VRN110755 Shows Initial Antitumor Activity Across Dose Levels in EGFR-Mutant NSCLC

April 22, 2026 | Courtney Flaherty

Key Takeaways

• VRN110755 is designed to selectively inhibit mutant EGFR (including C797S) with brain penetration to address acquired resistance and CNS disease, potentially improving intracranial target engagement beyond osimertinib.
• Clinical activity was observed across multiple doses, with PRs spanning 40–400 mg, an ORR of 25.8% and DCR of 96.8% in a third-line-plus population, and 87.5% confirmed ORR in an EGFR-confirmed subset.
• Baseline cohort characteristics reflected high unmet need, including median three prior systemic lines and CNS involvement in 45% (brain 38%; leptomeningeal 2%; both 5%).
• ctDNA reductions occurred in all evaluable patients with complete clearance in most, while PK demonstrated dose-proportional exposure and concentrations exceeding mutation-relevant IC50 beginning at 160 mg.
• Safety appeared favorable with 60% any-grade TRAEs and 2% grade ≥3, no grade 4 events, and no DLTs through 480 mg, with comparatively lower common EGFR-TKI toxicities versus osimertinib.

The next-generation noncovalent EGFR TKI VRN110755 demonstrated deep, consistent antitumor activity across dose levels in patients with EGFR-mutant non–small cell lung cancer (NSCLC), including those with C797S mutations, according to data from the ongoing, first-in-human phase 1a REACH-EGFR study presented at the 2026 AACR Annual Meeting.¹

Among response-evaluable patients with confirmed EGFR mutations (n = 8), 7 achieved a partial response (PR), corresponding to a confirmed overall response rate (ORR) of 87.5%. In the overall heavily pretreated patient population, patients treated with VRN110755 monotherapy as a third or later line of therapy at doses of 160 mg to 400 mg (n = 65) achieved an ORR of 25.8% and a disease control rate (DCR) of 96.8%. Best responses included PRs (n = 8), stable disease (SD; n = 21), and disease progression (PD; n = 1).

No dose-limiting toxicities (DLTs) were observed at any dose level up to 480 mg, and no clinically meaningful QT prolongation or interstitial lung disease were observed in treated patients.

“Tumor shrinkage and objective responses [were] observed [with VRN110755] in the current dataset,” Hong-ryul Jung, PhD, of Pohang University of Science and Technology in South Korea, and coauthors wrote in their poster presentation of the data. “The study is ongoing, and these data support continued dose optimization and phase 1b expansion in multiple cohorts.”

What unmet needs might VRN110755 address in NSCLC?

Although first-, second-, and third-generation EGFR TKIs have transformed the treatment landscape in NSCLC, substantial unmet needs remain in the setting of acquired resistance and central nervous system metastases. VRN110755 is a potent, brain-penetrant EGFR inhibitor designed to selectively target EGFR oncogenic mutations over EGFR wild-type and other kinases. The agent was developed to address activity against common and uncommon EGFR driver mutations, including C797S-mediated resistance following osimertinib (Tagrisso).

In preclinical models, VRN110755 demonstrated robust systemic and intracranial antitumor activity and a pharmacokinetic and safety profile supporting once-daily oral dosing, supporting the hypothesis that it may surpass the intracranial target engagement of osimertinib. Moreover, data from a phase 1/2 trial evaluating VRN110755 , which were shared at the 2025 ESMO Asia Congress, showed an ORR of 19% and a DCR of 90% with the agent at doses of 80 mg or greater in heavily pretreated patients (n = 21).² These data confirmed the agent’s activity and high brain permeability in TKI-resistant, EGFR C797S–mutant NSCLC.

How is the REACH-EGFR study designed?

REACH-EGFR is enrolling patients age 18 years or older with NSCLC with a documented EGFR mutation, measurable disease per RECIST 1.1 criteria, prior receipt of an EGFR TKI with disease progression, and an ECOG performance status of 0 or 1.¹

The study evaluated 10 doses ranging from 10 mg up to 640 mg, with 30 patients across dose levels above 80 mg and 21-day cycle DLT evaluation periods. Intrapatient dose escalation is allowed. The study also includes dose expansion cohorts at 160 mg, 240 mg, 320 mg, and 400 mg; the 480-mg dose level is marked as completed in the escalation schema.

The study’s primary end point is the incidence of DLTs. Secondary end points included incidence of adverse effects (AEs), PK, ORR, duration of response, DCR, progression-free survival (PFS), and intracranial ORR/PFS. ctDNA was also assessed at one or more time points in the study.

Of note, the recommended phase 2 dose (RP2D) had not yet been determined at the data cutoff of March 10, 2026.

