Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy. Most patients present with advanced disease at diagnosis, and despite robust initial response to first-line treatment, recurrence is common, typically within 1 year. Indeed, therapeutic advances in SCLC have generally lagged behind those seen with the more-common non-small cell lung cancer, but the past few years have witnessed the development of targeted and immunotherapy approaches. For example, tarlatamab is a bispecific T-cell engager that targets the T-cell marker CD3 and a specific neuroendocrine marker, delta-like ligand 3 (DLL3), that has high expression on the surface of SCLC tumor cells, minimal expression in normal tissues, and has been recognized as an established therapeutic target for patients with SCLC.
Tarlatamab is indicated for treatment of adult patients with extensive-stage SCLC (ES-SCLC) that has progressed during or after prior platinum-based therapy. While there has been clinical success with tarlatamab in the relapsed/refractory setting, more than 50% of patients still experience progression within 6 months of initiating therapy. To determine whether these patients with poor prognosis could be identified and selected for alternate therapy approaches, researchers at Massachusetts General Hospital investigated potential biomarkers for use as predictors of response to tarlatamab.
As published in Cancer Discovery, Dr Avanish Mishra and colleagues discovered that pretreatment DLL3 expression on circulating tumor cells (CTCs) in patients with SCLC was highly predictive of response to tarlatamab. Using baseline and longitudinal blood specimens for CTC analysis, they found that patients with abundant DLL3-positive CTCs (≥25%) derived clinical benefit from tarlatamab, while those with a lower fraction rarely had a response. Scoring DLL3-positive vs DLL3-low patients for clinical benefit from tarlatamab had a sensitivity of 85%, a specificity of 100%, and a positive predictive value of 100%, supporting its use as a predictive biomarker for patients with ES-SCLC.
High level
The finding that CTC expression of DLL3 is predictive of clinical response to tarlatamab is a proof of concept, and these results will need to be validated in a larger multi-institutional trial and using different CTC analysis platforms. Future studies investigating the impact of CTC DLL3 expression on clinical outcomes to alternative regimens are warranted, and clinical trials may help determine whether sequential or simultaneous targeting of distinct markers in SCLC leads to improved disease control. If the results of this study are confirmed, this research may have potential implications for the treatment of other cancers that express DLL3 as they become more aggressive and for the field of antibody-directed cancer therapies as a whole. While the procedure for CTC isolation and imaging will require clinical standardization prior to its widespread incorporation, CTC scoring may ultimately enable better selection of patients for antibody-based therapeutics.
Ground level
This study illustrates the rapid progress of therapeutic innovations and hope for improved outcomes in patients with SCLC, who have historically suffered a heavy burden of disease and toxicity from aggressive chemotherapies. With the development of antibody-based approaches, therapies are becoming more adept at targeting SCLC cells. CTC-based quantitation for DLL3 expression in advanced SCLC may be used in the future to identify patients likely to have a response to tarlatamab, as well as to dissect distinct mechanisms of acquired resistance during treatment that could suggest additional therapeutic considerations. While further research is needed, this discovery could enable clinicians to rapidly and noninvasively determine which patients with SCLC are most likely to benefit from tarlatamab using liquid biopsy.
