# Exploring biomarkers of clinical benefit to VEGFR inhibitor combined with PD-L1 inhibitor in recurrent/metastatic Adenoid Cystic Carcinoma

> **NIH NIH R03** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $162,000

## Abstract

Adenoid Cystic Carcinoma (ACC), the 2nd most common salivary gland tumor, is chemotherapy-refractory and
there is no standard of care treatment for patients with recurrent/metastatic (R/M) disease, highlighting a major
clinical unmet need. Vascular endothelial growth factor receptor (VEGFR) inhibitors are frequently used to treat
ACC, but render mostly disease stabilization. ACC is also resistant to single agent immune checkpoint inhibitors
(ICI), consistent with its low tumor mutational burden (TMB) and overall uninflamed tumor immune
microenvironment (TIME). To test if the immunomodulatory role of anti-VEGFR therapy can enhance ICI efficacy
and overcome resistance to VEGFR inhibitor monotherapy, we are conducting an investigator-initiated phase II
trial, where progressing R/M ACC patients receive axitinib (a VEGFR tyrosine kinase inhibitor) and avelumab
(anti-PD-L1 antibody). Study accrual has recently completed with 28 patients evaluable for the efficacy analysis.
Interim results revealed an overall response rate of 18% (5/28) per RECIST 1.1, which is superior over VEGFR
or ICI monotherapy, and a clinical benefit rate, defined as objective response or disease stability > 6 months, of
50%. Recently, we have conducted a comprehensive proteogenomic analysis of 54 ACC which revealed two
distinct subtypes ACC-I and ACC-II. ACC-I is enriched with NOTCH1 activating mutations and MYC
overexpression and is associated with poor prognosis while ACC-II exhibited upregulation of TP63 and receptor
tyrosine kinases and longer patient survival. Thus far, IHC tumor staining for P63/MYC is available for 22 of 28
trial patients; 12 are ACC-I and 10 are ACC-II demonstrating significant representation of both ACC molecular
subtypes. Computational analysis of RNA-seq data of our published cohort with 54 ACC suggested that the
ACC-I subtype has a distinct TIME with increased CD8 T cells, along with upregulation of immune suppressive
markers. On the basis of our intriguing data, we hypothesize 1) genomic heterogeneity is associated with
differential responses to axitinib/avelumab in R/M ACC, and 2) distinct ACC immune landscape and T cell
attributes are associated with the clinical outcomes of patients treated with axitinib/avelumab. We will test these
hypotheses leveraging the unique tumor tissue and blood from our trial with two aims: 1) Identify genetic
determinants of clinical benefit to axitinib and avelumab in ACC. Using the baseline tumors (n=28), we will
conduct whole exome sequencing (seq) and RNA-seq and assess if any specific gene alterations, TMB or gene
expression profile are associated with benefit. 2) Assess stroma and immunologic determinants of clinical benefit
to axitinib and avelumab in ACC. We will examine ACC TIME composition using imaging mass cytometry and
determine if the composition of the TIME correlates with clinical benefit. We will also assess tumor-associated
T-cell attributes via baseline tumors TCR-seq and circulated T-cell attributes ...

## Key facts

- **NIH application ID:** 10525029
- **Project number:** 1R03DE031333-01A1
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Renata Ferrarotto
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $162,000
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10525029

## Citation

> US National Institutes of Health, RePORTER application 10525029, Exploring biomarkers of clinical benefit to VEGFR inhibitor combined with PD-L1 inhibitor in recurrent/metastatic Adenoid Cystic Carcinoma (1R03DE031333-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10525029. Licensed CC0.

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