Topline Takeaways From REACH-EGFR

What should be known about baseline patient characteristics in this population?

As of the data cutoff, 65 patients were enrolled in the VRN110755 monotherapy cohort, with a median age of 60 years (range, 45-87). The majority of patients were female (66%) and Asian (98%). ECOG PS was 0 or 1 in 43% and 57% of patients, respectively. Central nervous system metastases were present at baseline in 45% of patients, including brain metastases in 38%, leptomeningeal metastases in 2%, and both brain and leptomeningeal metastases in 5% of patients. Patients had received a median of 3 prior lines of systemic therapy (range, 1-6).

By EGFR mutation type, the distribution in the overall cohort was as follows:

• Classical mutations (Del19 or L858R, without C797S): 45%
• Classical + C797S: 11%
• Classical + T790M: 9%
• Atypical mutations: 8%
• Atypical + T790M mutation: 2%
• Other mutations: 25%

What additional data were presented?

Across all dose cohorts, including patients expressing C797S and at least 1 additional EGFR mutation, prior TKI treatment histories included combinations and sequences such as dacomitinib (Vizimpro) plus osimertinib, osimertinib alone, lazertinib (Lazcluze) plus osimertinib, afatinib (Gilotrif) plus lazertinib, and osimertinib alone at higher doses. Seven patients at doses of 40 mg through 400 mg achieved a PR as their best overall response, with one patient at 320 mg achieving a best response of progressive disease. Best percentage changes from baseline in target lesion size ranged from approximately −41% to −54.5%.

Of note, observed responses in C797S-mutant NSCLC were also reported from 2 separate early clinical datasets: in the phase 1 VRN110755 dataset (n = 8), the best response rates were PR in 7 patients (87.5%), SD in 0, PD in 1 (12.5%). In contrast, data from thephase 2 BDTX-1535-101 trial (NCT05256290) evaluating silevertinib (BDTX-1535) showed 4 PRs (44.4%) and 5 instances of SD (55.5%) as best response among evaluable patients (n = 9).

What did ctDNA and PK data show?

Molecular response assessment demonstrated circulating tumor DNA (ctDNA) reduction in all 6 evaluable patients, with complete ctDNA clearance observed in 5 of those patients. ctDNA variant allele frequency dynamics showed meaningful decreases from baseline to cycle 1, day 15 across dose levels from 40 mg through 320 mg, consistent with on-target EGFR inhibition.

The agent’s pharmacokinetic (PK) profile showed dose-proportional systemic exposure, with plasma concentrations exceeding the half-maximal inhibitory concentration for relevant EGFR mutations starting at 160 mg. The PK/pharmacodynamic relationship showed a robust response consistent with the observed clinical activity.

What was the safety profile of VRN110755 monotherapy?

VRN110755 showed an overall favorable safety profile comparing favorably with approved osimertinib and other third-generation EGFR TKIs. In the overall population (n = 65), any-grade treatment-related AEs (TRAEs) occurred in 60% of patients, 2% of which were grade 3 or higher. No grade 4 TRAEs were reported across any dose level. The most commonly reported TRAEs were stomatitis, rash, dry skin, pruritus, diarrhea, anorexia, nausea, and fatigue.

Any-grade AEs by dose cohort are as follows:

• 10 mg (n = 3): 33%
• 20 mg (n = 4): 50%
• 40 mg (n = 3): 33%
• 80 mg (n = 12): 25%
• 160 mg (n = 13): 54%
• 240 mg (n = 14): 86%
• 320 mg (n = 7): 57%
• 400 mg (n = 5): 100%
• 480 mg (n = 4): 100%

A comparison of the safety profile of VRN110755 (ranging from 80 mg to 480 mg; n = 55) vs osimertinib (80 mg; n = 201) showed that VRN110755 was associated with lower rates of both any grade or grade 2 and higher stomatitis, rash, dry skin, pruritus, diarrhea, anorexia, nausea, and fatigue. This was highlighted by the investigators as supporting the tolerability of VRN110755 relative to the current third-generation standard.

Disclosures: Jung reported being employed by Voronoi Inc.

References

Jung H-r, Lee J, Ahn M-J, et al. VRN110755: a next-generation non-covalent EGFR tyrosine kinase inhibitor for EGFR-mutated NSCLC. Presented at: 2026 AACR Annual Meeting; April 17-22, 2026; San Diego, CA. Abstract LB336.

Ahn M-J, Lee KH, Shim BY, et al. Safety profile and anti-tumor efficacy of VRN110755, a highly selective, brain penetrant EGFR inhibitor for patients with EGFR-driven non-small cell lung cancer. Ann Oncol. 2025,36(suppl 4): S2106.doi:10.1016/j.annonc.2025.10.680