# Therapeutic strategies against EGFR exon 20 mutant lung cancer

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $529,607

## Abstract

PROJECT SUMMARY
Approximately 10-12% of non-small cell lung cancer (NSCLC) patients with EGFR mutations harbor in-frame
mutations or insertions within exon 20 of EGFR. Unlike NSCLC patients bearing “typical” EGFR mutations
(L858R or exon 19 deletions), these patients with exon 20 mutations are highly resistant to FDA-approved first-
generation tyrosine kinase inhibitors (TKIs) such as erlotinib or gefitinib, with an objective response rate of
approximately 4-8% and a median PFS of 2 months; by comparison, first-generation TKIs lead to an objective
response rate of ~60% and a PFS of ~10 months in patients with typical EGFR mutations. The population
impacted by EGFR exon 20 mutations is sizable: approximately 2,000-3,000 patients per year in the US and
approximately 27,000 patients per year worldwide. Until recently, no treatment strategies had been identified
that were tailored for this patient population. We recently reported the results of a detailed structure-function
analysis and screening effort that led to the identification of the TKI poziotinib as a potent and clinically active
inhibitor of EGFR exon 20 mutant tumors. Based on our preclinical data we have conducted a phase II trial of
poziotinib. Initial results indicate high anti-tumor activity with best objective response of PR (partial response) in
55% of 44 evaluable patients. However, some patients do not initially respond to treatment (primary resistance)
and, for the patients who do respond initially, acquired resistance is a clinical challenge. Our goals are to
elucidate the mechanisms of primary and acquired resistance to poziotinib and other potential EGFR exon 20-
targeted therapies. We find that in preclinical models, primary resistance may be associated with size and
location of the specific insertion, with a greater distance of the insertion from the α-c-helix associated with a lower
sensitivity to poziotinib. Moreover, we have generated evidence from preclinical models and NSCLC patients
indicating that acquired resistance may be mediated through multiple mechanisms, some EGFR-dependent (e.g.
additional EGFR alterations) and others EGFR-independent (e.g. activation of alternate signal bypass
pathways). We hypothesize that a) the sensitivity of different exon 20 insertions/mutations to specific TKIs will
be dictated by the insertion size and location and treatment may be tailored based on this information; and b)
that acquired resistance occurs through both EGFR-dependent and independent mechanisms that can be
targeted. We will test these hypotheses through an integrative, multidisciplinary effort involving preclinical
studies, molecular modeling, and ongoing clinical studies. In Aim 1, we will investigate primary resistance and
the structure-function relationship between specific insertions and drug response; in Aim 2, we will investigate
the mechanisms of EGFR-dependent acquired resistance, and in Aim 3 we will investigate EGFR-independent
mechanisms. These studies will hel...

## Key facts

- **NIH application ID:** 10745273
- **Project number:** 5R01CA234183-05
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** John V. Heymach
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $529,607
- **Award type:** 5
- **Project period:** 2019-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10745273

## Citation

> US National Institutes of Health, RePORTER application 10745273, Therapeutic strategies against EGFR exon 20 mutant lung cancer (5R01CA234183-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10745273. Licensed CC0.

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