DLL3 Immunohistochemical Expression in Neuroendocrine-Transformed EGFR-Mutant Lung Cancer and Two Cases of Tarlatamab...

Histologic transformation to high-grade neuroendocrine carcinoma occurs in resistance to EGFR targeted treatment in approximately 3% to 4% of patients with EGFR-mutant lung cancer and is associated with poor outcomes. The bispecific T-cell engager, tarlatamab, targets DLL3 and CD3 and has exhibited activity in classical SCLC. We evaluated DLL3 expression in patients with neuroendocrine-transformed EGFR-mutant lung cancer and present two cases who received tarlatamab.

Patients with high-grade neuroendocrine EGFR-mutant lung cancer de novo or after treatment with osimertinib were evaluated at two academic centers. DLL3 expression in neuroendocrine tissue was assessed by immunohistochemistry using the VENTANA SP347 assay (Roche Diagnostics International AG, Rotkreuz, Switzerland).

Twelve patients were identified. Initial histologic diagnoses included adenocarcinoma (n = 10), adenosquamous (n = 1), and combined small cell carcinoma with an adenocarcinoma component (n = 1), with eight having EGFR exon 19 deletions and four with EGFR L858R. TP53 co-mutations and RB1 loss were detected in all patients tested (10 and 7, respectively). The median time from osimertinib initiation to neuroendocrine transformation was 27.8 months (range 3.6-52.9). DLL3 expression was positive in 11 patients with 15 samples (median 80%, range 1-100) and negative in one patient. Two patients with small cell transformation and 100% tumor DLL3 expression underwent treatment with tarlatamab with progression; osimertinib was subsequently added to tarlatamab in one patient with substantial improvement in all lesions.

In this study, neuroendocrine-transformed EGFR-mutant lung cancer exhibited variable DLL3 expression. Tarlatamab appeared effective when added to osimertinib. Further analysis of the combination of bispecific DLL3 T-cell engager and EGFR tyrosine kinase inhibitor is warranted to confirm these findings.