Pembrolizumab/Radiation/Surgery Improves DFS in Stage III Soft Tissue Sarcoma

The addition of pembrolizumab (Keytruda) to preoperative radiotherapy followed by surgery significantly prolonged disease-free survival (DFS) in patients with grade 3, stage III soft tissue sarcoma of the extremity compared with radiotherapy and surgery without pembrolizumab, according to findings from the phase 2 SU2C-SARC032 trial (NCT03092323), which were published in The Lancet.1

At a median follow-up of 43.1 months, among 127 evaluable patients in the modified intention-to-treat (mITT) analysis, patients who received pembrolizumab (n = 64) achieved an estimated 2-year DFS rate of 67% (90% CI, 58%-78%) vs 52% (90% CI, 42%-64%) in patients who underwent radiotherapy and surgery without pembrolizumab (n = 63; HR, 0.61; 90% CI, 0.39-0.96; 1-sided stratified log-rank P = .035).

Among patients in the mITT population with grade 2 disease (n = 42), investigators did not observe a meaningful difference in DFS between the 2 arms (HR, 0.84; 95% CI, 0.26-2.76; P = .78). Among patients in the mITT population with grade 3 disease, DFS was prolonged in the experimental arm (HR, 0.57; 95% CI, 0.31-1.03; P = .064).

“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,” lead study author Yvonne M. Mowery, MD, PhD, and colleagues, wrote in the paper.

Dr Mowery is a physician scientist and an associate professor of radiation oncology at the University of Pittsburgh Medical Center Hillman Cancer Center in Pennsylvania.

Trial Rationale

Previously, the phase 2 SARC028 trial (NCT02301039) showed that pembrolizumab elicited overall response rates of 23% in patients with metastatic undifferentiated pleomorphic sarcoma and 10% in those with pleomorphic or dedifferentiated liposarcoma.2

Based on these findings, as well as prior data demonstrating the synergistic effects of radiation therapy and immune checkpoint blockade on local and distant tumor response, the SU2C-SARC032 trial investigators hypothesized that adding pembrolizumab to preoperative radiation therapy and surgery could improve DFS for patients with stage III soft tissue sarcoma.1

Study Design

Between November 18, 2017, and November 14, 2023, the open-label, randomized trial enrolled 143 patients with grade 2 or 3, stage III undifferentiated pleomorphic sarcoma or dedifferentiated or pleomorphic liposarcoma of the extremity and limb girdle across 20 global sites. Patients needed to be at least 12 years of age and have resectable cT2N0M0 disease with an ECOG performance status of 0 or 1. Patients were not eligible if they planned to receive chemotherapy.

Patients were randomly assigned 1:1 to receive preoperative pembrolizumab with image-guided external beam radiotherapy followed by surgery and postoperative pembrolizumab (experimental arm; n = 71) or preoperative radiotherapy followed by surgery (control arm; n = 72).

Pembrolizumab was administered at 200 mg intravenously every 3 weeks for 3 neoadjuvant cycles and a maximum of 14 adjuvant cycles. The first dose of pembrolizumab was administered within 7 days of enrollment.

Radiation therapy was delivered at 50 Gy in 25 daily fractions (excluding in 3 patients treated during the COVID-19 pandemic who received hypofractionated radiation therapy for all or part of the treatment). Radiotherapy was 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 done 3 to 6 weeks after the third cycle of pembrolizumab in the experimental arm.

DFS served as the trial’s primary end point. Secondary end points included distant DFS (DDFS), local recurrence-free survival (LRFS), overall survival (OS), adverse effects (AEs), and wound complications.

Baseline Characteristics

The treatment arms were well balanced for intermediate- and high-grade histology. In the experimental arm, 34% and 66% of patients had grade 2 and 3 disease, respectively. In this arm, sarcoma histologic subtypes at initial diagnosis included dedifferentiated liposarcoma (6%), myxofibrosarcoma (11%), and undifferentiated pleomorphic sarcoma (83%). In the control arm, 32% and 68% of patients had grade 2 and 3 disease, respectively. In this arm, sarcoma histologic subtypes at initial diagnosis included dedifferentiated liposarcoma (6%), pleomorphic liposarcoma (8%), myxofibrosarcoma (10%), and undifferentiated pleomorphic sarcoma (76%).

In the experimental arm, the median number of pembrolizumab cycles among patients who started treatment was 14 (interquartile range [IQR], 5-17), and 6 patients were still receiving adjuvant pembrolizumab at the time of data analysis. The median time from the end of radiation therapy to surgery was 36 days (IQR, 31-45), and the median time from cycle 3 of pembrolizumab to surgery was 34 days (IQR, 27-39).

In the control arm, the median time from the end of radiation therapy to surgery was 34 days (IQR, 29-39).

Three of the patients in the mITT population did not undergo surgery: 2 (1 from each arm) who had disease progression before surgery, and 1 patient from the experimental arm who discontinued treatment because of AEs. No patients in the mITT population were treated with adjuvant chemotherapy.

