Personalizing Treatment for Atypical EGFR-Mutated NSCLC

Atypical EGFR mutations represent a diverse and clinically significant subset of non–small cell lung cancer (NSCLC), requiring nuanced therapeutic strategies, as highlighted in a presentation at the 26th Annual International Lung Cancer Congress, by Sukhmani K. Padda, MD, assistant professor and Vice Chair of Medical Oncology at Fox Chase Cancer Center at Temple University Hospital in Philadelphia, Pennslyvania.1

During her presentation, Padda discussed the structure–function-based classification of EGFR mutations and highlighted the ways in which evolving treatment paradigms are tailoring treatment to target these atypical alterations.

“As the field grows more complex, structure–function-based classification is likely to play an increasingly central role in optimizing treatment selection and improving patient outcomes,"‌ Padda noted in her presentation.

Defining Atypical EGFR Mutations

Atypical or uncommon EGFR mutations are defined as those outside the classical exon 19 deletions and exon 21 L858R substitutions, accounting for approximately 30% of EGFR-mutant NSCLC cases. “Nine percent of those are exon 20 insertions, but an additional 13% are atypical mutations, and another 9% are complex atypical mutations, meaning there are multiple atypical mutations present,” Padda explained.

Most atypical mutations occur in exon 18 and exon 20, frequently within critical structural regions such as the phosphate-binding loop (P-loop) and αC-helix. These areas contribute to what is termed “PAC” (P-loop/αC-helix compressing) mutations, which are believed to alter protein conformation and impair drug binding, Padda explains.

Structure–Function-Based Classification

In a 2021 paper published in Nature, Roubichaux et al introduced a structure–function-based framework that classifies EGFR mutations into groups based on their predicted impact on tyrosine kinase structure and drug affinity. These include PAC mutations, T790M-like mutations, and exon 20 insertions.

“This is where the structure–function-based classification becomes important,” Padda emphasized. “These mutations are predicted to change the orientation of the P-loop and αC-helix, which can impact drug binding.” Common PAC mutations include G719X, S768I, and L861Q, even though L861Q is sometimes considered classical-like in clinical behavior.

Optimizing EGFR TKI Selection in the Frontline Setting

Identifying the optimal EGFR TKI for atypical mutations remains a central challenge. Preclinical data and real-world observations suggest that second-generation TKIs such as afatinib (Gilotrif) may offer greater activity against PAC mutations compared with third-generation TKIs such as osimertinib (Tagrisso). “Afatinib relies less on interaction with the P-loop, whose orientation is altered in PAC mutations, compared with osimertinib,” Padda noted.

Evidence from the combined post hoc analysis of the phase 2 LUX-Lung 2 (NCT00525148), phase 3 LUX-Lung 3 (NCT00949650), and phase 3 LUX-Lung 6 (NCT01121393) trials showed that afatinib conferred a 71.1% (95% CI, 54.1%-84.6%) objective response rate (ORR) in patients with atypical mutations, with a median progression-free survival (PFS) of 10.7 months (95% CI, 5.6-14.7) and median overall survival (OS) of 19.4 months (95% CI, 16.4-26.9).3 Subset data revealed favorable outcomes for Gly719Xaa (n = 18; ORR 77.8%, median PFS 13.8 months), Ser768Il1 (n = 8; ORR 100%, median PFS 14.7 months), and Leu861Gln (n = 16; ORR 56.3%, median PFS 8.2 months).

In contrast, osimertinib has demonstrated modest activity in this population across multiple phase II trials.4 In the Korean KCSG-LU15-09 study (NCT03433469), osimertinib yielded an ORR of 50% (95% CI, 33%-67%) and a median PFS of 8.2 months (95% CI, 5.9-10.5) in EGFR TKI–naive patients. Similarly, in the Japanese phase 2 UNICORN study (NCT03410043), the median PFS was 9.4 months (95% CI, 3.7-15.2), with compound atypical mutations associated with superior outcomes compared to solitary atypical mutations. A third US-based phase 2 trial (NCT03810807) was terminated early due to limited accrual.

