Small cell lung cancer (SCLC) is one of the most aggressive and challenging malignancies characterized by rapid proliferation and early metastases. It accounts for approximately 15% of all lung cancers and in  2024 approximately 16,000 cases were diagnosed in the United States.¹ It is strongly associated with tobacco exposure, with about 95% of cases occurring in smokers.¹ At diagnosis, nearly 70% of patients present with extensive-stage disease (ES-SCLC), meaning the cancer has already spread beyond one lung.¹ Relapse is almost inevitable, and only 5% of patients survive two years after initial diagnosis.²˒³

Historically, treatment options for ES-SCLC have been limited, and survival rates remain among the lowest in oncology. However, the landscape is slowly changing as incremental advances in therapy begin to reshape patient outcomes, bringing cautious optimism, while simultaneously challenging payers with a market shift from lower-cost chemotherapy to higher-cost targeted treatments.⁴ 

For nearly four decades, treatment for SCLC has relied exclusively on platinum-based chemotherapy, which often yields an initial response but is followed by rapid disease recurrence within months.¹˒⁵ In 2019, the IMpower133 and CASPIAN trials marked the first significant progress in ES-SCLC in over 20 years. These studies introduced PD-L1 inhibitors alongside traditional chemotherapy, delivering a modest overall survival benefit of an additional 2–3 months compared to chemotherapy alone. ⁶˒⁷ The combination is frequently viewed as falling short of cost-effectiveness thresholds due to its modest survival gain. Notably, these evaluations considered only drug costs and survival, omitting major drivers such as symptomatic care and hospitalizations.⁸ Despite these considerations, these regimens are FDA-approved and included in NCCN guidelines.  

In 2020, Zepzelca (lurbinectedin), an alkylating agent, received accelerated approval as monotherapy for metastatic SCLC after progression on platinum-based chemotherapy.⁹ Since then, its role has expanded, with full FDA approval in October 2025 for use in combination with Tecentriq (atezolizumab) as first-line maintenance therapy for ES-SCLC following induction chemoimmunotherapy. This approval was supported by the Phase 3 IMforte trial, which demonstrated a significant improvement in overall survival (13.2 vs 10.6 months) and progression-free survival (5.4 vs 2.1 months) compared to atezolizumab alone.⁹

A  major milestone for the ES-SCLC community was the introduction of Imdelltra (tarlatamab), a first-in-class bispecific T-cell engager (BiTE) targeting DLL3, a protein expressed on the surface of SCLC cells.¹⁰ This medication not only demonstrated a significant OS benefit of 13.6 vs 8.3 months compared to chemotherapy but opened the horizons to the use of targeted immunotherapy.¹⁰ Initially granted accelerated approval in May 2024 for patients with disease progression after platinum-based chemotherapy, its recent conversion to full FDA approval in November 2025 was based on the pivotal Phase 3 DeLLphi-304 trial.¹¹

Expert opinion widely regards tarlatamab as a game changer, offering a novel immunotherapy approach for a population with historically poor outcomes. Today, tarlatamab carries an NCCN category 1 recommendation for second-line therapy, and ongoing evaluation in the phase 1b DeLLphi-303 trial for first-line maintenance signals potential expansion into earlier treatment settings.¹⁰˒¹² While enthusiasm is high, clinicians remain vigilant about managing toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).¹⁰ 

Historically, molecular targets have been uncommon in SCLC, limiting opportunities for precision medicine. However, ongoing research is changing this landscape, a shift catalyzed by the approval of tarlatamab. Research has identified several actionable targets, including DLL3, B7-H3, SEZ-6, and TROP2, which are highly expressed in SCLC cells but minimally present in normal tissue.¹³˒¹⁴ These therapies aim to personalize treatment, which could lead to better outcomes and longer durability of response. Emerging therapies include antibody drug conjugates (ADCs), Chimeric Antigen Receptor T-Cell therapies (CAR T) and additional BiTE therapies.¹⁵

The introduction of high-cost targeted therapies in the SCLC space means payers must balance clinical innovation with affordability as analysts project the SCLC market to grow from $1.5 billion to $5 billion over the next decade.¹⁵ This is driven by not only the high-cost of recently approved agents such as PD-L1 inhibitors, lurbinectedin combinations, and tarlatamab but also the emerging agents - ADCs, additional BiTEs, and cell therapies. Beyond drug costs, payers must consider administration expenses, biomarker testing, and adverse events such as CRS and ICANS, which often lead to hospitalizations and emergency care, representing more than half of total treatment costs. Proactive strategies to manage financial impact will be critical. 

To address these challenges, payers should consider innovative approaches that align clinical outcomes with economic sustainability. Potential strategies include: 

• Innovative value-based agreements  
• Copay assistance and financial navigation programs 
• Site of service opportunities  
• Care management and navigation programs to mitigate adverse effects and acute care utilization 

Looking ahead, payers will need to integrate real-world evidence into coverage decisions, develop budget impact models for pipeline therapies, and collaborate with providers to ensure adherence and toxicity management. These steps will be critical to balancing access, affordability, and innovation in a rapidly evolving SCLC treatment landscape.