Extensive-stage small cell lung cancer (ES-SCLC) represents one of the most challenging malignancies to treat, with a 5-year survival rate of less than 5% and limited therapeutic options after first-line treatment failure. A new retrospective study from the First Affiliated Hospital of Zhengzhou University suggests that combining the multi-targeted tyrosine kinase inhibitor anlotinib with immune checkpoint inhibitors (ICIs) may offer a promising treatment strategy for patients who have previously failed immunotherapy.
The single-center study analyzed 68 patients with ES-SCLC who had experienced disease progression or intolerance to prior ICI-based therapy between September 2018 and September 2024. All patients subsequently received at least one cycle of anlotinib combined with ICIs as part of their clinical care.
Clinical Efficacy Demonstrates Encouraging Results
The combination therapy achieved notable clinical outcomes in this heavily pretreated population. The objective response rate (ORR) reached 32.4% (95% CI: 21.5-44.8%), with 22 patients achieving partial response and 28 patients maintaining stable disease. The disease control rate was 73.5% (95% CI: 61.4-83.5%). No patients achieved complete response, while 14 patients experienced disease progression and 4 were not evaluable due to incomplete imaging assessments.
The median progression-free survival (PFS) was 5.6 months (95% CI: 3.87-7.33), with 12-month and 24-month PFS rates of 30.9% and 9.2%, respectively. Among the 22 patients who achieved partial response, the median duration of response was 6.8 months (95% CI: 0.80-12.83), with a 12-month duration of response rate of 40.4%.
Survival Outcomes Show Promise Against Historical Controls
After a median follow-up of 12.5 months, the median overall survival (OS) reached 13.2 months (95% CI: 7.09-19.31), with 24-month and 30-month OS rates both at 27.6% (95% CI: 16.3-40.2%). These results compare favorably to historical data for standard second-line treatments in ES-SCLC, where topotecan monotherapy typically achieves a median OS of 6-8 months and lurbinectedin shows a median OS of 9.3 months.
The study also revealed important prognostic factors. Patients with ECOG performance status of 0-1 demonstrated significantly longer median OS of 16.2 months compared to 9.5 months for those with ECOG score of 2 (P = 0.021). Additionally, patients who were intolerant to prior immunotherapy had better outcomes than those who experienced disease progression, with median OS of 15.5 months versus 10.9 months (P = 0.031).
Treatment Protocol and Patient Characteristics
The study population had a median age of 61 years, with 75% being male. Notably, 69.1% of patients had platinum-resistant disease, and 77.9% had experienced disease progression on prior immunotherapy. The majority (69.1%) had previously received PD-L1 inhibitors, while 30.9% had received PD-1 inhibitors, reflecting the earlier approval and widespread use of PD-L1 inhibitors in China.
Anlotinib was administered at doses of 8-12 mg orally once daily on a two-week on, one-week off schedule. The ICIs used included PD-1 inhibitors (tislelizumab and serplulimab) and PD-L1 inhibitors (atezolizumab and adebrelimab), administered intravenously every three weeks according to standard protocols.
Safety Profile Proves Manageable
The combination therapy demonstrated a manageable safety profile. Treatment-related adverse events (TRAEs) occurred in 89.7% of patients, with 54.4% experiencing grade 3 or higher events. The most common TRAEs included fatigue (55.9%), nausea and vomiting (45.6%), hypertension (41.2%), hematologic toxicity (33.8%), and liver function abnormalities (26.5%).
Notably, the incidence of pneumonia was 11.8%, significantly lower than the 20-30% typically observed with PD-1 inhibitor monotherapy. The researchers attributed this difference to anlotinib's inhibition of VEGF pathways, which may reduce pulmonary edema. No unexpected or grade 5 TRAEs were observed during the study period.
Mechanistic Rationale Supports Combination Approach
The theoretical basis for combining anlotinib with ICIs lies in their complementary mechanisms of action. Anlotinib targets multiple angiogenesis-related pathways including VEGFR, FGFR, and PDGFR, while also modulating the tumor microenvironment by reducing tumor-associated macrophages and myeloid-derived suppressor cells. This creates conditions that may enhance the infiltration and function of effector T cells.
The researchers noted that anlotinib may facilitate vessel normalization, reduce tumor interstitial pressure, and promote CD8+ T cell infiltration while reversing the immunosuppressive microenvironment. These effects potentially synergize with ICIs' blockade of the PD-1/PD-L1 pathway to restore anti-tumor T cell activity.
Study Limitations and Future Directions
The researchers acknowledged several limitations of their retrospective analysis, including the single-center design, limited sample size, and absence of a formal control group. The heterogeneity of ICIs used and varying anlotinib dosages may have influenced outcomes. Additionally, the study lacked biomarker analysis such as PD-L1 expression or tumor mutational burden, which could have provided insights for patient stratification.
Despite these limitations, the study provides valuable real-world evidence for treatment selection in ES-SCLC patients who have failed prior immunotherapy. The researchers emphasized that larger, multicenter prospective trials are needed to validate these findings and optimize treatment regimens for this challenging patient population.
The results suggest that immune rechallenge strategies, particularly when combined with anti-angiogenic agents like anlotinib, may represent a viable therapeutic approach for patients with previously immunotherapy-treated ES-SCLC, addressing a significant unmet medical need in this aggressive malignancy.
