VRN11: An Investigational Approach in EGFR-Mutant Lung Cancer

VRN11 Beyond Third-Generation EGFR Therapy

VRN11 is being developed to address key limitations of current EGFR-targeted therapies, including brain metastases, diverse EGFR mutations, C797S resistance, and treatment-related adverse events. Below are findings to date in each area.

VRN11 and Brain Metastases

Brain metastases remain a significant concern for patients with EGFR-mutant lung cancer. In FLAURA2, approximately 40% of patients had CNS metastases at baseline.^[1] Among patients with baseline CNS metastases treated with third-generation EGFR therapy, CNS progression was reported in approximately 20%, including new CNS lesions in approximately 12%.^[2] In FLAURA2, median progression-free survival (PFS) with monotherapy was 13.8 months in patients with baseline CNS metastases versus 21.0 months in those without.^[3]

After CNS progression, treatment options may be limited. NCCN Guidelines recommend considering local therapies such as stereotactic radiosurgery (SRS), whole-brain radiation therapy (WBRT), or neurosurgery depending on disease extent and symptoms.^[4] These treatments may add further treatment burden for patients.

VRN11 was designed to achieve drug exposure in the CNS and is being evaluated for activity in patients with brain metastases.

Phase 1 · Human Data

Unbound CSF-to-plasma ratio (Kpuu, CSF) (What does this measurement mean? →)

When cancer progresses in the CNS during standard treatment, subsequent options may be limited. VRN11 was developed to achieve drug exposure in the CNS.

The CSF value shown in the graph (green circle) was measured in a patient who developed brain metastases after osimertinib treatment and received 240 mg of VRN11.

Comparison of Progression-Free Survival (PFS) and Intracranial Progression-Free Survival (iPFS) (How to Read This Graph? →)

In the early clinical trial, some patients with brain metastases experienced shrinkage or complete disappearance of brain lesions. VRN11 data are based on 15 patients with brain metastases, 14 of whom had received prior third-generation EGFR TKI therapy (data cutoff: March 12, 2026). Osimertinib iPFS is based on 11 patients with T790M-negative brain metastases previously treated with first- or second-generation EGFR TKIs.

Brain Metastasis Responses After 3rd Generation Treatment Failure

Clinical Case · Brain Lesion at a Low Dose

Brain Lesion Response Observed at a Low Dose

Disappearance of a brain lesion was observed even at the lowest 40 mg dose. PK analysis also showed that plasma drug exposure increased with dose.

Clinical Case · Progression After Osimertinib

47-year-old woman · EGFR Del19/C797S

After more than three years of treatment with third-generation therapy including osimertinib, the disease progressed. Following VRN11 320 mg, the brain lesions were no longer observed.

Clinical Case · Progression After Osimertinib and Lazertinib

71-year-old man · EGFR L858R

After more than six years of third-generation treatment including osimertinib and lazertinib, the disease progressed. Following VRN11 400 mg, the brain lesion was no longer observed.

VRN11 Across EGFR Mutation Types

EGFR mutations include common alterations such as exon 19 deletions and L858R, as well as a range of atypical mutations. Existing treatments may work differently depending on the EGFR mutation. VRN11 is being studied across a range of EGFR mutations, including classic, C797S, and atypical mutations.

Preclinical Data · Target Engagement Ratio vs Osimertinib

VRN11 showed potent inhibition of the proliferation of cells harboring a range of EGFR mutations in cell-based assays. Each bar in the graph represents the drug concentration required to inhibit proliferation of the corresponding mutant cell line by 50% (IC₅₀). The dotted line indicates the trough concentration at steady state following repeated dosing at 320mg, expressed on an unbound (protein-free) basis. The higher the dotted line sits above a bar, and the wider that margin, the more the circulating drug concentration exceeds the concentration required to inhibit cell proliferation. For classic mutations, this trough concentration was presented at approximately 56-fold the IC₅₀. Inhibition of cell proliferation activity was also observed against atypical mutations and against compound mutations including C797S, which is implicated in osimertinib resistance. (How was this calculated? →)

Target engagement is calculated as the ratio of actual drug exposure to the concentration required for tumor inhibition. For classic mutations, the modeled difference is 4× systemically; in the brain, incorporating the difference in CNS penetration (VRN11 200% vs osimertinib 20%; see Chapter 2) increases the modeled ratio to 40×.

