Targeted Therapies for NSCLC With Nonclassical EGFR Mutations Grow Increasingly Personalized

The variety of EGFR mutations that drive non–small cell lung cancer (NSCLC) development and progression necessitates the use of next-generation sequencing (NGS) to identify tumors’ individual mutational profiles, which may consist of nonclassical EGFR mutations that require unique treatment strategies, according to Christine M. Lovly, MD, PhD, FASCO.

“[Nonclassical] EGFR mutations are detected in a clinically significant cohort of patients with NSCLC,” Lovly said during a presentation at the 22nd Annual Winter Lung Cancer Conference®, an event held by Physicians’ Education Resource, LCC.1 Lovly is the Ingram Associate Professor of Cancer Research and an associate professor of medicine (hematology/oncology) in the Division of Hematology-Oncology at Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

Definitions and a Note on Nomenclature

Lovly began by explaining that she chooses to use the word “nonclassical” instead of “atypical” when discussing EGFR mutations as a patient-focused consideration, to hopefully alleviate some patient concerns about having these types of mutations.

She emphasized the utility of NGS, which sequences the entire EGFR gene sequence structure, to find mutations across the whole EGFR protein, including extracellular domain, transmembrane domain, kinase domain, and C-terminus mutations. Classical EGFR mutations, which comprise approximately 90% of all EGFR mutations, are exon 19 deletions (ex19del) and L858R mutations. All other EGFR mutations are nonclassical.

Some of the most common nonclassical EGFR mutations include those in G719, S768I L861Q, L747P, and E709. Compound nonclassical EGFR mutations, defined as 2 mutations on the same gene, can also occur. Tavernari, et al, divided nonclassical EGFR alterations into 5 categories: common uncommon point mutations, rare uncommon point mutations, uncommon/uncommon compound mutations, uncommon/common compound mutations, and uncommon deletions.2

Shifting From Nomenclature-Based Distinctions to Structure-Based Design

“Not all mutations in EGFR are the same,” Lovly emphasized.1

For instance, although osimertinib demonstrates survival advantages in patients with EGFR ex19del, those with L858R mutations do not experience the same level of benefit with the agent, she explained. Although both EGFR alterations are often treated the same in clinical practice, they are biochemically, structurally, and enzymatically unique, and thus should be targeted in different ways, Lovly highlighted.

Due to these differences, several research groups have proposed structure-based designation systems for EGFR mutations. EGFR mutations are typically classified based on prevalence (classical/common vs nonclassical/uncommon) and the mutation’s exon location. Conversely, structure-based classifications are based on the mutation’s location within the 3-dimensional structure of the EGF receptor, consider the shape of the protein, and may help predict a mutation’s sensitivity to varying agents.

Existing Treatment Options for Nonclassical EGFR Altered–NSCLC

The National Comprehensive Cancer Network guidelines have different treatment recommendations for patients with classical vs nonclassical EGFR mutations. Afatinib (Gilotrif) and osimertinib (Tagrisso) are both recommended for the treatment of patients with nonclassical EGFR mutations.3 Notably, afatinib is FDA approved for patients with NSCLC harboring EGFR S768I, L861Q, and G719X mutations.1 Osimertinib is not indicated for use in patients with nonclassical EGFR mutations.

The LUX-Lung studies included cohorts of patients with NSCLC harboring nonclassical EGFR mutations. In a combined post hoc analysis of the phase 2 LUX-Lung 2 (NCT00525148), the phase 3 LUX-Lung 3 (NCT00949650), and phase 3 LUX-Lung 6 (NCT01121393) trials, among patients with any nonclassical mutations (n = 38)—the most common of which were G719X, L861Q, and S768I—who received afatinib, the overall response rate (ORR) was 71.1% (95% CI, 54.1%-84.6%), the median duration of response (DOR) was 11.1 months (95% CI, 4.1-15.2), the median progression-free survival (PFS) was 10.7 months (95% CI, 5.6-14.7), and the median overall survival (OS) was 19.4 months (95% CI, 16.4-26.9).4 PFS outcomes differed between the uncommon mutation subgroups. The median PFS was 13.8 months (95% CI, 6.8-not evaluable [NE]) in patients with G719X mutations (n = 18), 14.7 months (95% CI, 2.6-NE) in those with S768I mutations (n = 8), and 8.2 months (95% CI, 4.5-16.6) in those with L861Q mutations (n = 16).

