Sintilimab-Anlotinib Combination Shows Promise in Advanced Sarcoma Treatment with Biomarker-Guided Approach

Overview: How Might Combined Therapy Transform Sarcoma Management?

The combination of sintilimab and anlotinib has demonstrated promising efficacy in patients with advanced sarcomas, according to results from a recent single-arm phase II trial conducted at Shandong Cancer Hospital and Institute. This study specifically evaluated the efficacy and safety of combining an anti-PD-1 monoclonal antibody (sintilimab) with a multitargeted tyrosine kinase inhibitor (anlotinib) in patients with locally advanced or metastatic sarcoma, with particular emphasis on non-alveolar soft-part sarcoma (non-ASPS) cases. Sarcomas represent a heterogeneous group of mesenchymal tumors with limited treatment options after progression on first-line anthracycline-based chemotherapy, making this investigation particularly relevant for clinical practice. The study also pioneered the investigation of tertiary lymphoid structures (TLS) as a potential predictive biomarker for therapeutic response to combined antiangiogenic and immune checkpoint blockade therapy, addressing a significant unmet need in sarcoma management.

The trial enrolled 42 patients with histologically confirmed advanced sarcoma, predominantly consisting of soft tissue subtypes (92.9%) including dedifferentiated liposarcoma (16.7%), synovial sarcoma (11.9%), leiomyosarcoma (7.1%), clear-cell sarcoma (7.1%), and fibrosarcoma (7.1%). Most patients had metastatic disease (85.7%), with the most common sites being lungs (42.9%), lymph nodes (21.4%), liver (16.7%), and bone (11.9%). The majority of participants (78.6%) received the combination as second-line therapy after progression on anthracycline-based regimens, though a small proportion (9.5%) received it as first-line treatment for chemotherapy-resistant subtypes like ASPS and clear-cell sarcoma. Patients received sintilimab intravenously at 200 mg every 3 weeks and anlotinib orally at individualized starting doses of 8, 10, or 12 mg (days 1-14 of each 21-day cycle) based on physical condition. This personalized dosing approach for anlotinib represented a departure from previous studies that employed fixed dosing, potentially contributing to the favorable toxicity profile observed in this trial.

After a median follow-up of 15.4 months, the combination therapy demonstrated an objective response rate (ORR) of 30.9% (95% CI, 16.4%-45.5%) with one complete response and 12 partial responses among the 42 evaluable patients. The disease control rate reached 76.2% (95% CI, 62.8%-89.6%), with 19 patients achieving stable disease. Median progression-free survival was 5.0 months (95% CI, 2.8-10.2), while median overall survival had not been reached at the data cutoff. The 12-month overall survival rate was 62.6% (95% CI, 47.3%-77.9%), suggesting durable benefits from the combination therapy. Notably, in the non-ASPS subgroup, the combination maintained substantial efficacy with an ORR of 27.5% (95% CI, 16.1%-42.8%) and a disease control rate of 75% (95% CI, 59.8%-85.8%), addressing a significant knowledge gap as most previous studies of multikinase angiogenesis inhibitors plus immune checkpoint inhibitors had cohorts heavily biased toward ASPS patients.

Are Safety and Biomarker Innovations Broadening Therapeutic Horizons?

The safety profile of the sintilimab-anlotinib combination appeared manageable, with all patients experiencing at least one treatment-related adverse event. The most frequently reported adverse events included elevated lactate dehydrogenase (28.6%), increased thyroid-stimulating hormone (23.8%), hypoproteinemia (21.4%), hyperuricemia (19.0%), and electrocardiogram T wave abnormalities (16.7%). Grade 3 or higher adverse events occurred at a relatively low frequency, with hypertension and hyponatremia (each 4.8%) being the most common. Two serious treatment-related adverse events were recorded: one case of hepatitis and one case of intestinal perforation. The individualized dosing approach for anlotinib likely contributed to the lower rate of dose adjustments compared to previous studies, with only 5% of patients requiring dose reduction due to adverse events. This favorable toxicity profile suggests that personalized dosing strategies may optimize the risk-benefit ratio when combining antiangiogenic agents with immunotherapy.

