A targeted therapy guided by the structural features of uncommon EGFR mutations achieved durable responses in patients with a specific subtype of non-small cell lung cancer (NSCLC), according to Phase Ib trial results.
The FURTHER trial, published in Cancer Cell, evaluated firmonertinib in 60 patients with advanced EGFR PACC-mutated NSCLC. PACC mutations are a structurally distinct subgroup accounting for approximately 12% of EGFR-mutant lung cancers, yet treatment responses often differ from those seen with more common mutations.
Patients receiving 160 mg or 240 mg daily lived a median of 11.1 months and 16 months, respectively, without disease progression. Among previously untreated patients, objective response rates were 43% with the lower dose and 68% with the higher dose. Responses occurred across multiple PACC mutation subtypes, including both single and compound mutations.
Rather than classifying uncommon EGFR mutations solely by their gene location, researchers grouped them by how they alter the EGFR protein structure, which may better predict therapeutic effectiveness. A unique chemical feature of firmonertinib enables it to bind more effectively to PACC-mutant proteins.
The therapy also showed encouraging results in patients with brain metastases, a common complication of EGFR-mutated lung cancer. Among 17 patients with brain involvement, 47% experienced tumour shrinkage, with 41% achieving complete responses.
Researchers monitored circulating tumour DNA (ctDNA) as a noninvasive measure of treatment response. Among evaluable patients, 80% achieved complete clearance of EGFR PACC mutations from their blood, and those with ctDNA clearance generally experienced better outcomes.
These findings prompted the launch of the Phase III ALPACCA trial comparing firmonertinib against osimertinib or afatinib as first-line treatment for this patient population.
Source: Le X et al. 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
