Structurally Guided Therapy Shows Promise for Patients With Specific EGFR-Mutated Lung Cancer in Phase 1b Trial

For patients with EGFR PACC-mutated non-small cell lung cancer (NSCLC), the targeted therapy firmonertinib achieved durable antitumor activity in a Phase 1b 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 Phase 1b FURTHER trial, published today 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.”

How Could the Structure of a Mutation Help Guide Treatment Decisions?

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.

How Effective was Firmonertinib in Treating PACC-Mutated NSCLC?

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 Phase 1b 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 3 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.

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This study was funded by ArriVent BioPharma, Inc. For a full list of collaborating authors, disclosures and funding sources, see the full paper in Cancer Cell.

"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."

Xiuning Le, M.D., Ph.D.

Thoracic/Head and Neck Medical Oncology