Leveraging Vulnerabilities of Molecular Subtypes to Identify Rational Combination Therapies-The Next Wave in...

The current landscape of extensive-stage SCLC treatment is dynamic, with exciting active agents including bispecific T-cell engagers, antibody-drug conjugates, and novel combinations. The foundation of SCLC frontline treatment is platinum-etoposide doublet plus anti-PD-L1 inhibitor, but most patients will develop refractory disease. Identifying effective treatments with manageable toxicity remains a major unmet clinical need. The study by Ponce et al, entitled "Combination of Lurbinectedin Plus Irinotecan: Preclinical and Early Clinical Results in Relapsed Small Cell Lung Cancer Patients," made significant contributions to the field. This study revealed that lurbinectedin and irinotecan induced synergistic antitumor activity in specific molecular subtypes of SCLC in preclinical models and then tested this combination in a phase I-II dose-escalation study in 26 patients with relapsed SCLC. This commentary will discuss how this work highlighted several impactful themes in SCLC: (1) innovative use of patient-derived xenografts; (2) synergistic combinations; (3) optimal sequencing of therapies; and (4) appropriate patient selection including the potential for biomarker-directed option for neuroendocrine subtypes.