Editor's Note: Soft tissue sarcoma (STS) is a rare and highly heterogeneous malignant tumor, and exploring treatment strategies for it has been a key focus in oncology research. In recent years, with the deepening of molecular biology and immunology research, clinical understanding and treatment methods for these diseases have continually advanced. At the recently concluded 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, several key studies on soft tissue sarcoma released the latest clinical data. "Oncology Frontier" invited Professor Lili Mao from Peking Cancer Hospital to provide an in-depth analysis of these studies, summarizing the current progress in STS treatment research and discussing the clinical significance and future application prospects of these findings.

1. Perioperative Doxorubicin+Ifosfamide vs. Gemcitabine+Docetaxel for High-Grade Soft Tissue Sarcoma: Final Results of the Japanese Clinical Oncology Group JCOG1306 Study (Abstract 11503)

Background: The research team previously reported long-term follow-up results of perioperative doxorubicin+ifosfamide (AI) chemotherapy for high-grade soft tissue sarcoma (STS) (JCOG0304). In the ASCO 2020 conference, a second interim analysis of a phase II/III trial was reported, which aimed to verify the non-inferiority of perioperative gemcitabine+docetaxel (GD) compared to the AI regimen for high-grade STS (JCOG1306). The study was terminated at the second interim analysis because the hazard ratio (HR) point estimate exceeded the preset allowable HR of 1.61. The analysis showed 2-year overall survival (OS) rates of 94.3% (95% CI: 83.4-98.1) for the AI group and 91.6% (95% CI: 80.9-96.4) for the GD group (HR 2.55, 95% CI: 0.80-8.14). This report presents the 5-year follow-up final results of the JCOG1306 study.

Methods: Patients with resectable FNCLCC grade 2/3 primary STS (T2bN0M0 or any TN1M0, AJCC 7th edition) or first local recurrence in the limbs or trunk were randomized to either the AI or GD group. The AI group received doxorubicin 60 mg/m² plus ifosfamide 10 g/m². The GD group received gemcitabine 1800 mg/m² plus docetaxel 70 mg/m². Patients received 3 cycles of preoperative and 2 cycles of postoperative chemotherapy, with a 3-week cycle. The primary endpoint of the phase III study was OS. The planned sample size was 140 patients, with a one-sided alpha of 0.1 and a power of 0.7, assuming a 3-year OS rate of 85% for AI and 87% for GD, with a non-inferiority margin of 8% (HR 1.61).

Results: From February 2014 to September 2018, 143 patients were enrolled. The 5-year follow-up was completed in September 2023. Efficacy analysis included 70 patients in the AI group and 73 in the GD group. At a median follow-up of 6.0 years, the estimated 5-year OS rates were 90.0% (95% CI: 80.1-95.1) for the AI group and 76.1% (95% CI: 64.5-84.4) for the GD group (HR 2.67, 95% CI: 1.23-5.80); the 5-year progression-free survival (PFS) rates were 65.2% (95% CI: 52.7-75.2) and 57.4% (95% CI: 45.2-67.8) respectively (HR 1.33, 95% CI: 0.81-2.18). No treatment-related deaths occurred in either group during the 5-year follow-up.

Conclusion: The final 5-year follow-up analysis confirmed the second interim analysis results, showing that GD was not non-inferior to AI in terms of OS. Therefore, AI remains the standard perioperative chemotherapy regimen for high-grade STS of the limbs and trunk.

Expert Commentary: The first neoadjuvant study was the Japanese JCOG1306 trial, which compared the efficacy of the traditional AI regimen (doxorubicin combined with ifosfamide) with the GD regimen (gemcitabine combined with docetaxel) in treating high-grade STS. Given the significant efficacy of the AI regimen, the study adopted a non-inferiority design. Both groups received 3-week chemotherapy cycles, with 3 preoperative and 2 postoperative cycles. The primary endpoint was OS.

At this year’s ASCO conference, the study’s 5-year OS follow-up results were presented, marking the final results of the study. From 2014 to 2018, 143 patients were enrolled, with 70 in the AI group and 73 in the GD group. The final analysis showed a numerical difference in the 5-year OS rate between the two groups, but it did not meet the pre-set non-inferiority criteria. This indicates that AI remains superior to other existing chemotherapy regimens for perioperative chemotherapy in high-grade STS of the limbs and trunk.

