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BackgroundB7-H6 is a member of the B7 family of immune receptors, which is expressed in several solid tumor types but very little expression can be detected in normal tissues.1 2 BI 765049 is a novel IgG-like bispecific T-cell engager designed to bind simultaneously to B7-H6 on tumor cells and CD3 on T cells, resulting in cytolytic synapse formation and tumor lysis. Preclinical studies have demonstrated that BI 765049 monotherapy induced dose-dependent anti-tumor activity in humanized in vivo CRC tumor models. Consistent with the mode of action, the treatment with BI 765049 led to target cell apoptosis, local T-cell activation/proliferation and cytokine production in the tumor tissue, with PD-(L)1 upregulation.3 Activation of the PD-(L)1 provides the rationale for combining BI 765049 with a PD1 inhibitor.MethodsNCT04752215 is a first-in-human, open-label, dose-escalation trial of BI 765049 ± the PD-1 inhibitor, ezabenlimab. Adults with advanced, unresectable and/or metastatic CRC, NSCLC, HNSCC, hepatocellular, gastric or pancreatic carcinoma are eligible. Patients must have failed on, or be ineligible, for standard therapies. B7-H6 positivity must be confirmed at screening by central review (immunohistochemistry assay) in archived tissues/in-study fresh biopsies (except CRC). Patients must have ≥1 evaluable lesion (modified RECIST 1.1) outside of the central nervous system and adequate organ function. The primary objective is to determine the maximum tolerated dose (MTD) or recommended dose for expansion of BI 765049 ± ezabenlimab, based on dose-limiting toxicities during the MTD evaluation period. Further objectives are to evaluate safety, tolerability, PK/PD and preliminary efficacy of BI 765049 ± ezabenlimab. The trial may assess up to 4 dosing regimens: A (BI 765049 once every 3 weeks [q3w]); B1 (BI 765049 qw); B2 (BI 765049 qw with step-in doses); C (BI 765049 + ezabenlimab [q3w]). Dose escalation will be guided by a Bayesian Logistic Regression Model with overdose control that will be fitted to binary toxicity outcomes using a hierarchical modelling approach to jointly model all dosing regimens. Treatment will be allowed to continue until confirmed progressive disease, unacceptable toxicity, other withdrawal criteria or for a maximum duration of 36 months, whichever occurs first. Approximately 150–175 patients will be screened and ~120 patients enrolled. As of July 2021, patients are being recruited in early dose-escalation cohorts.AcknowledgementsMedical writing support for the development of this abstract, under the direction of the authors, was provided by Becky O’Connor, of Ashfield MedComms, an Ashfield Health company, and funded by Boehringer Ingelheim.Trial RegistrationNCT04752215ReferencesBrandt et al. J Exp Med 2009;206:1495–503.Boehringer Ingelheim. Data on file.Hipp et al. AACR Annual Meeting 2021.Ethics ApprovalThe trial will be carried out in compliance with the protocol, the ethical principles laid down in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good Clinical Practice (GCP) and the EU directive 2001/20/EC/EU regulation 536/2014.

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.

IntroductionAvelumab, an antiprogrammed death ligand-1 antibody, is approved as a monotherapy for treatment of metastatic Merkel cell carcinoma and advanced urothelial carcinoma, and in combination with axitinib for advanced renal cell carcinoma. We report the efficacy and safety of first-line avelumab in advanced non-small cell lung cancer (NSCLC).MethodsIn a phase I expansion cohort of the JAVELIN Solid Tumor trial, patients with treatment-naive, metastatic, or recurrent NSCLC received 10 mg/kg avelumab intravenously every 2 weeks. Endpoints included best overall response, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.ResultsOverall, 156 patients were enrolled and treated. Median duration of follow-up was 18.6 months (range, 15 to 23 months). The objective response rate was 19.9% (95% CI, 13.9 to 27.0), including complete response in 3 (1.9%) and partial response in 28 (17.9%). Median DOR was 12.0 months (95% CI, 6.9 to not estimable). Median PFS was 4.0 months (95% CI, 2.7 to 5.4) and the 6-month PFS rate was 38.5% (95% CI, 30.7 to 46.3). Median OS was 14.1 months (95% CI, 11.3 to 16.9) and the 12-month OS rate was 56.6% (95% CI, 48.2 to 64.1). Treatment-related adverse events (TRAEs) occurred in 107 patients (68.6%), including grade ≥3 TRAEs in 19 (12.2%). Immune-related adverse events and infusion-related reactions occurred in 31 (19.9%) and 40 patients (25.6%), respectively. No treatment-related deaths occurred.ConclusionAvelumab showed antitumor activity with a tolerable safety profile as a first-line treatment in patients with advanced NSCLC. These data support further investigation of avelumab in the phase III JAVELIN Lung 100 study.Trial registration detailsClinicalTrials.gov NCT01772004; registered January 21, 2013.