What was the outcome of the CASPIAN study regarding the effect of maintenance durvalumab (durvalumab) on overall survival in patients with small cell lung cancer (SCLC) who responded to initial chemotherapy?

CASPIAN Study Overview and Maintenance Durvalumab Outcomes in Extensive-Stage Small Cell Lung Cancer

The CASPIAN trial demonstrated that first-line durvalumab plus platinum-etoposide chemotherapy for 4 cycles followed by maintenance durvalumab significantly improved overall survival compared to chemotherapy alone in patients with extensive-stage small cell lung cancer, establishing this regimen as a standard of care. 1

Study Design and Patient Population

The CASPIAN trial was an international, phase III, open-label study that enrolled 805 treatment-naïve patients with extensive-stage SCLC across 209 sites in 23 countries. 1, 2 Patients were randomized 1:1:1 to three arms:

• Chemotherapy alone: Platinum-etoposide (PE or CE) for up to 6 cycles 1
• Durvalumab plus chemotherapy: 4 cycles of platinum-etoposide plus durvalumab 1500 mg every 3 weeks, followed by maintenance durvalumab 1500 mg every 4 weeks until progression 1, 2
• Durvalumab plus tremelimumab plus chemotherapy: 4 cycles followed by maintenance durvalumab (this arm did not show significant benefit) 1

Primary Efficacy Outcomes with Maintenance Durvalumab

Overall Survival Benefits

Maintenance durvalumab following initial chemoimmunotherapy produced clinically meaningful and statistically significant improvements in overall survival. 1, 2

• Median OS: 13.0 months with durvalumab plus chemotherapy versus 10.3 months with chemotherapy alone (HR 0.73,95% CI 0.59-0.91; P=0.005) 1, 2
• 1-year OS rate: 54% versus 40% 1
• 18-month OS rate: 32% with durvalumab versus 25% with chemotherapy alone 1
• Updated analysis at 25.1 months median follow-up showed sustained benefit with median OS of 12.9 months versus 10.5 months (HR 0.75,95% CI 0.62-0.91; nominal P=0.0032) 3

Progression-Free Survival and Response Rates

• 1-year PFS rate: 18% with durvalumab versus 5% with chemotherapy alone (HR 0.78) 1
• Objective response rate: 68% versus 58% 1
• The PFS benefit was maintained throughout the maintenance phase, demonstrating the value of continued immunotherapy beyond initial chemotherapy completion 3, 2

Safety Profile of Maintenance Durvalumab

Overall toxicity was similar between the durvalumab and chemotherapy-alone arms, with immune-related adverse events being the primary distinguishing safety concern. 1

• Grade 3-4 adverse events: 62% in both arms 1
• Treatment-related mortality: 5-6% in the durvalumab arm versus 1% in chemotherapy alone 1
• Immune-related adverse events: 20% with durvalumab versus 3% with chemotherapy alone 1
• Treatment-related deaths in the durvalumab arm included cardiac arrest, dehydration, hepatotoxicity, interstitial lung disease, pancytopenia, and sepsis 3

Patient-Reported Outcomes During Maintenance

Maintenance durvalumab preserved quality of life and delayed symptom deterioration compared to chemotherapy alone. 4

• Patients experienced longer time to deterioration for all key symptoms including cough (HR 0.78), dyspnea (HR 0.79), chest pain (HR 0.76), fatigue (HR 0.82), and appetite loss (HR 0.70) 4
• Appetite loss showed statistically significant improvement favoring durvalumab (difference -4.5,99% CI -9.04 to -0.04; P=0.009) 4
• Global health status and quality of life were maintained throughout the maintenance phase 4

Clinical Guideline Recommendations

ASCO strongly recommends first-line platinum-etoposide plus durvalumab for 4 cycles followed by maintenance durvalumab as a preferred treatment for extensive-stage SCLC (Category 1 recommendation). 1

The 2023 ASCO-Ontario Health guideline explicitly states that patients with ES-SCLC should receive platinum and etoposide plus either durvalumab or atezolizumab for four cycles followed by maintenance immunotherapy, based on high-quality evidence with strong recommendation strength. 1

The NCCN guidelines similarly recommend durvalumab plus etoposide plus carboplatin or cisplatin as a preferred first-line option followed by maintenance durvalumab (Category 1). 1

Biomarker Analysis and Patient Selection

The benefit of maintenance durvalumab was observed regardless of PD-L1 expression or tissue tumor mutational burden status. 5

• OS benefit with durvalumab plus chemotherapy versus chemotherapy alone was consistent across all PD-L1 subgroups, with hazard ratios falling within the 95% CI of 0.47-0.79 5
• There was no evidence of interaction between tTMB and treatment effect on OS (P=0.916) 5
• Clinical implication: PD-L1 testing is not required for patient selection, and all patients with ES-SCLC should be considered for this regimen unless contraindications to immunotherapy exist 1, 5

Critical Considerations for Maintenance Therapy

Duration and Monitoring

• Maintenance durvalumab is administered at 1500 mg every 4 weeks until disease progression or unacceptable toxicity 1, 2
• The maintenance phase can continue for up to 2 years in some protocols, though the CASPIAN trial allowed continuation until progression 3, 2

Common Pitfalls to Avoid

• Do not discontinue maintenance durvalumab prematurely without clear evidence of progression or unacceptable toxicity, as the survival benefit is dependent on continued immunotherapy 4, 3
• Do not add tremelimumab to the durvalumab-chemotherapy regimen, as the three-drug combination (durvalumab plus tremelimumab plus chemotherapy) failed to significantly improve outcomes and increased toxicity 1, 3
• Monitor vigilantly for immune-related adverse events during maintenance, particularly pneumonitis (38.2% any grade with durvalumab versus 30.2% with chemotherapy alone), as early recognition and intervention with corticosteroids is critical 1

Contraindications to Consider

Patients with the following should not receive maintenance durvalumab:

• Active autoimmune disease requiring systemic immunosuppression 1
• History of grade ≥2 pneumonitis from prior immunotherapy 1
• Interstitial lung disease or active pneumonitis 1

Comparative Context with Other Immunotherapy Regimens

The CASPIAN results are consistent with the IMpower133 trial (atezolizumab plus chemotherapy), which showed similar magnitude of OS benefit (HR 0.76) in ES-SCLC. 1 A meta-analysis including CASPIAN, IMpower133, KEYNOTE-604, and EA5161 confirmed strong evidence for improvement in both PFS and OS with addition of immunotherapy, with no significant difference between anti-PD-L1 and anti-PD-1 agents. 1