Preoperative Immunotherapy in Pleomorphic Sarcoma – Pembrolizumab Results

Soft tissue sarcomas are malignant tumors arising from extraskeletal connective tissues, including the nervous system outside the brain and spinal cord. They can occur anywhere in the body but are most common in the arms and legs, particularly the legs.

Systemic chemotherapy is a standard component of treatment for several sarcomas predominantly seen in children (for example, rhabdomyosarcoma, Ewing sarcoma, and osteogenic sarcoma). However, adult soft tissue sarcomas are generally less sensitive to chemotherapy than childhood sarcoma types. While types such as rhabdomyosarcoma and Ewing sarcoma in children respond strongly to chemotherapy, adult types such as leiomyosarcoma and pleomorphic sarcoma may be more resistant. Local treatments such as surgery and radiotherapy are therefore generally prioritized in adults. Nevertheless, the optimal treatments before and after surgery for early-stage adult soft tissue sarcomas (for example, leiomyosarcoma, liposarcoma, synovial sarcoma, and pleomorphic sarcoma) and the role of immunotherapy in these cancers remain unclear.

The Significance of Pleomorphic Sarcoma

Pleomorphic sarcoma is an aggressive soft tissue tumor, particularly seen in older adults, that contains different cell types and grows irregularly. It most commonly occurs in the extremities (arms and legs) and the retroperitoneum (behind the abdominal cavity). It is a rare tumor type, accounting for 5-10% of soft tissue sarcomas. Unlike other sarcomas, it is characterized by undifferentiated cells and a heterogeneous microscopic appearance, so a specific tissue of origin cannot be identified.

Why Treat Before Surgery?

Soft tissue sarcomas, particularly undifferentiated pleomorphic sarcoma (UPS) of the extremities and similar tumors, require challenging treatment because of their aggressive course and high metastasis rates. Metastases develop in approximately half of localized, high-risk soft tissue sarcomas, seriously affecting patient survival rates. Although traditional treatment approaches focus on surgery and radiotherapy, treatment options have begun to expand with the introduction of immunotherapy.

The Lancet Study

Published on 23 November 2024 in THE LANCET, the new clinical trial SU2C-SARC032 examines how pembrolizumab (anti-PD-1 immunotherapy), combined with neoadjuvant (preoperative) radiotherapy and surgery, affects disease-free survival in the treatment of undifferentiated pleomorphic sarcoma. The study's findings could be game-changing for soft tissue sarcoma treatment.

Study Design

This open-label, randomized clinical trial was conducted in patients diagnosed with stage III undifferentiated pleomorphic sarcoma or pleomorphic/dedifferentiated liposarcoma. Participants were recruited from 20 academic centers in Australia, Canada, Italy, and the USA. The study population was divided into two groups:

• Control Group: Neoadjuvant radiotherapy followed by surgery.

• Experimental Group: Neoadjuvant pembrolizumab (a total of three cycles before, during, and after radiotherapy), followed by surgery and postoperative pembrolizumab.

Pembrolizumab was administered intravenously at 200 mg every three weeks, and patients received up to 14 cycles of adjuvant treatment.

Findings

Between 18 November 2017 and 14 November 2023, the study enrolled 143 patients. The median follow-up among the 127 patients in the modified intention-to-treat population was 43 months.

• 2-Year Disease-Free Survival Rate: In the experimental group, the rate was 67% (90% CI 58-78), compared with 52% (90% CI 42-64) in the control group.

• Risk of Disease Progression: In the pembrolizumab group, compared with the control group, the risk of disease progression was 39% lower (HR: 0.61; 90% CI 0.39-0.96).

• Adverse Events: The rate of grade ≥3 adverse events was 56% in the experimental group and 31% in the control group.

Discussion and Conclusion

The study results show that adding pembrolizumab to surgery and radiotherapy significantly improves disease-free survival in soft tissue sarcomas of the extremities. However, this approach is also associated with serious adverse event rates. Grade ≥3 adverse events, in particular, should be considered during treatment decisions.

Key Considerations for Clinical Decision-Making

• Short- and Long-Term Effects: The study reported a median follow-up of 43 months. Further data are therefore needed to clarify the effects on long-term overall survival.

• The Importance of Patient–Treatment Compatibility: Because of their cost, administration process, and adverse effects, immunotherapies require detailed decision-making between the patient and physician.

• Managing Adverse Events: Early detection and management of adverse events are crucial to treatment success.

In conclusion, the SU2C-SARC032 study has shown pembrolizumab to be a promising option for treating soft tissue sarcoma. However, treatment suitability may vary with individual patient factors. The benefits and risks of immunotherapies should be evaluated comprehensively, with decisions made jointly with patients. With long-term survival data, this strategy may gain an important place in treatment regimens for patients with high-risk sarcoma.