Dr Salgia on Biomarker-Driven Therapies of Interest for Second-Line SCLC

"Clearly, DLL3 and B7H3 are important targets. At the same time, we've shown that the mitochondrial functionality in SCLC is important [to target], so those are some interesting therapies that should come to fruition."

Ravi Salgia, MD, PhD, a medical oncologist and the Arthur & Rosalie Kaplan Chair of medical oncology at City of Hope, emphasized several emerging biomarker-driven strategies that may inform future second-line treatment approaches in small cell lung cancer (SCLC), as discussed during the 2025 Bridging the Gaps in Lung Cancer consensus meeting,

Among the most promising targets is delta-like ligand 3 (DLL3), which continues to gain traction as a viable therapeutic focus, Salgia begins. Another immunologic target of interest is B7-H3, which may also serve as a foundation for novel agents in development, he noted.

In addition to these surface markers, mitochondrial biology is increasingly recognized as relevant to SCLC pathogenesis, Salgia continued, underscoring the unique mitochondrial density and functional complexity in SCLC tumor cells. As a result, investigational agents that impair mitochondrial function could offer therapeutic benefit, particularly when used in combination strategies, he explained.

Ongoing efforts to develop more personalized treatment regimens include attempts to molecularly subcategorize SCLC into distinct genomic subtypes, with the aim of matching targeted therapies to specific molecular profiles. One biomarker of interest in this regard is SLFN11, which has been associated with sensitivity to DNA-damaging agents and may serve as a predictive biomarker in both second- and third-line settings.

Salgia pointed to several therapeutic combinations under consideration, such as combining immunotherapy with agents like lurbinectedin (Zepzelca), or pairing lurbinectedin with mitochondrial inhibitors. These rational combinations are expected to be a key part of evolving SCLC treatment paradigms, particularly as the field shifts toward biomarker-informed clinical decision-making.

Overall, the future of second-line SCLC therapy will center around biomarker-driven approaches that incorporate both novel targets and mechanistically guided combination regimens, Salgia concluded.