VEGF

A protein that helps cancer cells form new blood vessels

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)

Read more about Combination checkpoint blockade plus VEGF inhibitor in EGFR-mutated NSCLC

EGFR/estrogen interactions: role in bronchioalveolar carcinoma and gender differences in the efficacy of antiangiogenic therapy

2007

Targeted Therapeutics Research Award

Funded equally by LUNGevity Foundation and Joan's Legacy

John Heymach, MD, PhD

MD Anderson Cancer Center

Houston

The role of the hormone estrogen in the development of lung cancer has been established. Dr. Heymach is studying how estrogen affects signaling by the EGFR gene and secretion of proteins that fuel the development of new blood vessels necessary to sustain the growth of the cancer.

Key words

Adenocarcinoma

Angiogenesis inhibitors

Epidermal growth factor receptor (EGFR)

Gender effect

Non-small cell lung cancer (NSCLC)

Targeted therapy

Tyrosine kinase inhibitors (TKIs)

VEGF

Read more about EGFR/estrogen interactions: role in bronchioalveolar carcinoma and gender differences in the efficacy of antiangiogenic therapy

Predictive blood-based markers of response to VEGF inhibitors in NSCLC

2011

Targeted Therapeutics Research Award

A Breath of Hope Lung Foundation

John V. Heymach, MD, PhD

University of Texas MD Anderson Cancer Center

Houston

David Carbone, MD, PhD

The Ohio State University

Columbus

Cancer cells make chemicals that attract blood vessels. This process is known as angiogenesis. Drugs that inhibit angiogenesis are already being used to treat lung cancer patients. Unfortunately, not all patients respond to angiogenesis inhibitors. Dr. John Heymach is studying what determines whether a patient will respond.

Research Summary

Drugs that target tumor blood vessels, such as bevacizumab and other inhibitors of the VEGF pathway, have improved survival in patients with advanced NSCLC, but only a subset of patients benefit significantly from the drugs while others experience no benefit or even life-threatening toxicities. Furthermore, almost all NSCLC tumors eventually become resistant to these treatments. There is therefore a critical unmet need for biomarkers to identify which patients will benefit from a VEGF inhibitor (predictive markers) and to understand how tumors become resistant to these agents. A major challenge for developing these markers is that tumor angiogenesis is promoted by circulating cytokines and angiogenic factors (CAFs) that may be produced by the tumor as well as the host. Therefore, it is likely that predictive markers for VEGF inhibitors may reflect both influences. For this reason, we hypothesize that by comprehensively profiling angiogenesis-related CAFs and other peptides in the blood, as well as germline variations in angiogenesis-related genes, predictive markers for identifying which patients benefit from VEGF inhibitors (alone or with chemotherapy) can be developed and validated. The PIs of this proposal have already conducted studies establishing three promising and potentially complementary approaches to identify predictive markers using blood samples: 1) multiplex CAF profiling; 2) proteomic analysis using mass spectroscopy (MALDI-TOF); and 3) a signature of single nucleotide polymorphisms (SNPs) in three angiogenesis genes. In this proposal, these three approaches will be tested using samples from completed clinical trials of VEGF inhibitors in NSCLC patients; the most promising markers will then be validated using samples from two independent randomized trials. These studies have the potential to significantly advance the treatment of NSCLC patients by identifying which patients are most likely to benefit from a VEGF inhibitor, and by sparing patients who are unlikely to benefit from these drugs. They can also provide critical insights into mechanisms of resistance that can guide future combination regimens.

Technical Abstract

Inhibitors of the VEGF pathway, including the VEGF antibody bevacizumab (BV) and multitargeted VEGFR tyrosine kinase inhibitors such as vandetanib, have in some cases improved progression-free survival (PFS) and/or overall survival (OS) in patients with advanced NSCLC. While benefits in the overall NSCLC population have thus far been modest, it is clear that a subset of patients have dramatic benefit, while others may experience no benefit or even life-threatening toxicities. Furthermore, virtually all patients who respond inevitably develop therapeutic resistance. Thus, the development of markers predictive of response or resistance for VEGF inhibitors is critically needed to advance NSCLC treatment. There are currently no validated predictive markers for VEGF inhibitors, and the development of such markers is made more challenging by the impact of both tumor- and host-derived circulating factors on tumor angiogenesis. Useful predictive markers will likely need to reflect factors from both sources. We hypothesize that by comprehensively profiling angiogenesis-related CAFs and other peptides in the blood, as well as germline variations in angiogenesis-related genes, non-invasive predictive markers for identifying which patients benefit from VEGF inhibitors (alone or with chemotherapy) can be developed and validated.

The investigators of this proposal have a longstanding collaboration to develop predictive markers for VEGF inhibitors and, along with other investigators, have identified three promising and potentially complementary approaches using blood-based markers that will be tested in this grant. We have also played leadership roles in major randomized clinical trials of VEGF inhibitors, which have enabled us to leverage a unique set of resources to address these questions.

In Aim 1, we will use multiplexed CAF profiling to identify high-priority candidate predictive markers for differential benefit from VEGF inhibitors with chemotherapy compared to chemotherapy alone using two independent sets of samples from randomized phase II trials: one testing bevacizumab (BV) with chemotherapy (pemetrexed/carboplatin or Pem/C) vs. Pem/C alone (BATTLE-FL) trial, and another testing the VEGFR/EGFR tyrosine kinase inhibitor vandetanib (VAN) plus carboplatin/paclitaxel (VCP) vs. CP, in first-line NSCLC trial. We will also test CAF markers of benefit for VAN vs. standard therapy with erlotinib using specimens from a recently completed randomized phase III trial (ZEST).

In Aim 2, we will use MALDI-TOF (matrix-assisted laser desorption/ionization time-of-flight) mass spectroscopy to develop a serum proteomic classifier for benefit for VEGF inhibitors, using samples from the same trials as in Aim 1. We previously used a similar approach to develop a serum proteomic marker of benefit (Veristrat) for EGFR inhibitors.

Finally, in Aim 3, we will validate a signature of SNPs from three angiogenesis-related genes that were found to be predictive of benefit for BV with CP (BCP) vs. CP in the ECOG4599 trial. This will be tested in the same three trials of VEGF inhibitors. It is worth noting that our interest is not in developing markers for a particular drug, but rather to identify markers and pathways relevant to predicting response or resistance to inhibitors of the VEGF pathway, a validated therapeutic target in NSCLC. Our data thus far suggest there will be overlap in markers for BV and VEGFR TKIs but it will be important to determine whether this is true, particularly as more potent and specific inhibitors are tested.

Impact. This project has the potential to address a critical unmet need in NSCLC by producing validated, non-invasive blood-based predictive markers for identifying patients more likely to benefit from VEGF inhibitors, and can provide critical insights into mechanisms of resistance to guide future combination regimens.

Key words

Angiogenesis inhibitors

Biomarker or biomarker testing

Chemotherapy

Liquid biopsy

Molecular profile or molecular testing

Mutation profile

Non-small cell lung cancer (NSCLC)

Targeted therapy

Tyrosine kinase inhibitors (TKIs)

VEGF