Given that this study was conducted earlier, and with the continuous emergence of new drugs, we look forward to more innovative drugs in the future to change the current status of perioperative treatment for STS.

2. SU2C-SARC032: A Randomized Trial of Neoadjuvant Radiotherapy and Surgery ± Pembrolizumab for STS (Abstract 11504)

Background: Surgery and radiotherapy provide high local control rates for limb and girdle STS. However, high-grade STS patients have a high risk of metastasis, with a median survival of 2 years for metastatic STS patients. SARC028 (NCT02301039) evaluated pembrolizumab in metastatic STS, showing response rates of 20% for undifferentiated pleomorphic sarcoma (UPS) and 8.7% for pleomorphic/dedifferentiated liposarcoma (LPS). The researchers hypothesized that neoadjuvant pembrolizumab combined with radiotherapy, followed by surgery and adjuvant pembrolizumab for stage III UPS (including myxofibrosarcoma) or LPS, would stimulate antitumor immune responses, eliminate micrometastatic disease, and improve disease-free survival (DFS). SU2C-SARC032 (NCT03092323) is a multicenter, international, randomized phase II trial to evaluate the safety and efficacy of adding pembrolizumab to standard radiotherapy and surgery in stage III UPS or LPS patients.

Methods: Patients aged >12 years with stage III (FNCLCC grade 2 or 3) limb and girdle UPS or LPS were randomized (1:1, stratified by grade) to receive neoadjuvant radiotherapy (50 Gy/25 fx) followed by surgery (SOC group) or neoadjuvant pembrolizumab and radiotherapy followed by surgery and adjuvant pembrolizumab (EXP group). Pembrolizumab (200 mg, IV, Q3W, 3 doses) was administered before, during, and after radiotherapy, with up to 14 adjuvant cycles. The primary endpoint was 2-year DFS. Secondary endpoints included local recurrence-free survival (LRFS), distant disease-free survival (DDFS), and OS. The target enrollment was 126 evaluable patients (up to 144), providing 80% power (one-sided α=0.05) to distinguish between the null hypothesis of a 50% 2-year DFS rate and the alternative hypothesis of a 75% 2-year DFS rate using a log-rank test, with the initial analysis at 45 DFS events.

Results: From July 2017 to November 2023, 143 patients were enrolled, predominantly UPS (85%) and grade 3 histology (64%). The median follow-up for surviving patients was 24.1 months. The estimated 2-year DFS rate was significantly higher in the EXP group than in the SOC group (72.5% vs. 54.5%; HR 0.57, 90% CI: 0.33-0.99, P=0.042).

Currently, differences in LRFS (HR 0.55, 95% CI: 0.21-1.42), DDFS (HR 0.57, 95% CI: 0.32-1.01), or OS (HR 0.39, 95% CI: 0.14-1.12) are not statistically significant. Grade 3 sarcoma patients showed improved DFS with pembrolizumab treatment (HR 0.47, 95% CI: 0.25-0.89), but no DFS difference was observed in grade 2 tumors (HR 1.21, 95% CI: 0.35-4.18). The proportion of patients with ≥ grade 3 adverse events was significantly higher in the EXP group than in the SOC group (52% vs. 26%; P=0.002).

Conclusion: Adding neoadjuvant and adjuvant pembrolizumab to radiotherapy and surgery significantly improved DFS in patients with grade 3 UPS and LPS of the limbs and girdle.

Expert Commentary: The second study focuses on the application of PD-1 inhibitors in the perioperative treatment of STS, an international, multicenter clinical trial. This study compared radiotherapy as the control group for neoadjuvant treatment with radiotherapy combined with PD-1 inhibitors as the trial group. Patients were randomized 1:1 to evaluate the efficacy and safety of the two therapies, with the primary endpoint being 2-year DFS. The results showed that the trial group had a significantly better DFS than the control group (P=0.042, HR=0.57). Further subgroup analysis indicated that patients with grade 3 pathology showed significant differences in DFS between the trial and control groups, while no significant difference was observed in grade 2 tumors. This suggests that patients with higher-grade STS may benefit more from PD-1 inhibitor treatment. However, it is noteworthy that PD-1 inhibitor treatment also led to a higher incidence of ≥ grade 3 adverse events, exceeding 50%.