Perhaps the most intriguing finding from this study was the exploratory analysis of TLS as a potential predictive biomarker. Among 35 evaluable patients, seven (20%) were TLS-positive as determined by immunohistochemistry and two-plex immunofluorescence staining. The ORR was significantly higher in TLS-positive patients compared to TLS-negative patients (71.4% vs. 25.0%, p=0.033), suggesting that TLS presence might identify patients more likely to benefit from the combination therapy. This finding aligns with recent evidence indicating that TLS may serve as a biomarker for immunotherapy response across various tumor types. The TLS-positive cases spanned multiple histologic subtypes, including angiosarcoma, ASPS, fibrosarcoma, undifferentiated pleomorphic sarcoma, and clear-cell sarcoma, suggesting that this biomarker might transcend traditional histologic classifications to identify immunologically "hot" tumors suitable for immunotherapy-based approaches.

The results for specific sarcoma subtypes are particularly noteworthy. All patients with angiosarcoma (2/2) achieved objective responses, including one complete response, consistent with findings from other studies suggesting particular sensitivity of this subtype to combined antiangiogenic and immunotherapeutic approaches. Similarly, undifferentiated spindle cell sarcoma (2/2) and a proportion of patients with synovial sarcoma (2/5) and myofibroblastic sarcoma (1/2) demonstrated objective responses. These findings suggest that certain histologic subtypes may be particularly amenable to this combination strategy, though larger studies are needed to confirm these signals. The study also reported an objective response in a TLS-positive patient with clear-cell sarcoma, a subtype typically resistant to conventional therapies, highlighting the potential value of biomarker-driven patient selection even within historically treatment-refractory histologies.

What Challenges and Future Directions Emerge for Advanced Sarcoma?

Several limitations of this study warrant consideration when interpreting its findings. The single-arm design without a comparator group makes it challenging to determine whether the observed activity is attributable to the combination regimen or to one of the agents alone. The relatively small sample size limits definitive conclusions about efficacy in specific sarcoma subtypes. The follow-up period, while substantial, may not be sufficient to fully characterize long-term toxicities or durability of response. Additionally, anlotinib is currently approved only in China, potentially limiting the global applicability of these specific findings, though similar multikinase inhibitors are available internationally. Despite these limitations, the study provides valuable insights into the potential of combining antiangiogenic therapy with immunotherapy in advanced sarcoma and highlights TLS as a promising biomarker for patient selection.

This study raises several important questions for future research. How might the integration of TLS assessment into clinical practice affect treatment decision-making for patients with advanced sarcoma? Could the personalized dosing approach for anlotinib be applied to other multikinase inhibitors to improve tolerability when combined with immunotherapy? What is the optimal duration of therapy for patients achieving disease control with this combination? Would a randomized trial comparing sintilimab-anlotinib to either agent alone or to standard second-line therapies confirm the promising signals observed in this single-arm study? As sarcoma treatment evolves toward more personalized approaches, the integration of both histologic and biomarker-driven strategies may ultimately optimize outcomes for patients with these challenging malignancies.

In conclusion, this phase II trial demonstrates that the combination of sintilimab and anlotinib shows promising efficacy with a manageable safety profile in patients with advanced sarcomas, particularly when guided by TLS as a biomarker. The study represents an important step toward more personalized treatment approaches for sarcoma patients and provides a foundation for larger, randomized trials to further define the role of combined antiangiogenic and immunotherapeutic strategies in this heterogeneous group of malignancies.

Summary

A phase II trial conducted at Shandong Cancer Hospital and Institute has demonstrated promising results for the combination of sintilimab, an anti-PD-1 monoclonal antibody, and anlotinib, a multitargeted tyrosine kinase inhibitor, in treating advanced sarcomas. The study enrolled 42 patients with histologically confirmed advanced sarcoma, predominantly soft tissue subtypes, with most having metastatic disease and receiving the combination as second-line therapy after anthracycline-based regimens. The treatment achieved an objective response rate of 30.9% and a disease control rate of 76.2%, with median progression-free survival of 5.0 months and a 12-month overall survival rate of 62.6%. The safety profile was manageable, with individualized dosing of anlotinib contributing to lower rates of dose adjustments compared to previous studies. A particularly significant finding was the exploratory analysis of tertiary lymphoid structures as a predictive biomarker, with TLS-positive patients showing significantly higher response rates (71.4% versus 25.0%). Certain sarcoma subtypes, including angiosarcoma and undifferentiated spindle cell sarcoma, demonstrated particularly favorable responses. While the single-arm design and small sample size limit definitive conclusions, the study provides valuable evidence for combining antiangiogenic therapy with immunotherapy in advanced sarcoma and highlights the potential of biomarker-driven patient selection to optimize treatment outcomes in these challenging malignancies.