Editor’s Note: EGFR P-loop-aC helix compression (PACC) mutation is a recently identified subtype of EGFR mutations in non-small cell lung cancer (NSCLC), and its potential for precision therapy had not been clinically validated until now. At the 2024 World Conference on Lung Cancer (WCLC 2024), during the Presidential Symposium Presentation, the global phase Ib FURTHER trial's proof-of-concept results were revealed. Furmonertinib as monotherapy in first-line treatment of NSCLC patients with EGFR PACC mutations demonstrated outstanding efficacy and safety. Oncology Frontier  interviews the study’s principal investigator, Dr. Xiuning Le from the MD Anderson Cancer Center, to delve into how EGFR PACC mutations moved from concept to clinic and how Furmonertinib is pioneering targeted therapy for this subtype of lung cancer.

01 In pursuit of precision medicine, a 2021 Nature article titled “Structure-based classification predicts drug response in EGFR-mutant NSCLC” introduced a classification system based on the EGFR kinase domain. One of the novel subtypes introduced was the PACC mutation, which accounts for 12% of known EGFR mutations. As one of the lead authors of this article, could you walk us through the discovery and definition of EGFR PACC mutations? Based on your clinical experience, what are the current treatment options and unmet needs for EGFR PACC-mutant NSCLC?

Dr. Xiuning Le: PACC is a subtype within the EGFR kinase domain classification. As clinicians, we conducted many NGS (next-generation sequencing) tests between 2019 and 2021, discovering that EGFR mutations in lung cancer had become more complex. Unlike PCR (polymerase chain reaction) tests, NGS can detect rare mutations across a broader spectrum, beyond common mutations like exon 19 deletions (19Del) or exon 21 point mutations (21 L858R). In clinical practice, we frequently encounter patients with these rare EGFR mutations.

Our team, led by Professor John V. Heymach, collaborated across multiple disciplines, bringing together experts in biochemistry, clinical science, and more. We categorized EGFR mutations and analyzed their structure-function relationships to better guide precision treatment.

From our analysis of 16,715 EGFR-mutant NSCLC cases, we classified four distinct subtypes: classical mutations, T790M-like mutations, exon 20 insertions, and PACC mutations. Unlike classical mutations, which occur far from the ATP binding pocket, PACC mutations are located on the inner surface of the ATP pocket or at the C-terminal end of the αC helix. This means their structure becomes smaller and narrower, requiring new drugs to effectively target them.

Overall, the purpose of our 2021 article was to address clinical needs. Since its publication, we’ve received a lot of positive feedback. Our study marks an important milestone for drug development and classification, offering valuable insights for future research and patient care.

02 The FURTHER study evaluated two dosing regimens of Furmonertinib for first-line treatment of advanced NSCLC patients with EGFR PACC mutations. During WCLC, the interim analysis data was presented. How do you assess these results? Which data points impressed you the most?

Dr. Xiuning Le: The FURTHER study consists of multiple cohorts. The WCLC data focused on Cohort 4, which evaluated NSCLC patients with EGFR PACC mutations treated with Furmonertinib monotherapy. When we first proposed the four EGFR mutation subtypes, PACC mutations were still unfamiliar. For this reason, we designed a cohort specifically for EGFR PACC-mutant patients, enrolling 60 patients who were divided into two dosing groups: 160 mg once daily (qd) and 240 mg qd.

The data we presented showed that the 240 mg qd group achieved a confirmed objective response rate (cORR) of 63.6%, with a disease control rate (DCR) of 100%. These results are incredibly exciting. Interestingly, the 160 mg qd dose was also effective, with a cORR of 34.8%. The waterfall plot presented at the conference demonstrated significant tumor shrinkage in both dosing groups.

While we focus on efficacy, we must also consider side effects. In the FURTHER study, the adverse events (AEs) for Furmonertinib at 240 mg were consistent with what we already know about the drug. The main side effects were diarrhea and rash, but most were mild (grade 1-2) and manageable. I’ve been involved in many studies on EGFR TKIs (tyrosine kinase inhibitors), and compared to other drugs, Furmonertinib’s safety profile stands out, allowing for easier management of side effects in clinical practice.

03 How do you think the FURTHER study data presented at WCLC will impact clinical practice? What opportunities and challenges do you foresee for treating advanced NSCLC with EGFR PACC mutations?

Dr. Xiuning Le: The FURTHER study’s inclusion in WCLC’s Presidential Symposium reflects both the impressive data and the significance of the research itself. EGFR PACC mutations are a novel concept, and many physicians and patients are still unfamiliar with them. No prospective studies had previously explored solutions for EGFR PACC-mutant NSCLC patients. Thus, I see FURTHER as a milestone, pioneering precision therapy for this subtype of lung cancer.

Looking ahead, EGFR PACC-mutant lung cancer could become a new classification in precision medicine. Regulatory bodies such as the FDA and China’s NMPA may recognize EGFR PACC-mutant lung cancer as a distinct disease subtype, attracting significant attention from pharmaceutical companies. This development is crucial for these patients, as it means there could be more novel therapies that provide better clinical outcomes.

04 After gaining approvals for classical mutations, T790M mutations, and breakthrough designation for exon 20 insertions, Furmonertinib is now making strong inroads into PACC mutations. Could you reflect on the classic studies of Furmonertinib and share your expectations for its clinical applications?

Dr. Xiuning Le: Furmonertinib is a third-generation EGFR TKI developed in China. Its clinical studies show similar efficacy to other third-generation TKIs. In the phase III FURLONG trial, Furmonertinib achieved a median progression-free survival (PFS) of 20.8 months in the first-line treatment of EGFR-sensitive NSCLC, which is outstanding. The drug is already widely used in China, and it offers patients great convenience.

Furmonertinib’s future development holds great promise. In addition to the approved indications, we’re expanding into other areas, including EGFR PACC mutations. At the 2023 WCLC, Professor Bao-Hui Han presented a study showing that a triple dose of Furmonertinib (240 mg qd) in first-line treatment of EGFR ex20ins lung cancer yielded excellent results. The FDA granted breakthrough therapy designation based on these findings.

In the FURTHER study, we also saw Furmonertinib’s promising efficacy and safety in EGFR PACC mutations. Currently, a global, multicenter phase III clinical trial is underway for Furmonertinib as a first-line treatment for EGFR ex20ins lung cancer. I hope future research will continue to focus on EGFR PACC mutations, leading to large-scale international phase III trials that provide higher-level evidence for Furmonertinib in treating NSCLC with these mutations.

Dr. Xiuning Le

• Holds dual PhDs in Medicine and Science
• Graduated from Peking Union Medical College
• Currently works in the Department of Thoracic/Head & Neck Medical Oncology at MD Anderson Cancer Center
• Serves as the national lead investigator for multiple large-scale clinical trials
• Research focuses on cancer genomics and precision medicine, primarily studying EGFR and MET ex14 lung cancer and immunotherapy
• Has presented at international conferences such as AACR, ASCO, and WCLC
• Published numerous articles in journals such as New England Journal of Medicine, Cancer Discovery, and Cancer Cell