Firmonertinib Shows Responses in Lung Cancer With EGFR PACC Mutations

Firmonertinib, an oral targeted therapy, shrank tumors in many patients with advanced non-small cell lung cancer (NSCLC) driven by uncommon EGFR mutations known as PACC mutations. The results come from the phase 1b FURTHER trial, published in Cancer Cell. Most patients received the drug as their first treatment for advanced disease.

EGFR (epidermal growth factor receptor) is a protein that helps cells grow. PACC (P-loop and alpha C-helix compressing) mutations change the shape of the pocket on the EGFR protein where targeted drugs attach. The change can make standard EGFR-blocking drugs work less well. PACC mutations make up an estimated 12% of EGFR mutations. The most common include G719X, S768I and E709X. Treatment guidelines include osimertinib and afatinib, two EGFR-blocking pills, for some PACC mutations, although the researchers noted that supporting data are limited.

“Results support further study of first-line firmonertinib in patients with EGFR PACC-mutant [non-small cell lung cancer],” the researchers wrote in the study, “Firmonertinib in advanced non-small cell lung cancer with epidermal growth factor receptor P-loop and αC-helix compressing mutations.”

How well did firmonertinib work for EGFR PACC-mutant lung cancer in the FURTHER trial?

The trial’s primary end point (main measure of success) was confirmed objective response rate. The response rate is the share of patients whose tumors shrank by a set amount or disappeared, with a later scan confirming the result. Outside reviewers who did not know which dose each patient received read the scans.

Among patients who received firmonertinib as a first treatment, 43% of those taking 160 milligrams once daily had a confirmed response. The response rate was 68% for those taking 240 milligrams once daily. On average, tumors shrank by 38.4% in the lower-dose group and 55.3% in the higher-dose group. Many patients had tumor shrinkage by their first scan.

Median progression-free survival (how long patients lived without their cancer growing or spreading) was 11.1 months at the lower dose and 16 months at the higher dose. Patients on the higher dose had a 17% lower risk of cancer growth or death than patients on the lower dose. However, the difference between doses may have been due to chance.

Responses lasted a median of 14.6 months at the higher dose. At the lower dose, the median length of response had not been reached. More than half of the patients who responded were still responding when researchers analyzed the data.

Responses occurred across mutation types. Among patients with compound mutations (more than one EGFR mutation), 64% (7 of 11 patients) at the lower dose and 75% (9 of 12 patients) at the higher dose responded. Among patients with a single PACC mutation, response rates were 25% (3 of 12 patients) and 60% (6 of 10 patients), respectively. Among patients who had received earlier treatment, 20% (1 of 5 patients) at the lower dose and 43% (3 of 7 patients) at the higher dose responded.

“These FURTHER trial results show promise with a distinct [targeted therapy] in patients with EGFR PACC-mutant [non-small cell lung cancer], who have a high unmet medical need,” the researchers said.

Did firmonertinib work in EGFR PACC-mutant lung cancer that spread to the brain?

Seventeen patients had cancer in the brain without symptoms when they joined the trial. Brain tumors responded in 47% (8 patients). In 41% (7 patients), the brain tumors disappeared on scans.

What did blood tests show in patients taking firmonertinib in the FURTHER trial?

Researchers tracked circulating tumor DNA (ctDNA), which consists of small pieces of tumor DNA found in the blood. Twenty-five patients had a PACC mutation detected in their blood at the start of treatment and a second sample at six weeks. Of these patients, 80% (20 patients) no longer had a detectable PACC mutation at six weeks.

Patients whose blood cleared had a response rate of 70%, compared with 20% for patients whose blood did not clear. Median progression-free survival, measured from the six-week mark, was 15.1 months for patients whose blood cleared and 3 months for those whose blood did not. The researchers noted that larger studies are needed to confirm whether blood testing can predict how patients will do.

Who took part in the FURTHER trial of firmonertinib?

FURTHER enrolled patients with advanced lung cancer at 40 sites in 10 countries. In the PACC group, patients who had not taken an EGFR-blocking pill were randomly assigned (chosen by chance) to receive 160 or 240 milligrams of firmonertinib once a day. Every patient in the PACC group received firmonertinib, so the trial did not compare the drug with a different treatment.

The median age was 65 in the lower-dose group and 68 in the higher-dose group. Of the patients in the PACC group, 75% had not received earlier drug treatment for advanced cancer. Median follow-up was 16.5 months.

Firmonertinib, also known as furmonertinib, is approved in China for other types of EGFR mutations. In lab studies, a part of the firmonertinib molecule that is unique to the drug gave it extra points of contact with PACC-mutated EGFR compared with osimertinib. The researchers linked the extra contact points to stronger activity against PACC mutations in cell and animal models.

ArriVent BioPharma and Shanghai Allist Pharmaceuticals sponsored the trial.

What are the side effects of firmonertinib for EGFR PACC-mutant lung cancer?

In the PACC group, 90% of patients at the lower dose and 97% at the higher dose had at least one side effect related to treatment. Side effects that were grade 3 or higher (severe or worse) occurred in 26% and 21% of patients, respectively.

Diarrhea was the most common side effect (42% and 72%). Severe diarrhea occurred in 6% and 10% of patients. Other common side effects included higher liver enzyme levels on blood tests (29% and 52%), rash (19% and 31%) and mouth sores (19% and 21%).

Side effects led to dose reductions in 19% of patients at the lower dose and 24% at the higher dose. One patient in the lower-dose group stopped treatment because of diarrhea. No patients with PACC mutations developed pneumonitis (lung inflammation). Across all 158 patients in the trial, four cases of pneumonitis occurred, and each led to permanent discontinuation of treatment.

What comes next for firmonertinib in EGFR PACC-mutant lung cancer?

The researchers noted that small patient groups and a short follow-up period made it difficult to determine how specific mutations, other gene changes and factors such as smoking history affected results.

The higher dose produced higher response rates, deeper tumor shrinkage and longer progression-free survival than the lower dose, and side effects were similar. Based on these results, researchers selected 240 milligrams for the phase 3 ALPACCA trial. ALPACCA compares firmonertinib with the investigator’s choice of osimertinib or afatinib as a first treatment for patients with EGFR PACC-mutant NSCLC.

References

1. 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. Published November 9, 2026.

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