Tarlatamab Retreatment in ES-SCLC and Resistance Mechanisms

Dr. Chiang addresses whether tarlatamab used in maintenance retains efficacy if used again after progression, acknowledging significant unknowns regarding resistance mechanisms for novel T-cell engager therapies compared to better-understood chemotherapy resistance. Given the distinct mechanism of physically engaging T cells with tumor cells, she believes retreatment possibilities shouldn't be dismissed and require further study, similar to how platinum rechallenge has been used previously.

Dr. Sands discusses preliminary data from blood-based RNA expression testing revealing that resistance mechanisms may involve subtype shifting from ASCL1 to NEUROD1 with loss of DLL3 expression, alongside increased T-cell exhaustion markers suggesting diminished immunotherapy effects within the tumor microenvironment. He emphasizes interest in real-time blood-based monitoring to track these dynamic changes, noting SCLC's exceptional plasticity compared to other tumor types.

Dr. Shields suggests that patients discontinuing tarlatamab for reasons other than progression, such as complications or shared decision-making despite good disease control without acquired resistance or multifocal progression, might represent appropriate retreatment candidates. She emphasizes incomplete understanding of post-tarlatamab tumor biology, noting SCLC's high circulating tumor DNA shedding makes it particularly amenable to liquid biopsy, with multiple groups actively investigating resistance mechanisms that likely involve multiple contributing factors rather than singular pathways.