Additional Efficacy Findings in the mITT and ITT Populations

In the mITT population, the HR for 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% (95% CI, 56%-80%) and 52% (95% CI, 40%-67%), respectively. Two local recurrences (grade 2 undifferentiated pleomorphic sarcoma and grade 2 myxofibrosarcoma) occurred in the experimental arm; both were managed with conventionally fractionated radiation therapy.

Investigators saw no significant difference in LRFS between the 2 arms in the mITT population (HR, 0.76; 95% CI, 0.38-1.55; P = .46).

The median OS in the mITT population was numerically but not statistically longer in the experimental arm vs the control arm (HR, 0.67; 95% CI, 0.33-1.39; P = .28). In these respective arms, the estimated 2-year OS rates were 88% (95% CI, 80%-97%) and 85% (95% CI, 76%-95%).

The addition of pembrolizumab also improved DFS in the ITT population (HR, 0.61; 90% CI, 0.39-0.95; 1-sided stratified log-rank P = .032). The estimated 2-year DFS rate was 68% (90% CI, 59%-78%) in the experimental arm and 52% (90% CI, 43%-65%) in the control arm.

Sensitivity Analysis Findings

Additional sensitivity analyses assessed the trial’s primary and secondary end points with patients censored at 2 years of follow-up. The DFS HR in the mITT population favored the experimental arm but was not statistically significant (HR, 0.62; 90% CI, 0.39-1.01; 1-sided stratified log-rank P = .052). The DFS HR in the ITT population also favored the experimental arm (HR, 0.62; 90% CI, 0.38-1.00; 1-sided stratified log-rank P = .048).

Among patients in the mITT population with grade 2 disease, the DFS outcomes were similar between the 2 arms (HR, 0.79; 95% CI, 0.21-2.95; P = .073). Among patients in the mITT population with grade 3 disease, the DFS HR was favored the experimental arm but was not statistically significant (HR, 0.59; 95% CI, 0.31-1.12; P = .11).

The HR for DDFS in the mITT population favored the experimental arm but was not statistically significant (HR, 0.64; 95% CI, 0.36-1.13; P = .13). Investigators observed no difference in LRFS (HR, 1.00; 95% CI, 0.38-2.68; P = .99) or OS (HR, 0.82; 95% CI, 0.30-2.27; P = .71) between the arms in the mITT population.

Post Hoc Analysis Findings

Post hoc subgroup analyses based on the grade of pretreatment biopsies showed that OS was numerically but not significantly longer in the experimental arm (HR, 0.58; 95% CI, 0.26-1.28; P = .18). Among patients with grade 2 disease, 4 deaths occurred (HR for OS, 1.34; 95% CI, 0.19-9.56).

Post hoc subgroup analyses based on final histology showed that DFS outcomes were better in the experimental arm vs the control arm for patients in the mITT population who were diagnosed with undifferentiated pleomorphic sarcoma in the final surgical resection specimen (n = 108; HR, 0.67; 95% CI, 0.38-1.19; P = .17). The HR for DFS also favored the experimental arm for patients in the mITT population with liposarcoma (n = 19; HR, 0.55; 95% CI, 0.11-2.73; P = .46).

Subgroup analysis findings were similar between the arms in patients in the ITT population with undifferentiated pleomorphic sarcoma and liposarcoma. Notably, the post hoc DFS comparisons in the histology subgroups were underpowered and thus had no statistical significance.

Safety Data

Of the patients in the experimental arm who received at least 1 dose of pembrolizumab, 56% (95% CI, 44%-67%) had at least 1 grade 3/4 AE, 47% had at least 1 serious AE, and 77% had an AE related to pembrolizumab as classified by central review.

Of the patients in the control arm who started study treatment (n = 67), 31% (95% CI, 22%-43%) had at least 1 grade 3/4 AE, and 13 had at least 1 serious AE.

No grade 5 AEs were reported. Grade 3 AEs that occurred in at least 5% of patients in the experimental arm included anemia (10%), wound infection (10%), hypertension (9%), and wound dehiscence (7%). Grade 4 fever and decreased lymphocyte counts occurred in 1 patient each in the experimental arm.

Furthermore, 28 major surgical complications were reported across 22 patients (11 in each arm), which were defined as grade 3 or higher wound complication, wound infection, wound dehiscence, or hematoma at the surgical site.

“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. “Therefore, for patients with resectable, intermediate-grade or high-grade undifferentiated pleomorphic sarcoma or liposarcoma measuring more than 5 cm, SU2C-SARC032 establishes pembrolizumab as a new treatment option.”

References

1. Mowery YM, Ballman KV, Hong AM, 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
2. Burgess MA, Bolejack V, Schuetze S, et al. Clinical activity of pembrolizumab (P) in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated/pleomorphic liposarcoma (LPS): final results of SARC028 expansion cohorts. J Clin Oncol. 2019;17(15). doi:10.1200/JCO.2019.37.15_suppl.11015