“L861Q is a classical-like mutation that has a better response to osimertinib vs G719 or S761I [mutations], which are PACC mutations,” Lovly contextualized.1

Lovly emphasized that when considering afatinib treatment for a patient with a nonclassical EGFR mutation, the presence of a T790M mutation needs to be determined. Although this mutation is often overlooked, it is an afatinib resistance mutation.

Bringing Other Agents Into the Nonclassical Context

The nonrandomized phase 2 UNICORN trial (jRCTs071200002) demonstrated the efficacy of first-line osimertinib in patients with NSCLC harboring uncommon EGFR mutations. Among evaluable patients with any nonclassical EGFR mutation (n = 40), the median PFS was 9.4 months (95% CI, 3.7-15.2), and the median OS was not yet reached ([NR]; 95% CI, 19.3 months-NR).5 These data support the off-label use of this agent in the nonclassical mutation population, Lovly suggested.1 Osimertinib is currently FDA approved for the frontline or subsequent-line treatment of patients with NSCLC harboring EGFR ex19del or L858R mutations.2

Furthermore, cohort C of the phase 1 CHRYSALIS-2 trial (NCT04077463) showed the activity of the investigational combination amivantamab-vmjw (Rybrevant) plus lazertinib (Lacluze) in patients with treatment-naive and pretreated nonclassical EGFR mutations, including G719X, L861X, S768X, and E709X mutations.6

Among evaluable treatment-naive patients (n = 49), at a median follow-up of 17.3 months, the ORR with the combination was 57% (95% CI, 42%-71%), the median PFS was 19.5 months (95% CI, 11.2-NE), and the median OS was NE (95% CI, 26.3 months-NE). Among the evaluable pretreated patients, 88% had received a prior TKI, including afatinib. At a median follow-up of 15.4 months, the median PFS was 7.8 months (95% CI, 5.4-11.1), and the median OS was 22.8 months (95% CI, 16.9-NE).

Emerging Nonclassical EGFR Mutation Treatment Options

Data from the phase 1 FURTHER/FURMO-002 trial (NCT05364073) of firmonertinib (AST2818) in patients with TKI-naive, locally advanced or metastatic NSCLC with EGFR PACC mutations were presented at the 2024 IASLC World Conference on Lung Cancer.7 The trial used structure-based mutation classification and specifically included patients with nonclassical EGFR PACC mutations, such as G719X, S768I, L747P, V769L, and rare ex19del; acquired mutations included those in C797S, G724S, L792H, T854I, and L718X. Notably, patients with L861Q mutations were excluded, as this mutation is considered osimertinib sensitive, Lovly explained. Patients were randomly assigned 1:1 to receive daily firmonertinib at 1 of 2 dose levels: 160 mg or 240 mg.

Among evaluable patients who received treatment at 240 mg daily (n = 22), the confirmed ORRs were 63.6% (95% CI, 40.7%-82.8%) and 68.2% (95% CI, 45.1%-86.1%) by blinded independent central review and investigator review, respectively. At a median DOR follow-up of 4.2 months, the median DOR was NR, and 90.9% of patients remained on treatment; the PFS and OS data were still immature.

Of evaluable patients with baseline brain metastases who received the agent at 240 mg (n = 7), the confirmed ORR in the central nervous system (CNS) was 42.9% (95% CI, 9.9%-81.6%). Lovly explained that this CNS activity was expected given that firmonertinib is an irreversible next-generation EGFR TKI.1

The safety profile was also as expected, she adds. Adverse effects (AEs) included diarrhea, elevated liver function test levels, and rash. A higher incidence of these AEs was observed at the higher dose level.7

The fourth-generation EGFR TKI BDTX-1535 also showed preliminary activity in patients with nonclassical EGFR mutations. The phase 1/2 BDTX-1535-101 study (NCT05256290) evaluated mutations across the full EGFR protein, including the extracellular and intracellular domains, in patients with recurrent NSCLC.8 Investigators hypothesized that achievable doses of BDTX-1535 could target several different classical and nonclassical EGFR mutations. Cohort 1 included patients with nonclassical driver mutations who had received a maximum of 2 prior lines of therapy. Cohort 2 consisted of patients with acquired EGFR C797S resistance mutations following treatment with up to 2 prior lines of therapy. Cohort 3 enrolled patients with nonclassical EGFR driver mutations in the frontline setting.

