Pembrolizumab Added to Preoperative Radiotherapy and Surgery Enhances DFS in Sarcoma

The SU2C-SARC032 study evaluating pembrolizumab plus radiotherapy and surgery found the regimen was well tolerated with infrequent surgical complications.

Pembrolizumab (Keytruda) in combination with radiotherapy and surgery enhanced disease-free survival (DFS) for patients with stage III undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma of the extremity vs placebo, according to findings from the phase 2 SU2C-SARC032 (NCT03092323) trial published in The Lancet.¹

Topline data revealed an estimated 2-year survival benefit in the pembrolizumab group at 67% (90% CI, 58%-78%) vs 52% (90% CI, 42%-62%) in the control group (one-sided stratified log-rank P = .035). Furthermore, the HR was 0.61 favoring the experimental group (90% CI, 0.39-0.96).

“The SU2C-SARC032 trial is, to our knowledge, the first [randomized] trial examining the role of adding immune checkpoint blockade to radiation therapy and surgery in patients with high-risk, [localized] soft tissue sarcoma of the extremity,” David G. Kirsch, MD, senior scientist at the Princess Margaret Cancer Centre and Peter Shelagh Godsoe Chair in Radiation Medicine, wrote in the phase 2 study with coinvestigators. “The trial showed a clinically meaningful improvement in disease-free survival with the addition of preoperative and postoperative pembrolizumab to preoperative radiation therapy and surgical resection for patients with stage III undifferentiated pleomorphic sarcoma or liposarcoma in the extremity or limb girdle.”

The phase 2 SU2C-SARC032 trial randomly assigned (1:1) 143 patients to receive either pembrolizumab, radiation therapy, and surgery (n = 71) or placebo, radiation therapy, and surgery (n = 72), of which 127 completed radiotherapy and were evaluated for DFS, including 63 in the control group and 64 in the experimental group. Histology and patient demographics were balanced in the control and experimental cohorts. Respectively, 62% and 64% of patients were male, the median age was 60 and 59 years, and 95% and 80% of patients were White.

In respective arms, 68% and 66% of patients had grade 3 disease, 76% and 83% had undifferentiated pleomorphic sarcoma and had average tumor size of 10 cm (range, 7-13) and 11 cm (range, 8-14). Additionally, most tumors were located in the lower limb (control, 60%; experimental, 64%) and radiation therapy was mostly conventionally fractionated (97% vs 98%).

Patients in the experimental group received 200 mg intravenous pembrolizumab every 3 weeks for 3 cycles before surgery––before, during, and after radiotherapy treatment––as well as up to 14 cycles after surgery for a maximum of 17 cycles. Pembrolizumab dosing began within 7 days of enrollment and radiation therapy started within 14 days of enrollment in the control group or 1 to 14 days after the initial pembrolizumab dose.

Furthermore, most patients received 50 Gy external beam radiation therapy in 25 daily fractions except for 3 patients treated with hypofractionated radiation therapy. Surgery was conducted 3 to 6 weeks after the third pembrolizumab cycle.

Among patients with grade 2 disease evaluable for efficacy analysis, no meaningful DFS difference was observed between cohorts (HR, 0.84; 95% CI, 0.26-2.76; P = .78). By contrast, for patients with grade 3 disease, a significantly longer DFS was observed with the experimental group (HR, 0.57; 95% CI, 0.31-1.03; P = .064). Additionally, a nonsignificant overall survival benefit was seen in the experimental group (HR, 0.67; 95% CI, 0.33-1.39; P = .28).

Of the 70 patients who received at least 1 dose of pembrolizumab, 39 (56%; 95% CI, 44%-67%) had 1 or more grade 3 or 4 adverse effects (AE), and 33 (47%) had at least 1 serious AE. For the control group (n = 67), it was 21(31%; 95% CI, 22%-43%) and 13, respectively. In the experimental group, 77% had an AE classified on central review as related to pembrolizumab.

Reference

Kirsch DG, Mowery YM, Ballman KV, et al. Safety and efficacy of pembrolizumab, radiation therapy, and surgery versus radiation therapy and surgery for stage III soft tissue sarcoma of the extremity (SU2C-SARC032): an open-label, randomised clinical trial. Lancet. 2024;404(10467):2053-2064. doi:10.1016/S0140-6736(24)01812-9