201703873, Rutgers eIRB Pro20170000733). Informed written consent was obtained from each patient before participating in the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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