Combination checkpoint blockade plus VEGF inhibitor in EGFR-mutated NSCLC

2022

Career Development Award

This grant was funded in part by The Huff Project

Joshua Reuss, MD

Georgetown University

Washington

Osimertinib is the standard of care for treating non-small cell lung cancer with EGFR mutations. Unfortunately, the tumors inevitably develop resistance to osimertinib. Currently, very few treatment options exist for patients whose cancers have become resistant to osimertinib. Dr. Reuss is conducting a phase 2 clinical trial to test whether two immunotherapy drugs, atezolizumab and tiragolumab, given with a VEGF inhibitor, bevacizumab, are effective in controlling EGFR-positive NSCLC that has become resistant to osimertinib.

Research Summary

The targeted-therapy (TT) osimertinib has become the frontline standard-of-care for patients with advanced non-small cell lung cancer (NSCLC) who have a mutation in the epidermal growth factor receptor (EGFR) gene, which causes the cancer to grow. Despite this, most people experience progression of the cancer, at which point effective treatments are limited. Immunotherapy targeting the programmed death-1 (PD-1) pathway, while revolutionary for patients without such a mutation, has shown limited benefit in patients with EGFR-mutated NSCLC. Therapies targeting additional immune barriers, as well as a molecule called vascular endothelial growth factor (VEGF), may change this. VEGF suppresses important immune cells and pathways that help make immunotherapy work, and high levels have been found in EGFR-mutated NSCLC. Crucially, several clinical studies have shown promise by combining therapies targeting VEGF with immunotherapy and chemotherapy in EGFR-mutated NSCLC. This suggests that treatments targeting VEGF may help immunotherapy work better in these patients, but how that happens is unclear. It is also unknown if these therapies can be combined without chemotherapy, or if additional immunotherapies can magnify this benefit. To address these questions, we are conducting a phase 2 clinical trial evaluating a novel immunotherapy drug tiragolumab (targeting a molecule called TIGIT) together with the PD-L1-targeting antibody atezolizumab and VEGF-targeting antibody bevacizumab in advanced TT-refractory EGFR-mutated NSCLC. Critically, tumor biopsies and blood samples will be obtained from patients pre- and on-treatment to examine what properties in EGFR-mutated NSCLC make it resistant to immunotherapy, and determine how the tumor and immune system change during treatment. By doing this, we aim to show how therapy targeting VEGF works together with immunotherapy to provide benefit. Knowledge gained from this could help unlock the power of immunotherapy for EGFR-mutant NSCLC, and provide a novel treatment for patients afflicted with this sub-type of NSCLC.

Technical Abstract

The targeted-therapy (TT) osimertinib is frontline standard-of-care for patients with advanced non-small cell lung cancer (NSCLC) harboring mutations in the epidermal growth factor receptor (EGFR) gene. However, nearly all patients develop resistance, at which point treatments are limited. While revolutionary for many cancers, anti-PD-(L)1 immune checkpoint blockade (ICB) has been ineffective in EGFR-mutated(m) NSCLC. Targeting angiogenesis, and specifically vascular endothelial growth factor (VEGF), may be key to changing this. VEGF promotes immunosuppression through multiple mechanisms including inhibition of cytotoxic T-cell trafficking and promotion of regulatory T-cell proliferation. Pre-clinical and clinical evidence has revealed activated EGFR to be a dominant regulator of angiogenesis in EGFRm NSCLC, with increased expression of VEGF and hypoxia inducible factor-1α observed in EGFRm compared to wild-type NSCLC. Clinically, combination chemotherapy with anti-PD-L1 and VEGF blockade has shown efficacy signals in EGFRm NSCLC. However, whether upregulated VEGF potentiates the uninflamed tumor immune microenvironment (TIME), and underlies the observed synergy of these therapies in EGFRm NSCLC, remains unexplored. It is further unknown if VEGF inhibition can be combined with PD-1 blockade to promote benefit in the absence of chemotherapy, or whether blockade of additional checkpoints can further expand anti-tumor immune populations, specifically NK cells, which appear to be upregulated in EGFRm NSCLC responsive to ICB. To address these impactful questions, we have designed a single-arm translationally-focused phase 2 clinical trial assessing the efficacy of tiragolumab (anti-TIGIT) plus atezolizumab (anti-PD-L1) and bevacizumab (anti-VEGF) in advanced TT-refractory, ICB-naïve, EGFRm NSCLC. Critically, the proposed analyses detailed herein of tumor and blood samples obtained pre- and on-treatment will focus on (1) immunopathologic features of ICB resistance in EGFRm-NSCLC and (2) TIME infiltration and immunologic reprogramming imparted by these therapies. The findings from this study will help to define the innate barriers preventing induction of durable anti-tumor immunity by ICB in EGFRm NSCLC, and identify strategies to overcome them.

Key words

Acquired resistance

Adenocarcinoma

Epidermal growth factor receptor (EGFR)

Immune checkpoint inhibitors

Immunotherapy

Metastatic

Non-small cell lung cancer (NSCLC)