SLFN11 Expansion Demonstrates Potential as a Predictive Biomarker in SCLC

Schlafen-11 (slfn11) expression may serve as a predictive biomarker for response to select treatments in patients with small cell lung cancer (SCLC), according to findings presented during the International Association for the Study of Lung Cancer 2021 Targeted Therapies of Lung Cancer Meeting.¹

“These data highlight the feasibility and utility of SLFN11 as a predictive biomarker in small cell lung cancer, both from [immunohistochemistry] and [circulating tumor cells],” said lead author Bingnan Zhang, MD, of the Department of Thoracic/Head & Neck Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, in a prerecorded presentation.

Currently, there are no validated predictive biomarkers to help with treatment decision-making in SCLC. However, investigators in preclinical and clinical studies have identified SLFN11 as a possible marker.

For example, in a phase 2 study (NCT01638546) of temozolomide with the PARP inhibitor veliparib or placebo in patients with relapse-sensitive or refractory SCLC, SLFN11 expression indicated which patients would have better clinical outcomes from treatment with the combination regimen. Patients with SLFN11-positive tumors treated with the doublet had significantly prolonged progression-free survival (5.7 vs 3.6 months; P = .009) and overall survival (12.2 vs 7.5 months; P = .014) compared with those with SLFN11-negative tumors.²

SLFN11, a putative DNA/RNA helicase that regulates response to DNA damage and replication stress, can be detected by immunohistochemistry (IHC) in tumor samples and in circulating tumor cells (CTCs) from blood samples. Investigators examined SLFN11 as assessed by IHC assay and CTC analysis as a potential clinical biomarker as a measure of response to therapeutic agents in SCLC.

The SLFN11 IHC assay used in the study was standardized and validated in the MD Anderson Cancer Center laboratory; positivity with the assay was defined as the percentage of tumoral labeling multiplied by intensity score, which was called the H score.

In 3 clinical trials (NCT01638546, NCT01286987, NCT02289690) of 207 SCLC clinical tumor samples, SLFN11 expression was found in 51.7%. The average H score in patients with SLFN11-positive SCLC ranged from 40.4 to 90.7 across the 3 trials.

For CTC analysis, 64 whole blood samples were collected from 42 patients and protein expression was assessed using an immunofluorescence assay, which was processed at Epic Sciences. Among the samples, approximately 6 stable morphometric clusters of SCLC cells were detected. SLFN11 expression was observed independently of morphologic subtype, but the majority of SLFN11-positive CTCs were localized to the nuclear department.

The investigators found that SLFN11 expression on CTCs changes dynamically over time with platinum-based chemotherapy treatment. For example, SLFN11 signals were more suppressed in CTCs while the patient was receiving platinum treatment, with 25% of patients showing SLFN11-positive CTCs during such treatment. In comparison, 71% of patients who were platinum-naive and 40% of patients who had relapsed on platinum treatment had SLFN11-positive CTCs. The investigators suggested that this dynamic nature could have implications for treatment decision-making for patients with SCLC.

Among 15 longitudinal patient blood samples, the investigators found that SLFN11 was most downregulated in correlation with response. Zhang et al recommended that liquid biopsy characterization of CTCs should be an alternative diagnostic tool as it is often challenging to obtain adequate SCLC tumor tissue samples on biopsy.

At present, investigators are using SLFN11 expression positivity as a biomarker to aid in patient selection for maintenance therapy with atezolizumab (Tecentriq) or talazoparib in an ongoing phase 2 study in patients with extensive-stage SCLC (NCT04334941), to further investigate SLFN11’s potential as a predictive biomarker. All patients must have SLFN11- positive expression by IHC testing in order to undergo randomization in the study.

_Reference:

_{1. Zhang B, Stewart CA, Gay CM, et al. Detection of DNA replication blocker SLFN11 in tumor tissue and circulating tumor cells to predict platinum and PARP inhibitors response in small cell lung cancer. Poster presented at: International Association for the Study of Lung Cancer 2021 Targeted Therapies of Lung Cancer Meeting; February 17-20, 2021; Virtual.}

_{2. Pietanza MC, Waqar SN, Krug LM, et al. Randomized, double-blind, phase II study of temozolomide in combination with either veliparib or placebo in patients with relapsed-sensitive or refractory small-cell lung cancer. J Clin Oncol. 2018;36(23):2386-2394. doi:10.1200/JCO.2018.77.7672}