Since the first EGFR-targeted TKI approval more than two decades ago, the field has gained a deeper understanding of the spectrum of EGFR alterations and the biology of EGFR-altered lung cancer. As a result, targeted therapies for EGFR-altered lung cancer have become progressively refined.
During the second of two Presidential Symposia at the 2024 World Conference on Lung Cancer, David Planchard, MD, Thoracic Oncologist and Head of the Thoracic Pathology Committee at Institut Gustave Roussy, Villejuif, France, shared new data on the efficacy and safety of furmonertinib, an oral, brain-penetrant, EGFR TKI, from the FURTHER trial.
Discussant Alfredo Addeo, MD, Senior Oncologist, University Hospital Geneva, Switzerland, framed the study context, stating, “When we are talking about EGFR mutation, we are talking about multiple entities, not a single one.”
Broadly, there are two major types of EGFR alterations in lung cancer. “Classical” EGFR mutations include the most common alterations (such as exon 19 deletions) and account for more than two-thirds of EGFR-mutated NSCLC. “Atypical” mutations include less common changes, such as those impacting the P-loop αC-helix compression (PACC) region of the EGFR protein.
Although less frequent, PACC mutations are clinically significant.
“Currently, the real-world data show that we do not have a broadly utilized standard of care in the first line for the population with PACC mutations,” Dr. Planchard said. He explained that PACC mutations, which account for about 12% of all EGFR mutations in NSCLC, narrow the drug-binding pocket, thereby reducing the sensitivity of cancer cells to EGFR TKIs.
Furmonertinib and its major metabolite AST5902 are both active against EGFR PACC mutations, making this an attractive agent for further development in patients with PACC-mutant positive NSCLC. While furmonertinib recently gained US Food and Drug Administration Breakthrough Therapy Designation for the treatment of patients with advanced NSCLC with EGFR exon 20 insertion mutations, the FURTHER trial is the first to evaluate this drug exclusively in EGFR TKI-naïve patients with locally advanced or metastatic NSCLC with EGFR PACC mutations.
Patients were randomized 1:1 to receive 160 mg or 240 mg furmonertinib; the study included previously untreated patients and those who received only non-EGFR–targeted therapies.
Furmonertinib demonstrated efficacy at both dose levels (confirmed overall response rate [ORR,] 35% and 64% with 160 mg and 240 mg, respectively). Moreover, furmonertinib yielded responses in patients with a wide range of PACC mutations, including those with single and compound PACC (multiple PACC mutations or a PACC mutation co-occurring with a classical mutation) profiles. Half of the patients in the study had compound mutations.
Dr. Planchard said that longer follow-up is ongoing and the data for median duration of response, progression-free survival, and overall survival are not yet mature.
Additionally, patients with asymptomatic brain metastases were included in this trial. About 30% of patients in all dose/prior treatment subgroups had brain metastases. The confirmed CNS ORRs were 56%, 43%, and 46% in the 160-mg, 240-mg, and treatment-naive PACC cohort, respectively.
Overall, the safety profile of furmonertinib was acceptable and manageable, with no grade 4–5 treatment-related adverse events. However, Dr. Addeo noted that while the drug is definitely active, it does cause some toxicity. He cautioned against dismissing the gastrointestinal toxicity as acceptable, as grade 3 diarrhea (seen in 10% of patients with the 240-mg dose) is defined by ≥7 stools per day, which can be disruptive to daily living activities.
In addition to commentary from Dr. Addeo, the audience also heard perspectives from Presidential Symposium participants on preclinical studies of compound PACC mutations and the importance of next-generation sequencing to detect PACC mutations.
Dr. Planchard concluded, “We need to have these types of drugs, which are highly efficient against compound EGFR PACC mutations.”
