A phase 2 trial published in The Lancet reveals that adding pembrolizumab (Keytruda) to preoperative radiotherapy and surgery significantly improves disease-free survival (DFS) in patients with grade 3, stage III soft tissue sarcoma of the extremity. The SU2C-SARC032 trial (NCT03092323) demonstrated a clinically meaningful improvement in DFS, marking pembrolizumab as a promising new treatment option for this patient population.
The open-label, randomized trial enrolled 143 patients with stage III undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma of the extremity and limb girdle across 20 global sites. Patients were randomized 1:1 to receive either pembrolizumab with image-guided external beam radiotherapy followed by surgery and postoperative pembrolizumab (n = 71) or preoperative radiotherapy followed by surgery alone (n = 72).
Improved Disease-Free Survival
At a median follow-up of 43.1 months, the estimated 2-year DFS rate was 67% (90% CI, 58%-78%) in the pembrolizumab arm compared to 52% (90% CI, 42%-64%) in the control arm (HR, 0.61; 90% CI, 0.39-0.96; 1-sided stratified log-rank P = .035). This indicates a 39% improvement in DFS with the addition of pembrolizumab.
Yvonne M. Mowery, MD, PhD, lead study author and associate professor of radiation oncology at the University of Pittsburgh Medical Center Hillman Cancer Center, stated, "Findings from SU2C-SARC032 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."
Trial Design and Patient Characteristics
Pembrolizumab was administered at 200 mg intravenously every 3 weeks for 3 neoadjuvant cycles and up to 14 adjuvant cycles. Radiation therapy was delivered at 50 Gy in 25 daily fractions, initiated 1 to 14 days after the first pembrolizumab dose in the experimental arm or within 14 days of enrollment in the control arm. Surgery was performed 3 to 6 weeks after the third cycle of pembrolizumab in the experimental arm.
The treatment arms were well-balanced. In the experimental arm, 34% and 66% of patients had grade 2 and 3 disease, respectively. Sarcoma histologic subtypes included dedifferentiated liposarcoma (6%), myxofibrosarcoma (11%), and undifferentiated pleomorphic sarcoma (83%).
Additional Efficacy Findings
In the modified intention-to-treat (mITT) population, the hazard ratio for distant DFS (DDFS) favored the experimental arm but was not statistically significant (HR, 0.62; 95% CI, 0.36-1.07; P = .085). The 2-year DDFS rates in the experimental and control arms were 67% and 52%, respectively. No significant difference in local recurrence-free survival (LRFS) was observed between the arms (HR, 0.76; 95% CI, 0.38-1.55; P = .46).
The median overall survival (OS) was numerically longer in the experimental arm, though not statistically significant (HR, 0.67; 95% CI, 0.33-1.39; P = .28). The estimated 2-year OS rates were 88% and 85% in the experimental and control arms, respectively.
Safety and Tolerability
Of the patients who received at least one dose of pembrolizumab, 56% had at least one grade 3/4 adverse event (AE), and 47% had at least one serious AE. In the control arm, these rates were 31% and 13%, respectively. No grade 5 AEs were reported. Common grade 3 AEs in the experimental arm included anemia (10%), wound infection (10%), and hypertension (9%).
"Concurrent pembrolizumab and radiation therapy were tolerated with an acceptable level of toxicity, and major surgical complications were low with a similar number of events in the control and experimental groups," the authors concluded.
