Perioperative Anti-PD-1 in Soft-Tissue Sarcoma Boosts Disease-Free Survival

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But absence of significant OS benefit raises questions about long-term benefit, expert says

by
Mike Bassett, Staff Writer, MedPage Today
November 13, 2024

Adding a PD-1 inhibitor to standard of care improved disease-free survival (DFS) in stage III soft-tissue sarcoma of the extremity, a randomized trial showed.

In patients with mostly undifferentiated pleomorphic sarcomas, 2-year DFS with the addition of preoperative and postoperative pembrolizumab (Keytruda) infusions reached 67%, as compared with 52% with standard preoperative radiotherapy and surgery alone (HR 0.61, 90% CI 0.39-0.96, P=0.035), reported David Kirsch, MD, PhD, of Princess Margaret Cancer Centre in Toronto, and colleagues.

The findings “indicate that pembrolizumab is a promising new treatment option for these patients and suggest a path for even greater therapeutic effect by further optimizing immunotherapy,” the researchers wrote in The Lancet, adding that “outcomes for these patients have not markedly changed over several decades.”

However, while overall survival (OS) was numerically greater in the pembrolizumab group, that improvement did not reach statistical significance (HR 0.67, 95% CI 0.33-1.39), with estimated 2-year OS rates of 88% with the PD-1 inhibitor and 85% in the control group.

“The most valuable insight from this trial is that it is the first to rigorously evaluate the potential of immunotherapy in the perioperative setting for soft-tissue sarcomas within a randomized controlled trial framework,” wrote Antoine Italiano, MD, PhD, of the University of Bordeaux in France, in a commentary accompanying the study.

“Although the results indicated an improvement in disease-free survival, suggesting that perioperative immunotherapy might reduce recurrence risk in some patients, the absence of a statistically significant overall survival benefit raises questions about the long-term effect of immunotherapy in this setting,” Italiano added.

In explaining the rationale behind the SU2C-SARC032 trial, Kirsch and colleagues pointed out that about half of patients with large, high-grade, localized soft-tissue sarcomas go on to develop metastatic disease.

“Patients with metastases receive chemotherapy, leading to a median survival of 12-24 months,” the study authors wrote. “Therefore, new therapeutic approaches are needed to reduce the development of metastatic disease in patients with high-risk, localized soft-tissue sarcomas.”

The randomized study was conducted from November 2017 to November 2023 across centers in Australia, Canada, Italy, and the U.S. Patients in the investigational arm received preoperative pembrolizumab with radiotherapy 1 to 14 days after the first dose of the checkpoint inhibitor, which was followed by surgery and postoperative pembrolizumab. The control arm received preoperative radiotherapy followed by surgery.

Of the 127 patients in the modified intent-to-treat population (those with undifferentiated pleomorphic sarcoma or liposarcoma histology who completed radiotherapy), the median age was about 60 years and 63% were male. All patients had stage III disease of the extremity or limb girdle, with the most common histology being undifferentiated pleomorphic sarcoma (80%) followed by myxofibrosarcoma (10%) and dedifferentiated (6%) or pleomorphic (4%) liposarcoma.

Tumors were located in the lower limb for 60%, lower limb girdle for 7%, upper limb for 15%, and upper limb girdle for 16%. About two-thirds had grade 3 disease, while the remaining had grade 2 disease.

Over a median follow-up of 43 months, 24 DFS events occurred in the pembrolizumab arm versus 32 in the control group. The researchers noted that a meaningful improvement in DFS with pembrolizumab was only seen in the subset with grade 3 disease:

• Grade 2: HR 0.84 (95% CI 0.26-2.76)
• Grade 3: HR 0.57 (95% CI 0.31-1.03)

While 2-year distant DFS favored the pembrolizumab group (67% vs 52% in the control group), that difference was not significant (HR 0.62, 95% CI 0.36-1.07).

Safety analysis showed that 56% of the 70 patients in the pembrolizumab group who received at least one dose of the drug had at least one grade 3/4 adverse event (AE), and 47% had at least one serious AE. In addition, 77% had an AE classified on central review as related to pembrolizumab. Among the 67 patients in the control group who started study treatment, 31% had at least one grade 3/4 AE and 19% had at least one serious AE. There were no grade 5 AEs.

Kirsch and colleagues acknowledged the study had several limitations, including its small size. Despite the fact that the study was conducted across 20 centers, it took 7 years to enroll due to the rarity of soft-tissue sarcoma.

“Therefore, this study is not powered for secondary endpoints and analyses, including comparison of overall survival between treatment groups,” they wrote.

The small size of the trial “highlights a key challenge in sarcoma research,” Italiano said in his commentary.

It “reduced the study’s ability to thoroughly explore how sarcoma subtypes, tumor grades, or other prognostic factors influence treatment outcomes,” he wrote. “This underscores the need for innovative trial designs, such as umbrella trials, which could improve recruitment efficiency and use surrogate endpoints, such as histological response, to identify the most promising therapeutic strategies for specific sarcoma subtypes.”