“This raises the question of whether some PAC mutations may be inherently resistant to third-generation TKIs,” Padda observed. Indeed, L861Q, despite being a PAC mutation—showed relatively better responses to osimertinib, likely due to its hybrid structural features, Padda suggests.

The Significance of Compound Mutations

Approximately 9% of EGFR-mutant NSCLC cases harbor compound atypical mutations, which may include two or more uncommon mutations or combinations of classical and atypical mutations. Padda highlighted that “compound atypical mutations demonstrated higher response rates than solitary atypical mutations,” and added that these alterations often exhibit a tobacco-associated mutational signature.

Data suggest that compound atypical mutations perform better across all EGFR TKI generations, including afatinib. Outcomes with osimertinib and first-generation agents have also been favorable in compound mutation subgroups, though direct comparisons are limited by heterogeneous trial designs and mutation profiles, Padda notes.

Investigational Approaches Beyond EGFR TKIs

In cases where TKI therapy is insufficient or resistance emerges, novel agents targeting atypical mutations are gaining traction. Amivantamab (Rybrevant), an EGFR-MET bispecific antibody, is being studied in combination with lazertinib (Leclaza) in the phase 1/1b CHRYSALIS-2 trial (NCT04077463).5 In Cohort C (n = 49), which enrolled patients with G719X, L861Q, and S768I mutations—excluding those with classical EGFR alterations—the ORR was 57% (95% CI, 42%-71%), the median duration of response was 20.7 months (95% CI, 9.9-not evaluable), and the median PFS was 19.5 months (95% CI, 11.2-NE). Notably, 47% of patients were treatment naive, and 40% had prior exposure to afatinib.

Another promising therapy is furmonertinib (Alflutinib), an investigational third-generation EGFR TKI evaluated in the phase 1b FURTHER trial (NCT05364073). Among first-line patients with PAC mutations treated with 240-mg daily, the confirmed ORR was 63.6% (95% CI, 40.7%-82.8%), with a best ORR of 81.8% (95% CI, 59.7%-94.8%). CNS activity was also observed. The safety profile was manageable; common adverse effects included diarrhea, elevated liver enzymes, rash, stomatitis, and skin/nail toxicities.

Additional structure-specific TKIs in development include sunvozertinib (DZD9008) and MRG003, which may offer further treatment options tailored to individual EGFR mutation profiles.

Persisting Challenges

Despite these advances, several barriers remain. Many commercial next-generation sequencing platforms fail to detect all atypical mutations, contributing to diagnostic gaps. Atypical EGFR mutations also remain underrepresented in clinical trials, and mutation-specific variability in drug sensitivity creates uncertainty in treatment selection.

“Afatinib is active in atypical PAC EGFR mutations and appears to be preferred over osimertinib in this subset,” Padda concluded. “Emerging strategies, including amivantamab and furmonertinib are beginning to address therapeutic gaps in this space. As the field grows more complex, structure–function-based classification is likely to play an increasingly central role in optimizing treatment selection and improving patient outcomes.”

References

1. Padda SK. Atypical EGFR mutations in NSCLC. Presented at: 26th Annual International Lung Cancer Congress; July 25-27, 2025; Huntington Beach, CA.
2. Robichaux JP, Le X, Vijayan RSK, et al. Structure-based classification predicts drug response in EGFR-mutant NSCLC. Nature. 2021;597(7878):732-737. doi:10.1038/s41586-021-03898-1
3. Yang JC-H, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015;16(7):830-838. doi:10.1016/s1470-2045(15)00026-1
4. Okuma Y, Kubota K, Shimokawa M, et al. First-line osimertinib for previously untreated patients with NSCLC and uncommon EGFR mutations. JAMA Oncology. 2024;10(1):43. doi:10.1001/jamaoncol.2023.5013
5. Cho BC, Wang Y, Felip E, et al. Amivantamab plus lazertinib in atypical EGFR-mutated advanced non-small cell lung cancer (NSCLC): results from CHRYSALIS-2. J Clin Oncol. 2024;42(suppl 16):8516. doi:10.1200/JCO.2024.42.16_suppl.8516