Structurally guided therapy shows promise for patients with specific EGFR-mutated lung cancer
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.
A Phase Ib trial of firmonertinib in patients with EGFR PACC-mutated non-small cell lung cancer (NSCLC) demonstrated durable antitumor activity, leading to an encouraging approach to selecting treatments based on the structural features of rare EGFR mutations. Researchers at The University of Texas MD Anderson Cancer Center found that patients treated with 160 mg or 240 mg daily of firmonertinib experienced a median progression-free survival of 11.1 months and 16 months, respectively.
This study, published in Cancer Cell, highlights the potential of understanding mutation structure to identify therapies better suited to a patient's cancer. PACC mutations, which account for about 12% of EGFR-mutant NSCLC, have historically lacked clear treatment guidance. In contrast to more common EGFR mutations, which are classified by their gene location, PACC mutations are grouped by how they alter the structure of the EGFR protein, potentially better predicting effective therapies.
Firmonertinib's unique chemical property allows it to bind more effectively to PACC-mutated EGFR proteins, resulting in potent antitumor effects. In preclinical models, firmonertinib showed tumor growth inhibition exceeding 90% across multiple PACC mutation subtypes in laboratory and patient-derived xenograft models. The global FURTHER trial, which enrolled 60 patients with advanced EGFR PACC-mutated NSCLC, reported objective response rates of 43% and 68% among untreated patients given 160 mg and 240 mg daily, respectively.
Responses were observed across various PACC mutation subtypes, and circulating tumor DNA (ctDNA) clearance was associated with better outcomes. Patients with ctDNA clearance had higher response rates and longer progression-free survival. Additionally, firmonertinib showed promising results in patients with brain metastases, with 47% experiencing tumor shrinkage and 41% achieving complete responses.
These findings support further development of structure-guided treatment strategies for uncommon EGFR mutations, prompting the launch of the global Phase III ALPACCA trial to evaluate firmonertinib against osimertinib or afatinib as a first-line treatment for advanced EGFR PACC-mutated NSCLC.
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