September 24, 2026
When delivered at a dose of at least 160 mg, the mutant-selective, central nervous system (CNS)–penetrant EGFR TKI VRN110755 elicited objective responses in patients with EGFR C797S–positive non–small cell lung cancer (NSCLC), according to data from the phase 1a portion of the phase 1/2 REACH-EGFR trial (NCT07699328) presented at the IASLC 2026 World Conference on Lung Cancer.¹
The maximum tolerated dose (MTD) of the agent was not identified, and no dose-limiting toxicities (DLTs) were observed. Treatment-related adverse effects (TRAEs) occurred in 60% of patients who received the agent at doses ranging from 10 mg to 480 mg (n = 67); they were grade 3 or higher for 3% of patients. No TRAEs resulted in permanent discontinuation of VRN110755, although dose reductions were required by 6% of patients.
Among patients with C797S mutations who received VRN110755 at doses of 160 mg or higher (n = 6), the objective response rate was 100%; all responses were confirmed partial responses, and every patient achieved a tumor reduction of more than 40% from baseline. The median progression-free survival (PFS) in this group was 11.0 months (95% CI, 4.6-not estimable [NE]), an estimate investigators characterized as immature, with 3 PFS events reported at the data cutoff date of July 2, 2026. Among patients with baseline brain metastases treated at 160 mg or higher (n = 19), the intracranial disease control rate was 100%, including complete responses (CRs) in 16% of patients; the median intracranial PFS was not reached (95% CI, 9-NE), and the median PFS was 6.7 months (95% CI, 3.7-9.1).
“At doses [of] 160 mg [or higher,] preliminary but promising clinical activity was observed in C797S-mutant disease, including an ORR of 100%, tumor reductions of [at least] 40% in all patients, a median PFS of 11.0 months, and marked ctDNA reductions in all 4 evaluable patients,” Myung-Ju Ahn, MD, PhD, of Hanyang University Medical Center, Hanyang University School of Medicine, in Seoul, Republic of Korea, and colleagues, wrote in the presentation. “Collectively, these findings support further clinical development in patients with EGFR-mutant NSCLC.”
How was the phase 1a REACH-EGFR study of VRN110755 designed?
The first-in-human dose-escalation portion enrolled patients with NSCLC harboring any EGFR activating mutation, including exon 19 deletion (Del19), L858R, C797S, and uncommon or complex mutations, identified by liquid biopsy or prior tumor biopsy. Patients were required to have at least 1 measurable lesion per RECIST v1.1. The primary objectives of the study were safety, tolerability, and determination of the MTD. VRN110755 was administered daily at doses ranging from 10 mg to 480 mg, and escalation to 560 mg is ongoing.
The treated population (n = 67) had a median age of 60 years (range, 45-87), and 45 patients (67%) were female. At baseline, 29 patients (43%) had brain metastases and 3 (4%) had brain and leptomeningeal metastases. Moreover, 7 patients (10%) had classic EGFR mutations with C797S, and no mutation was detected in 18 patients (27%). Patients had received a median of 3 prior systemic therapies (range, 1-10), including osimertinib (Tagrisso) in 37 patients (55%) and lazertinib (Lazcluze) in 24 patients (36%).
What did the pharmacokinetic, ctDNA, and intracranial analyses show with VRN110755?
Plasma exposure to VRN110755 increased in a dose-dependent manner, and at doses of 160 mg or higher, systemic exposures exceeded the 90% growth inhibitory concentrations in Ba/F3 models harboring Del19/C797S and L858R/C797S. Activity was also observed at 40 mg: a patient with an EGFR L858R/C797S/R776H mutation had a 51% reduction in a pleural target lesion and disappearance of a brain lesion. In the C797S-positive group (n = 6), circulating tumor DNA (ctDNA) analyses showed clearance of C797S ctDNA in all patients with evaluable ctDNA, with concurrent clearance of Del19 ctDNA in 3 patients.
Of the 45 patients treated at doses ranging from 160 mg to 480 mg, 19 had brain metastases at baseline, including 5 with measurable and 14 with nonmeasurable CNS lesions. By Response Assessment in Neuro-Oncology Brain Metastases criteria, all 3 CRs occurred in patients with nonmeasurable lesions, all 5 patients with measurable lesions had stable disease, and no patients had intracranial progression as best response. In a patient with brain metastases in the 240-mg cohort, the unbound cerebrospinal fluid–to-plasma partition coefficient was 2.0, which investigators cited as evidence of high brain penetration.
What did the safety analysis of VRN110755 show?
“Most [TRAEs] were mild and consistent with the expected on-target toxicity profile of EGFR inhibition,” Ahn added. The most common TRAEs experienced with VRN110755 were rash (22%), pruritus (16%), diarrhea (15%), dry skin (13%), increased aspartate aminotransferase level (10%), increased alanine aminotransferase level (9%), nausea (8%), anorexia (6%), and paronychia (6%)—none of which occurred at grade 3 or higher.
What are the next steps for VRN110755 in EGFR-mutant NSCLC?
A phase 1b/2 expansion is examining single-agent VRN110755 at a once daily dose of 320 mg (n = 20) and at a higher once daily dose to be determined (n = 20).
Monotherapy cohorts include patients with common EGFR mutations plus C797S (cohort A), treatment-naive patients with common EGFR mutations (cohort B), patients with atypical or uncommon EGFR mutations following 1 prior TKI (cohort C) or who are TKI-naive (cohort D), and patients with common EGFR mutations and CNS disease that progressed after a third-generation TKI (cohort E). A separate dose-escalation cohort (cohort G) is evaluating VRN110755 with standard chemotherapy in patients with any EGFR mutation following exposure to a third-generation TKI.
Disclosures: Ahn reported receiving honoraria from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Bristol Myers Squibb, MSD, Lilly, Merck, Roche, Takeda, Yuhan, and Amgen, and serving as a consultant or advisor for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Ono, Takeda, Merck, MSD, Johnson & Johnson, Amgen, Novartis, Roche, Yuhan, Pfizer, AimedBio, Genexin, Voronoi, Daewoong, Dong-A, and BioNTech.
References
- Ahn MJ, Lee KH, Hong MH, et al. Safety, pharmacokinetics, and preliminary antitumor activity of VRN110755 in EGFR mutant NSCLC. Presented at: IASLC 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, Republic of Korea. Abstract MO12.01.
