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. Comparable values were observed in animal studies (2.3 in rats and 2.7 in monkeys).

Intracranial progression-free survival (iPFS) and intracranial response (How to Read This Graph? →)

Data are from 20 patients with brain lesions without C797S who received VRN11 ≥160 mg, 17 of whom had received prior third-generation EGFR TKI therapy (data cutoff: October 9, 2026). In the table, CR indicates that all brain lesions disappeared, and disease control is the number of patients whose brain lesions did not progress. Osimertinib values are from studies of osimertinib 80 mg in 11 T790M-negative patients previously treated with first- or second-generation EGFR TKIs.^[5][6] These results come from different studies and patient populations and cannot be compared directly.

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 40 mg, the dose at which activity was first observed. PK analysis showed that plasma drug concentrations increased in proportion to 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 woman · 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^[7] and approximately 14% after later-line use.^[8] There is currently no approved therapy that directly targets C797S. VRN11 was designed to inhibit this mutation.

Change in target lesion size in 8 patients with EGFR C797S receiving ≥160 mg

An unconfirmed partial response (uPR) means that target lesions decreased by at least 30% but the follow-up scan needed to confirm the response is not yet available. The median time to maximum target lesion reduction was 26 days after the start of treatment.

The dotted line marks the partial response threshold (30% decrease).

Case of a Patient With C797S

Clinical Case

63-year-old man, EGFR L858R/C797S

This patient had previously developed a different resistance mechanism, MET amplification, and was treated with osimertinib plus the MET inhibitor savolitinib, after which C797S was identified. After six prior lines of therapy including this combination, the patient received VRN11 480 mg, and all four target lesions in the lung and lymph nodes decreased in size.

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 · All Patients Treated at 10–560 mg (N=82)

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

The most common treatment-related adverse events were diarrhea, pruritus, rash, and nausea, most of which were Grade 1–2. No permanent discontinuations due to treatment-related adverse events were reported at doses up to 560 mg.

Change in Adverse Event Grade During Treatment in 60 Patients Receiving ≥160 mg

This graph groups the patients on treatment at each time point by the highest grade of adverse event present at that time. The bar on the right applies the same grouping to all treatment days; on approximately 90% of treatment days, patients had no adverse event or only a Grade 1 event. The numbers below the graph (At risk) show how many patients were on treatment at each time point.

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 aim of this clinical trial is to determine whether VRN11 can control cancer for longer, in the brain as well as the lungs, from first-line treatment through the emergence of resistance.

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. Eide IJZ, et al. Osimertinib in T790M-positive and -negative patients with EGFR-mutated advanced non-small cell lung cancer: the TREM study. Lung Cancer. 2020;143:27–35.
6. Eide IJZ, et al. Acta Oncol. 2021;60:1565–71. (Intracranial progression-free survival with osimertinib in T790M-negative patients previously treated with first- or second-generation EGFR TKIs)
7. 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)
8. 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%.)
9. 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)