Exploratory evaluation of baseline tumor biomarkers and their association with response and survival in patients with previously treated advanced gastric cancer treated with andecaliximab combined with nivolumab versus nivolumab.

Abstract

148 Background: Andecaliximab (ADX) is a monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9). Preclinical studies suggest that MMP9 inhibition relieves immune suppression and promotes T cell infiltration to potentiate checkpoint blockade. In the phase 2 study combining ADX with nivolumab (N) versus N monotherapy (NCT02864381), addition of ADX to N did not improve objective response rate, progression-free survival (PFS), or overall survival (OS). Methods: Archival tumor samples were collected from all patients (n = 141). CD8 and PD-L1 (28-8 DAKO) were assessed by immunohistochemistry. CD8+ cell density was measured in the tumor area. PD-L1 was prospectively scored by a pathologist for tumor cell (TC) and associated immune cell (IC) positivity. IFNg, Teffector (Teff), and activated CD8+ T cell (ActT) gene signatures were assessed by RNA sequencing. Due to a small number of responders, treatment arms were combined to evaluate response. Cox proportional hazards models were used for survival analyses. Nominal p-values are reported. Results: Baseline biomarkers of T cell infiltration and activation did not differentiate responders from non-responders (IFNg, Teff, ActT, CD8+; p > .10). None of the evaluated biomarkers were associated with PFS or OS for all treated patients or per treatment arm (IFNg, Teff, ActT; p > .10), with the exception of CD8+ (PFS HR = .43, p = .02). The majority of baseline samples were positive for IC PD-L1 (< 1%, n = 36; 1-10%, n = 50; > 10-25%, n = 32; > 25%, n = 20) and negative for TC PD-L1 (H = 0, n = 88; H < 1, n = 27; H > 1; n = 27). Comparing ADX/N to N, there was a trend toward longer OS for the PD-L1+ (TC + IC ≥ 1%) population (n = 102, HR = .621, p = .098), the TC H < 1 group (HR = .464, p = .08) and the IC > 10-25% (HR = .466, p = .08). Conclusions: Neither CD8+ cell density nor IFNg, Teff or ActT gene signatures were associated with response or survival to checkpoint blockade. While TC was low, IC intermediate and TC + IC ≥ 1% PD-L1+ groups trended toward better survival for the ADX+N arm, consistent with the hypothesis that ADX potentiates N activity; this did not translate into better outcome. Clinical trial information: NCT02864381.