8087 Background: Tarlatamab is a DLL3-targeted bispecific T-cell engager used to treat small cell lung cancer (SCLC). SCLC subtypes can be defined by relative expression of master transcription factors (TFs). Whether subtype and DLL3 expression are associated with outcomes on tarlatamab is unknown. Methods: We analyzed all patients (pts) with SCLC, including SCLC transformed from lung adenocarcinoma, treated with tarlatamab at Memorial Sloan Kettering prior to October 2025. DLL3 expression and subtyping were determined by IHC by dedicated thoracic pathologists. Expression of subtype TFs ASCL1, NEUROD1, POU2F3, and YAP1 was assessed. “Neuroendocrine (NE)-high” was defined as any ASCL1 or NEUROD1 expression. Pts with any “neuroendocrine (NE)-low” subtype expression—POU2F3 or YAP1—were grouped for analysis. DLL3 fractional expression was dichotomized as “high” (≥50%) or “low” (0-49%). Progression-free and overall survival (PFS, OS) were analyzed with Kaplan-Meier curves and compared with the Cox proportional hazards model. Results: We identified 39 pts with SCLC treated with tarlatamab with DLL3 and/or subtyping data available. Median age was 65, 49% were women, and median prior lines of therapy was 1. DLL3 expression was available in 34 pts. Median fractional DLL3 expression was 80% and ranged from 0 to 100%. 7 pts had low expression and 27 had high expression. There were more pts with transformed SCLC in the DLL3-low group (3/7 43% vs 1/27 4%, p=0.02). Among pts with response data available, response was inferior in the DLL3-low group: complete or partial response (CR or PR) in 0/7 (0%; 95% CI, 0 to 35) vs 12/25 (48%; 95% CI, 30 to 67); stable disease (SD) in 2/7 (29%) vs 5/25 (20%); progressive disease (PD) in 5/7 (71%) vs 8/25 (32%); p=0.049. Median PFS was 1.4 mos in DLL3-low vs 4.5 mos in DLL3-high disease (p0.9). 30/39 pts had subtyping data available. 28/30 pts had NE-high tumors (15/28 ASCL1+/NEUROD1+; 11/28 ASCL1+/NEUROD1-; 2/28 ASCL1-/NEUROD1+). 5/30 had subtype biomarkers of NE-low status: 4 YAP1+ and 1 POU2F3+; the 4 YAP1+ tumors also expressed ASCL1. Response rates were similar between pts with and without NE-low expression: 1/5 (20%; 95% CI, 1 to 62) vs 11/25 (44%; 95% CI, 27 to 63), p=0.6. PFS was also similar (mPFS 1.1 vs 2.7 mos, p=0.3). Conclusions: Low DLL3 expression was potentially associated with inferior response to tarlatamab. A contributing factor may be enrichment of transformed SCLC, which is associated with poor outcomes. We did not detect an impact of POU2F3/YAP1 expression. The majority of pts in this cohort had DLL3-high, NE-high SCLC—in line with prior studies—and they had a response rate of 48%. These data emphasize the need for more discerning predictive biomarkers for tarlatamab in an evolving landscape of treatment options.
Ross et al. (Thu,) studied this question.