At a mean follow-up of 4.7 months, preliminary data showed an ORR of 42% among evaluable patients with PACC nonclassical mutations (n = 19), including those with nonclassical mutations, as well as those with C797S resistance mutations. Response rates varied across the different mutation subgroups, Lovly emphasized. For example, one patient with an EGFR G719/S768I compound mutation achieved an unconfirmed complete response exceeding 7 months. Many of these responses were durable, Lovly explained.

The safety profile of BDTX-1535 appears consistent with that of other EGFR inhibitors. Rash, diarrhea, and stomatitis were observed; no patients had liver enzyme elevation, QTC prolongation, or grade 3/4 diarrhea. Among 20 enrolled patients, 1 discontinued treatment, and 4 required dose reductions.

Ultra-Rare EGFR Mutations

Lovly presented a brief overview of ultra-rare EGFR mutations that oncologists should be prepared to see in their practice.1 These include activating A647T transmembrane domain mutations, EGFR kinase domain duplication, EGFR fusions, and C-terminal deletions.

“These are only going to be reported by case reports and anecdotes in the literature right now,” Lovly noted.

She encouraged colleagues to reach out to EGFR mutation researchers if they have patients with ultra-rare mutations. Additionally, she recommended checking the literature for relevant case reports.

Lovly concluded by highlighting the importance of NGS testing for delivering precise mutational analyses that can help guide individualized treatment decisions.

“We have no way to know what we’re going to get until we sequence [the tumors],” she said.

Disclosures: Over the past 24 months, Lovly reported serving as a consultant for and receiving honoraria from Anheart, Arrivent, Astra Zeneca, Blueprints Medicine, Boehringer Ingelheim, Cepheid, D2G, Daiichi Sankyo, EMD Serono, Foundation Medicine, Genentech, Indupro, Janssen, Medscape, Novartis, Pfizer, Roche, and Takeda; she also serves as a DSMB chair for a Janssen study, uncompensated.

References

1. Lovly CM. Uncommon / non-classical EGFR mutations in lung cancer. Presented at: 22nd Annual Winter Lung Cancer Conference; January 31-February 2, 2025; Hollywood, FL.
2. Tavernari D, Borgeaud M, Liu X, et al. Decoding the clinical and molecular signatures of EGFR common, compound, and uncommon mutations in NSCLC: a brief report. J Thorac Oncol. Published online December 16, 2024. doi:10.1016/j.jtho.2024.12.012
3. NCCN. Clincial Practice Guidelines in Oncology. Non-Small Cell Lung Cancer, version 3.2025. Accessed February 4, 2025. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
4. Yang JC, 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):830-8. doi:10.1016/S1470-2045(15)00026-1
5. Okuma Y, Kubota K, Shimokawa M, et al. First-line osimertinib for previously untreated patients with NSCLC and uncommon EGFR mutations.JAMA Oncol. 2024;10(1):43-51. doi:10.1001/jamaoncol.2023.5013
6. 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(16)8516. doi:10.1200/JCO.2024.42.16_suppl.8516
7. Le X, Yu Y, Zhao Y, et al. FURTHER: a global, randomized study of firmonertinib at two dose levels in TKI-naive, advanced NSCLC with EGFR PACC mutations. J Thorac Oncol. 2024;19(10):S5-S6. doi:10.1016/j.tho.2024.09.019
8. Patel J, Spira A, Stevenson J, et al. A phase 2 study to assess safety and efficacy BDTX-1535, an oral EGFR inhibitor, in patients with non-small cell lung cancer. Presented at: 2024 World Conference on Lung Cancer. September 7-10, 2024; San Diego, CA. Ep.12H.01.