First-line treatment of unresectable or metastatic HER2 positive esophagogastric adenocarcinoma: liquid biomarker analysis of the phase 2 INTEGA trial

Abstract

BackgroundThe addition of nivolumab to trastuzumab and chemotherapy in first-line unresectable or metastatic HER2 positive esophagogastric adenocarcinoma (HER2+ EGA) results in long progression-free and overall survival as shown by the INTEGA (ipilimumab or FOLFOX in combination with nivolumab and trastuzumab in HER2 positive esophagogastric adenocarcinoma) trial. This trial suggested that the chemotherapy backbone is needed in an unselected HER2+ patient population. Yet, it remains an open question if there are specific patient subsets that may benefit from an enhanced immunotherapeutic but chemotherapy-free approach.MethodsWe analyzed blood T cell repertoire metrics determined by next-generation sequencing, circulating tumor cell (CTC) counts detected by CellSearch and their expression of HER2 and PD-L1 as potential liquid biomarkers predicting outcomes on ipilimumab versus FOLFOX (folinic acid, FOL, fluorouracil, F, oxaliplatin, OX) chemotherapy added to a backbone of trastuzumab and nivolumab in patients with HER2+ EGA in the INTEGA trial population.ResultsPatients with two out of three baseline-determined liquid biomarkers—high T cell repertoire richness, absence of CTCs or HER2-expression on CTCs—made up approximately 44% of HER2+ EGA cases and did not show compromise in efficacy if treated with a chemotherapy-free regimen. Long-term responders showing a progression-free survival of >12 months were enriched in this biomarker triad, especially if treated on the chemotherapy-free arm.ConclusionProspective validation of this liquid biomarker triad is needed to molecularly define HER2+ EGA patient subsets with different needs in the first-line systemic treatment setting.

Pembrolizumab and trastuzumab in combination with FLOT in the perioperative treatment of HER2-positive, localized esophagogastric adenocarcinoma—a phase II trial of the AIO study group (AIO STO 0321)

“…Tumor-infiltrating lymphocyte (TiL) repertoires will be determined by next-generation sequencing (NGS) of the T-cell receptor beta (TCRβ) and immunoglobulin heavy locus (IGH). In previous studies, the diversification of T cells during therapy or TiL clone expansion in the peripheral blood was associated with response to immunotherapies ( 25 , 26 ). Resistance to HER2-targeting in HER2-positive tumors might be already present at time of first diagnosis or will eventually develop during antitumor treatment.…”

Extracellular Vesicles, Circulating Tumor Cells, and Immune Checkpoint Inhibitors: Hints and Promises

“…The function of this checkpoint acts as a "don't-find-me" signal to the adaptive immune response [170]. PD-L1 has been established as a predictive biomarker of the response to PD-L1/PD-1 inhibitors [171]. However, it is reported that >50% patients with high PD-L1 expression in tumor tissue do not benefit from first-line Pembrolizumab [172], and 10% of patients with a PD-L1 negative tumor do respond to second-line inhibitors [173].…”

“…However, some studies have shown that determination of PD-L1 expression in CTCs is not useful to predict treatment outcome. In the phase 2 INTEGA trial conducted on esophagogastric patients, PD-L1 expression on CTCs using CellSearch was not associated with a specific outcome in the Ipi arm (Trastuzumab and Nivolumab in combination with Ipilimumab) [171]. In metastatic renal cell carcinoma patients, Bootsma et al focused on the expression of PD-L1 and HLA-I in CTCs, captured and enriched using a versatile exclusion-based rare sample analysis (VERSA).…”