Abstract

Rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate directed against Delta-like protein 3 (DLL3), is under development for patients with small cell lung cancer (SCLC). DLL3 is expressed on the majority of SCLC samples. Because SCLC is rarely biopsied in the course of disease, data regarding DLL3 expression in relapses is not available. The aim of this study was to investigate the expression of DLL3 in chemorelapsed (but untreated with Rova-T) SCLC samples and compare the results with chemonaive counterparts. Two evaluation methods to assess DLL3 expression were explored. Additionally, we assessed if DLL3 expression of chemorelapsed and/or chemonaive samples has prognostic impact and if it correlates with other clinicopathological data. The study included 30 paired SCLC samples, which were stained with an anti DLL3 antibody. DLL3 expression was assessed using tumor proportion score (TPS) and H-score and was categorized as DLL3 low (TPS < 50%, H-score ≤ 150) and DLL3 high (TPS ≥ 50%, H-score > 150). Expression data were correlated with clinicopathological characteristics. Kaplan–Meier curves were used to illustrate overall survival (OS) depending on DLL3 expression in chemonaive and chemorelapsed samples, respectively, and depending on dynamics of expression during course of therapy. DLL3 was expressed in 86.6% chemonaive and 80% chemorelapsed SCLC samples without significant differences between the two groups. However, the extent of expression varied in a substantial proportion of pairs (36.6% with TPS, 43.3% with H-score), defined as a shift from low to high or high to low expression. TPS and H-score provided comparable results. There were no profound correlations with clinicopathological data. Survival analysis revealed a trend toward a more favorable OS in DLL low-expressing chemonaive SCLC (p = 0.57) and, in turn, in DLL3 high-expressing chemorelapsed SCLC (p = 0.42) as well as in SCLC demonstrating a shift from low to high expression (p = 0.56) without being statistically significant. This is the first study to investigate DLL3 expression in a large cohort of rare paired chemonaive-chemorelapsed SCLC specimens. Comparative analysis revealed that DLL3 expression was not stable during the course of therapy, suggesting therapy-based alterations. Unlike in chemonaive samples, a high DLL3 expression in chemorelapsed samples indicated a trend for a more favorable prognosis. Our results highlight the importance to investigate DLL3 in latest chemorelapsed SCLC tumor tissue.

Highlights

  • Small cell lung cancer (SCLC) is known as a highly aggressive type of cancer with a miserable prognosis

  • In case of a loss of Delta-like protein 3 (DLL3) expression in chemorelapsed SCLC samples one could assume that a therapy with Rovalpituzumab tesirine (Rova-T) is not promising

  • One of the two cases with concordant DLL3-low expression derived from an autopsy so that loss of expression may originate from autolysis

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Summary

Introduction

Small cell lung cancer (SCLC) is known as a highly aggressive type of cancer with a miserable prognosis. It is the second most common lung cancer type and accounts for ∼15% of lung cancer cases. Therapy remained essentially unchanged in recent years and is usually based on chemotherapy with etoposide and a platinating agent (1), whereas, lately, clinical activity of immunotherapies has been observed in patients with refractory or metastatic SCLC. SCLC-targeted therapy research has progressed, in contrast to non-small cell lung cancer (NSCLC) no personalized targeted therapy options have been derived so far. Further research into the mechanism of SCLC and the exploration of new therapeutic targets for SCLC are indispensable (4)

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