Abstract CT251: Phase 3 INTerpath-009 study: Individualized neoantigen therapy V940 (mRNA-4157) plus pembrolizumab for resected stage II-IIIB (N2) NSCLC with incomplete pathological response to neoadjuvant immunochemotherapy

Abstract Background: Patients (pts) with non-small-cell lung cancer (NSCLC) who do not achieve pathologic complete response (pCR) after neoadjuvant chemoimmunotherapy and surgery have a worse prognosis than those who achieve pCR, and escalation of therapy for improved outcomes may be warranted. Pembrolizumab (pembro) is approved in several countries as monotherapy for the adjuvant treatment of pts with NSCLC following neoadjuvant pembro plus platinum-based chemotherapy (chemo) and resection. V940 (mRNA-4157) is a novel, mRNA-based, individualized neoantigen therapy that encodes up to 34 neoantigens specific to each pt’s unique tumor mutanome and is encapsulated in a lipid nanoparticle that is administered intramuscularly (IM). Preliminary antitumor activity for V940 as monotherapy and in combination with pembro was shown in the phase 1 KEYNOTE-603 study in solid tumors, including NSCLC, and in KEYNOTE-942 in melanoma. The INTerpath-009 study (NCT06623422) evaluates adjuvant pembro with and without V940 in pts with resected stage II-IIIB (N2) NSCLC that did not achieve pCR after neoadjuvant pembro plus chemo. Methods: This phase 3, multicenter, double-blind study is enrolling pts ≥18 years old with histologically-confirmed stage II-IIIB (N2) squamous (sq) or nonsquamous (nonsq) NSCLC (AJCC v8) with no tumor-activating EGFR and no known ALK alterations. Eligible pts are able to undergo protocol therapy, including surgery, and have ECOG PS 0 or 1. Pts eligible for randomization must have resected (R0 or R1) tumors that did not achieve pCR after ≤4 cycles of neoadjuvant pembro plus chemo, and surgical tumor sample available for biomarker analysis and next-generation sequencing. Pts who received neoadjuvant pembro plus chemo prior to enrollment are eligible provided other eligibility criteria are met. Approximately 680 pts will be randomized 1:1 to V940 1 mg IM or placebo Q3W for 9 doses, both in combination with pembro (400 mg IV Q6W for 7 cycles). Treatment will continue until PD, pt withdrawal, unacceptable toxicity, or an additional malignancy requiring treatment. Randomization will be stratified by histology (sq vs nonsq), PD-L1 expression (TPS <1% vs ≥1%), disease stage (II vs III), and geographic location (North America/Western Europe/Australia vs rest of world). Tumor imaging will occur at baseline and every 12 wk until wk 48, every 24 wk through year 3, and every 48 wk thereafter from randomization until distant recurrence, death, withdrawal of consent, or end of study. The primary endpoint is disease-free survival (DFS) per investigator assessment. Secondary endpoints include OS, distant metastasis-free survival, DFS after next-line therapy, lung cancer-specific survival, patient-reported outcomes, and safety. The first pt was screened on October 21, 2024, and recruitment is ongoing. Citation Format: Tina Cascone, Nir Peled, Alona Zer, David Chism, Danko Martincic, Laureen S. Ojalvo, Joydeep Banerjee, Zheng Wang, Steven M. Keller, Jonathan D. Spicer. Phase 3 INTerpath-009 study: Individualized neoantigen therapy V940 (mRNA-4157) plus pembrolizumab for resected stage II-IIIB (N2) NSCLC with incomplete pathological response to neoadjuvant immunochemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT251.