Recent developments in small cell lung cancer (SCLC) treatment are reshaping the therapeutic landscape, with the FDA's accelerated approval of tarlatamab and positive results from trials like ADRIATIC and IMforte influencing treatment strategies. These advancements offer new hope for patients with this aggressive cancer.
Tarlatamab Approval and its Impact
In May 2024, the FDA granted accelerated approval to tarlatamab-dlle (Imdelltra), a bispecific T-cell engager (BiTE), for the treatment of SCLC that has progressed on or after platinum-based chemotherapy. This approval was based on the phase 2 DeLLphi-301 study (NCT05060016). According to Ariel Lopez-Chavez, MD, this approval is changing how second-line SCLC is treated.
ADRIATIC Trial: Durvalumab Consolidation
The ADRIATIC trial (NCT03703297) has demonstrated the benefit of durvalumab consolidation after concurrent chemoradiation in limited-stage SCLC. Misty Dawn Shields, MD, PhD, highlighted that consolidation durvalumab significantly boosted progression-free survival (PFS) and overall survival (OS) in these patients. At a median follow-up of 37.2 months, the median OS was 55.9 months (95% CI, 37.3-not evaluable) with durvalumab alone vs 33.4 months (95% CI, 25.5-39.9) with placebo (HR, 0.73; 95% CI, 0.57-0.93; P = .0104). The median PFS in the respective arms was 16.6 months (95% CI, 10.2-28.2) vs 9.2 months (95% CI, 7.4-12.9; HR, 0.76; 95% CI, 0.61-0.95; P = .0161).
This data supported the FDA approval of durvalumab in December 2024 for adults with limited-stage SCLC whose disease has not progressed after concurrent platinum-based chemotherapy and radiation.
IMforte Trial: Lurbinectedin in Maintenance Setting
The IMforte trial (NCT05091567) explored the use of lurbinectedin in the maintenance setting after induction chemoimmunotherapy. The trial read out positive, indicating that the combination of lurbinectedin and atezolizumab led to a significant OS and PFS benefit over atezolizumab alone when used as frontline maintenance in this population. This is particularly relevant in the limited-stage setting, according to Dr. Lopez-Chavez.
Current Approaches and Unmet Needs
For recurrent SCLC, newer agents like lurbinectedin and tarlatamab offer better tolerability compared to older drugs like topotecan and irinotecan. However, there are currently no validated biomarkers to predict patient responses to immunotherapy in extensive-stage SCLC. Comprehensive genomic profiling is primarily reserved for patients who have never smoked or when the diagnosis is unclear.
Future Directions
Ongoing research is focused on integrating novel agents into the SCLC treatment paradigm. Clinical trials remain a top priority, with newer agents showing promise in the second-line setting and beyond. The B7-H3 targeted antibody-drug conjugate, which recently received breakthrough therapy designation from the FDA, is also being closely watched. Additionally, trials like DeLLphi-305, which is moving tarlatamab into the maintenance setting, are nearing completion.
Shields also noted the phase 3 DELLphi-306 study (NCT06117774) examining tarlatamab vs observation in LS-SCLC, and posed the question of whether DLL3-targeted BiTEs can improve outcomes post-chemoradiation.
