‘Most important study’ in soft tissue sarcomas in decades shows benefit of immunotherapy
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Key takeaways:
- The addition of pembrolizumab to radiation and surgery reduced relapse risk by 43%.
- Results showed no significant difference in OS with pembrolizumab.
CHICAGO — The addition of immunotherapy to radiation therapy and surgery significantly extended DFS for certain patients with soft tissue sarcoma, according to results of a randomized phase 2 trial.
Researchers reported a 43% reduction in risk for relapse at 2 years among patients who received pembrolizumab (Keytruda, Merck) in the neoadjuvant and adjuvant settings.
“Immunotherapies have transformed cancer care for many cancers but ... we haven’t seen any significant advances for these kinds of sarcoma. This study will change that,” researcher David G. Kirsch, MD, PhD, head of the radiation medicine program at Princess Margaret Cancer Centre at University Health Network in Toronto, said in a press release. “From my point of view, this is the most important study for patients with these sarcomas in 30 years because it’s addressing an important unmet need.”
Radiation followed by surgery is standard treatment for soft tissue sarcomas that have not metastasized. The approach provides high local control rates for patients with soft tissue sarcomas of the extremity and limb girdle.
However, many patients with high-grade stage III soft tissue sarcoma develop metastases, and median survival for those with metastatic disease is less than 2 years, according to study background.
A prior study showed the anti-PD-1 antibody pembrolizumab has activity in two common sarcoma subtypes, showing response rates of 20% for patients with metastatic undifferentiated pleomorphic sarcoma (UPS) and 8.7% for those with metastatic pleomorphic/dedifferentiated liposarcoma (LPS).
The SU2C-SARC032 trial — run by the Stand Up To Cancer Catalyst Research Team — assessed the addition of pembrolizumab in the neoadjuvant and adjuvant settings would stimulate anti-tumor immune response and extend DFS.
Researchers enrolled 143 patients aged 12 years or older with stage III UPS (85%) or LPS (15%) of the extremity and limb girdle. About two-thirds (64%) had grade 3 histology. The cohort included patients treated at 20 hospitals in the United States, Italy, Australia and Canada.
Researchers randomly assigned half of the trial participants to neoadjuvant radiation followed by surgery. The other half received neoadjuvant pembrolizumab and radiation, followed by surgery and adjuvant pembrolizumab.
Patients assigned to the experimental group received three doses of 200 mg IV pembrolizumab in the neoadjuvant setting — before, during and after radiation — and then received up to 14 cycles in the adjuvant setting.
Two-year DFS served as the primary endpoint. Secondary endpoints included OS, local RFS and distant DFS.
The efficacy analysis — performed after median follow-up of 24.1 months — included 127 patients.
Results — presented at ASCO Annual Meeting — showed a significantly higher percentage of patients assigned pembrolizumab achieved 2-year DFS (70% vs. 53%; HR = 0.57; 90% CI, 0.35-0.91).
Patients with grade 3 sarcomas derived a significant DFS benefit with pembrolizumab (HR = 0.47; 95% CI, 0.25-0.89) but those with grade 2 histology did not (HR = 1.21; 95% CI, 0.35-4.18).
In the overall study population, differences in local RFS (HR = 0.55; 95% CI, 0.21-1.42), distant DFS (HR = 0.57; 95% CI, 0.32-1.01) and OS (HR = 0.39; 95% CI, 0.14-1.12) had not reached statistical significance.
Grade 3 or higher adverse events occurred more frequently in the experimental group (52% vs. 26%; P = .002).
“Sarcoma doesn’t affect anywhere near the number of patients as breast, lung, prostate or colorectal cancer, but people impacted by sarcoma arguably need clinical trials even more,” Steven Young, president and CEO of Sarcoma Alliance for Research Collaboration (SARC), said in the release. “SARC was delighted to have this research build on our prior trial to determine if we could achieve meaningful advances of novel treatment strategies that will profoundly impact the sarcoma community.”
References:
- Mowery YM, et al. Abstract #11504. Presented at: ASCO Annual Meeting; May 31-June 4, 2024; Chicago.
- Sarcoma clinical trial funded by Stand Up To Cancer reduces risk of relapse by 43% (press release). Available at: https://standuptocancer.org/press/sarcoma-clinical-trial-funded-by-stand-up-to-cancer-reduces-risk-of-relapse-by-43/. Published June 3, 2024. Accessed Aug. 23, 2024.
Perspective
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Dale Shepard, MD, PhD
Patients with localized soft tissue sarcoma in the extremities are traditionally treated with radiation followed by surgery, but about half of those with a high-risk sarcoma develop local recurrence or metastatic disease.
This study by Mowery and colleagues shows a 43% reduction in the 2-year risk for relapse among patients with high-grade UPS or dedifferentiated LPS in the extremity or limb girdle receiving neoadjuvant and adjuvant pembrolizumab compared with standard therapy.
This is very significant. Historically, use of adjuvant chemotherapy for patients with resected soft tissue sarcoma has been controversial, with most studies showing minimal benefit.
Immunotherapy currently has limited application for most patients with metastatic sarcoma. More fully understanding the benefits of this therapy — which has dramatically improved the lives of patients with many other cancers — for patients with sarcoma in an adjuvant setting is a substantial contribution.
The SARC028 trial previously established that patients with UPS and LPS have a good response rate when treated with pembrolizumab in the metastatic setting. Unlike previous adjuvant trials for patients with resected soft tissue sarcoma, which enrolled patients with a wide range of subtypes, the SU2C-SARC032 trial only enrolled patients with UPS or pleomorphic/dedifferentiated LPS. I have little doubt that lumping numerous subtypes of soft tissue sarcoma in this study would have led to another failed trial. Hopefully, these data reinforce the lesson that proper selection of soft tissue sarcoma subtypes for inclusion in clinical trials is crucial.
Studies with patients with rare cancers like sarcoma are hard. The investigators for the SU2C-SARC032 trial are to be commended for their persistence and dedication to this research, in which 20 hospitals in four countries collaborated to enroll 127 patients in a 6-year effort. This study was only possible due to the vision and commitment by Sarcoma Alliance for Research through Collaboration and Stand Up to Cancer, which underscores the need for these organizations to be supported to improve the lives of our patients.
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