Background Neoantigens arising from mutations in cancer cell DNA are important targets for T cell mediated anti-tumor immunity. NEO-PV-01 is a personal neoantigen vaccine of up to 20 peptides (14–35 amino acids) based on a patient‘s HLA profile and bioinformatic analysis of tumor neoantigens. We report here clinical and immune data for NT-002, a Phase 1b study of NEO-PV-01 with pemetrexed, carboplatin, and pembrolizumab as first-line therapy for advanced non-squamous NSCLC.

Methods Patients received 12 weeks of pembrolizumab (Q3W) plus carboplatin and pemetrexed. NEO-PV-01 was then given subcutaneously in a prime-boost format spanning 12 weeks, followed by pembrolizumab for up to 2 years. The primary objective was safety; secondary objectives included overall response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). Comprehensive immune assessments were performed with peripheral blood mononuclear cells and biopsies collected at weeks 0, 12, and 24.

Results A total of 38 patients initiated study treatment (ITT population); 21 patients received at least 1 dose NEO-PV-01 (vaccinated group, VAX). The demographics included 61% women and 82% with a smoking history. The regimen was well tolerated consistent with the pembrolizumab plus pemetrexed/carboplatin safety profile, with transient low-grade injection site reactions present in VAX (29%). Treatment-related study discontinuations were rare (2/38). The ORR/CBR for the ITT and VAX were 37%/69% and 57%/95%, respectively. Median PFS was 7.2 months (95% CI: 5.6,16.8) for both the ITT and VAX, and median OS 16.8 months (95% CI: 11.6, NR) for both groups. Interim immune analysis on 8 patients revealed neoantigen-specific CD4+ and CD8+ T cell responses against 48% of vaccine peptides. T cell responses were durable at 52 weeks and exhibited a memory phenotype with cytolytic potential. Epitope spread was observed in 3 of 5 patients analyzed thus far. Further, assessments of immune and molecular correlates of clinical response identified both tumor mutation burden and baseline levels of T cell infiltration in tumor as highly predictive of durable PFS (p= 0.005 and p= 7.2e-07 (for CD8), respectively). Additional correlates of clinical outcomes with molecular and immunologic responses will be presented.

Conclusions NEO-PV-01 in combination with pembrolizumab and carboplatin/pemetrexed is feasible, has a good safety profile, and induces de novo immune responses in first line non-squamous NSCLC. The association of baseline disease characteristics to prolonged PFS suggests future patient enrichment strategies for evaluation of this novel regimen in a phase 2 trial.

Trial Registration NCT03380871

Ethics Approval The clinical study is conducted in accordance with ethical principles founded in the Declaration of Helsinki and approved by the local institutional review board and health authorities.