VRN11 activity against the EGFR C797S mutation

Cancer can progress after treatment for several reasons. One is the emergence of a new EGFR mutation such as C797S. C797S has been reported in approximately 6% of patients after first-line osimertinib^[5] and approximately 14% after later-line use.^[6] There is currently no approved therapy that directly targets C797S. VRN11 was designed to inhibit this mutation.

Patients With EGFR C797S · Best Response in Target Lesion Size in 6 Patients Receiving Active Doses (≥160 mg)

All six patients had a 40–52% reduction in target lesion size and achieved a confirmed partial response (cPR), with C797S ctDNA clearance observed in all

Bar colors indicate dose (160, 240, 320, or 400 mg). Tumor shrinkage was observed across active-dose levels.

VRN11's Safety Profile

VRN11 was designed to target cancer-driving mutant EGFR more selectively than wild-type EGFR, with the goal of reducing effects on normal cells. (What is “selective inhibition”? →)

Safety Data · 80–480 mg Dose Groups (N=55)

Treatment-related adverse events (What are grade levels? →)

The most commonly reported treatment-related adverse events with VRN11 were Grade 1-2 rash (22%), pruritus (16%), dry skin (13%), and diarrhea (13%). There were only 2% of Grade ≥3 treatment-related adverse events. No permanent discontinuations due to treatment-related adverse events were reported through the dose level 480 mg. The osimertinib comparator shown in the table is based on the AURA study with 2L+ T790M-positive patients.

VRN11: Expanding into the First-Line Setting

VRN11 was initially studied in patients whose disease progressed after prior EGFR therapy. Early findings included CNS penetration, activity across EGFR mutations, C797S responses, and safety. REACH-EGFR is now evaluating VRN11 in treatment-naïve patients in the first-line setting.

From Later-Line Evidence to First-Line Development

Osimertinib, a third-generation EGFR therapy, was first studied in previously treated patients before being evaluated in treatment-naïve patients in FLAURA and becoming a first-line standard. VRN11 is now being evaluated to determine whether findings from earlier studies extend to the first-line setting.

Another example helps illustrate this development pathway. The table below compares EGFR-targeted therapies (osimertinib and VRN11) and the ALK-targeted therapy lorlatinib, showing how intracranial outcomes differed between previously treated and treatment-naïve patients with brain metastases side by side. Lorlatinib provides an example in which activity observed in 2L+ was subsequently demonstrated in the 1L setting.

The REACH-EGFR trial is evaluating VRN11 in the first-line setting, including its activity in systemic and CNS disease and its safety profile.

References

1. Jänne PA, Planchard D, Kobayashi K, et al. CNS efficacy of osimertinib with or without chemotherapy in epidermal growth factor receptor–mutated advanced non–small-cell lung cancer. J Clin Oncol. 2024;42(7):808-820. doi:10.1200/JCO.23.02219
2. Reungwetwattana T, et al. CNS Response to Osimertinib Versus Standard Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients With Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2018;36(33):3290-3297. doi:10.1200/JCO.2018.78.3118. (FLAURA CNS subgroup analysis: among patients with baseline CNS metastases [cFAS; osimertinib n=61, standard EGFR-TKI n=67], CNS progression occurred in 20% [12/61] vs 39% [26/67]; progression due to new CNS lesions occurred in 12% [7/61] vs 30% [20/67].)
3. Planchard D, et al. Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. (FLAURA2)
4. Riely GJ, et al. Non–Small Cell Lung Cancer, Version 4.2026, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2026;24(4).
5. Chmielecki J, et al. Candidate mechanisms of acquired resistance to first-line osimertinib in EGFR-mutated advanced non-small cell lung cancer. Nat Commun. 2023;14(1):1070. (FLAURA first-line resistance analysis)
6. Chmielecki J, et al. Analysis of acquired resistance mechanisms to osimertinib in patients with EGFR-mutated advanced non-small cell lung cancer from the AURA3 trial. Nat Commun. 2023;14(1):1071. (AURA3 later-line resistance analysis; C797X 18% [14/78] in the abstract includes C797S and C797G; C797S alone was 14%.)
7. Garcia-Campelo R, et al. Depth of Response and Progression-Free Survival in Patients With Advanced ALK-Positive Non–Small-Cell Lung Cancer Treated With Lorlatinib. J Clin Oncol. 2025;43(16_suppl):8589. doi:10.1200/JCO.2025.43.16_suppl.8589. (CROWN post hoc analysis)