Structurally guided therapy shows promise for patients with specific EGFR-mutated lung cancer

by University of Texas MD Anderson Cancer Center

edited by Sadie Harley, reviewed by Alexander Pol

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For patients with EGFR PACC-mutated non-small cell lung cancer (NSCLC), the targeted therapy firmonertinib achieved durable antitumor activity in a Phase Ib trial led by researchers at The University of Texas MD Anderson Cancer Center, supporting an approach to selecting treatments based on the structural features of uncommon EGFR mutations.

Results from the FURTHER trial, published in Cancer Cell, revealed that patients receiving 160 mg or 240 mg daily lived a median of 11.1 months and 16 months without their disease worsening (progression-free survival), respectively. The trial was led by Xiuning Le, M.D., Ph.D., associate professor of Thoracic/Head and Neck Medical Oncology.

"Patients with uncommon EGFR mutations have long faced limited evidence to guide treatment decisions," Le said. "The responses we observed with firmonertinib in patients with EGFR PACC mutations are encouraging and suggest that understanding mutation structure may help identify therapies better matched to a patient's cancer."

PACC mutations are a structurally distinct subgroup of EGFR mutations that account for approximately 12% of EGFR-mutant NSCLC, yet treatment responses can differ from those seen with more common EGFR mutations.

Rather than classifying uncommon EGFR mutations only by their location within the gene, researchers have proposed grouping them by how they change the structure of the EGFR protein, which may better predict which therapies will be effective. Building on that work, this study found that a unique chemical feature of firmonertinib enables it to bind more effectively to PACC-mutant EGFR proteins.

In preclinical models, firmonertinib demonstrated potent antitumor effects across multiple PACC mutation subtypes, producing tumor growth inhibition that frequently exceeded 90% in laboratory and patient-derived xenograft models.

The global FURTHER trial enrolled 60 patients with advanced EGFR PACC-mutated NSCLC. Among previously untreated patients, objective response rates were 43% with 160 mg daily and 68% with 240 mg daily. Responses were observed across multiple PACC mutation subtypes, including both single and compound mutations.

Researchers also evaluated circulating tumor DNA (ctDNA)—fragments of tumor-derived DNA found in the bloodstream—which can provide a noninvasive way to monitor treatment response.

Among evaluable patients, 80% achieved complete clearance of EGFR PACC mutations from their blood after treatment. Patients with ctDNA clearance generally experienced higher response rates and longer progression-free survival, highlighting the potential of ctDNA dynamics to help predict which patients might derive the greatest benefit from therapy.

Firmonertinib also showed encouraging results in patients whose cancer had spread to the brain, a common complication of EGFR-mutated lung cancer, including those whose brain lesions had not previously been treated with radiation therapy. Among 17 patients with brain metastases at the start of treatment, 47% experienced tumor shrinkage in the brain, with 41% achieving complete responses.

What's next for this approach?

The findings support continued development of structure-guided treatment strategies for uncommon EGFR mutations. The results of this study prompted the launch of the global Phase III ALPACCA trial, which evaluates firmonertinib against osimertinib or afatinib as a first-line treatment for patients with advanced EGFR PACC-mutated NSCLC.

Future studies will continue investigating ctDNA as a potential biomarker of treatment response, with the goal of determining whether ctDNA dynamics can help monitor outcomes and inform future treatment decisions.

Publication details

Firmonertinib in Advanced Non-Small Cell Lung Cancer with Epidermal Growth Factor Receptor P-Loop and αC-Helix Compressing Mutations, Cancer Cell (2026). DOI: 10.1016/j.ccell.2026.09.011. www.cell.com/cancer-cell/fullt … 1535-6108(26)00430-7

Journal information: Cancer Cell

Key medical concepts

Progression-Free SurvivalCirculating Tumor DNA

Clinical categories

Oncology Provided by University of Texas MD Anderson Cancer Center Who's behind this story?

Sadie Harley

BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries. Full profile →

Alexander Pol

PhD nano-engineering from Delft University. Published researcher and journal reviewer. Brings scientific insight to content standards. Full profile →

Citation: Structurally guided therapy shows promise for patients with specific EGFR-mutated lung cancer (2026, October 16) retrieved 18 October 2026 from https://medicalxpress.com/news/2026-10-therapy-patients-specific-egfr-mutated.html This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.