Structure-Function–Based Classification System Could Refine TKI Selection for Atypical EGFR-Mutant NSCLC Subsets

April 20, 2026 | Courtney Flaherty

Classifying EGFR mutations into molecular subgroups according to structure and function further refines diagnosis and is critical for targeted treatment selection, particularly for patients with non–small cell lung cancer (NSCLC) harboring P-loop alpha-C helix compressing (PACC) mutations, which are less responsive to current TKIs, according to Jonathan W. Riess, MD, MS.

“By adopting this structure-based classification, we can utilize a nuanced treatment algorithm: either referring patients for clinical trials, considering afatinib [Gilotrif], or perhaps adding chemotherapy to an osimertinib[-based regimen] to cover our bases, since these mutations may not perform as well with osimertinib [Tagrisso] monotherapy,” Riess said in an interview with OncLive® regarding his presentation at the 2026 IASLC 2026 Targeted Therapies of Lung Cancer Meeting.

In addition to outlining the argument for structure–function-based classification of EGFR mutations, Riess discussed mechanisms of TKI underperformance in EGFR PACC–mutant disease, key data with furmonertinib (AST2818) monotherapy from the phase 1 FURTHER trial (NCT05364073), and the ways in which treatment sequencing may evolve with continued drug development to target these atypical alterations.

Riess is the medical director of Thoracic Oncology and an associate professor of medicine in the Division of Hematology & Oncology at the University of California Davis Comprehensive Cancer Center in Sacramento.

Existing TKIs demonstrate limited and variable activity against PACC mutations. What is the mechanistic explanation for why certain agents underperform in the PACC space, and does that inform which new agents are most rationally designed?

For EGFR PACC mutations, the structure of the receptor is changed. This change impacts drug binding, either directly or indirectly, via displacement of the P-loop and/or alpha-C helix. This structural shift impacts how currently approved EGFR TKIs, such as osimertinib, bind to the receptor. Therefore, other drugs designed to bind better to these specific structural changes may prove to be more effective.

How does furmonertinib monotherapy compare with current standard approaches in EGFR PACC-mutated NSCLC per data from the FURTHER trial, and what aspects of the data are most practice-informing?

Furmonertinib is an EGFR TKI already approved in China for classical [EGFR] mutations and T790M. However, it was found that increasing the dose potential increased activity against PACC mutations. The FURTHER study looked at 2 dose levels [of furmonertinib]: 160 mg and 240 mg.1 They found response rates were higher at the 240-mg daily dose, with a best overall response rate [(ORR) by blinded independent central review] of [81.8% (n = 22; 95% CI, 59.7%-94.8%)] and a [median] PFS of 16.1 months.^1,2

This [median] PFS is numerically better than what previous studies reported with osimertinib or afatinib for these PACC mutations. It is now being studied in a randomized, global phase 3 study called ALPACCA [FURMO-006; NCT07185997].2 This trial is [randomly assigning] patients with advanced metastatic EGFR PACC-mutated NSCLC to furmonertinib at 240 mg vs investigator’s choice of osimertinib or afatinib. This highlights that there is currently no clear standard of care for these patients. The primary end points are ORR for the interim analysis and PFS for the final analysis.

In your experience, how often are EGFR PACC mutations missed or misclassified by standard next-generation sequencing (NGS) panels, and what guidance would you give to community oncologists?

With NGS, we are now able to pick up these mutations. Back when I started my fellowship, tests were often PCR-based and did not detect the broad heterogeneity of these uncommon EGFR mutations, but NGS is very effective at picking them up.

The biggest pitfall I see is taking circulating tumor DNA [ctDNA] results as gospel when they are negative. If a liquid biopsy is positive, it is usually a true positive, but if it is negative, it may simply reflect a lack of shed tumor DNA in the blood. In those cases, you really want to have tissue results, particularly for a patient who fits the characteristics of having an oncogene driver mutation, such as a non-smoker.

When a patient presents with a compound PACC mutation, how does that layer of complexity change your risk stratification and treatment selection?

For compound EGFR PACC mutations, we generally follow the treatment algorithm for PACC-mutated lung cancer. Sometimes they are associated with a common EGFR mutation, which means you could potentially treat them with osimertinib as you would a classical-like mutation.

However, a compound mutation would likely be a signal for treatment intensification. Now that we have intensified regimens, I would consider the [phase 3] FLAURA2 [NCT04035486] regimen [of osimertinib plus chemotherapy], which would be on-label for that indication. I would also consider the [phase 3] MARIPOSA [NCT04988295] regimen [comprising amivantamab-vmjw (Rybrevant) and lazertinib (Lazcluze)], which has shown both a PFS and an overall survival benefit compared with osimertinib alone. Additionally, if the patient is eligible for ongoing trials like ALPACCA, that would be a good choice.

How do you envision the sequencing algorithm for PACC-mutated patients evolving over the next 3 to 5 years, and what is the most critical unanswered question?

We have a number of exciting drugs in this space now after it was neglected for a long time. [Beyond furmonertinib], we have a number of exciting drugs that, either preclinically or clinically, have shown activity, such as BH30643. [We also have] osimertinib, which has some data in EGFR PACC–mutated NSCLC with promising early activity. There are also zipalertinib [CLN-081/TAS6417] and sunvozertinib [Zegfrovy], some of which are also being developed for EGFR exon 20 insertions. We have to see how the data evolve and how the efficacy comes out in these studies as we get more patients to determine how they will shake out in terms of optimal sequencing. Ideally, we would want a TKI-first approach, but we need to do the studies to see where they fit into [the treatment paradigm].

In general, when we look at the components of a successful EGFR PACC-mutant targeted therapy, we want to have activity against a wide spectrum of EGFR PACC mutations. We want to overcome anticipated resistance mechanisms such as T790M. We want to be as much EGFR wild-type sparing as possible for manageable toxicity, and we want central nervous system activity because that is an important sanctuary site of recurrence or persistence in EGFR-mutated lung cancer. TKIs that fit the bill on these will have the promise to eventually become first-line treatments, but we need to do the clinical studies to find the answers in patients.

References

1. Results from the FURTHER Trial demonstrate firmonertinib is a promising potential therapy for patients with NSCLC with EGFR PACC mutations. News Release. IASLC. September 9, 2024. Accessed April 20, 2026. https://www.iaslc.org/iaslc-news/press-release/results-further-trial-demonstrate-firmonertinib-promising-potential
2. ArriVent announces first patient dosed in global pivotal phase 3 ALPACCA trial evaluating firmonertinib for first-line treatment of EGFR PACC mutant non-small cell lung cancer. News Release. ArriVent. December 22, 2025. Accessed April 20, 2026. https://ir.arrivent.com/news-releases/news-release-details/arrivent-announces-first-patient-dosed-global-pivotal-phase-3