In a phase II clinical trial, immune checkpoint blockade before surgery was associated with favorable responses and outcomes in undifferentiated pleomorphic sarcoma (UPS) and recurrent dedifferentiated liposarcoma (DDLPS), Keung et al reported at the 2022 ASCO Annual Meeting (Abstract LBA11501).
After a minimum of 2 years’ follow-up, the median progression-free survival was not reached for patients with resectable UPS of the trunk or extremities; the median progression-free survival was 18 months for patients with resectable, largely recurrent, retroperitoneal DDLPS. The 2-year progression-free survival rate was 70% for UPS and 35% for DDLPS.
The median overall survival was not reached, and the 2-year overall survival rate was 90% for UPS and 82% for DDLPS. In correlative studies, the authors also identified an association between intratumoral B-cell receptor (BCR) repertoire at baseline and survival following immune checkpoint blockade, the first time this biomarker has been reported in sarcoma.
“The 2-year follow-up data from this study confirms that recurrence rates and survival are favorable with the addition of neoadjuvant immunotherapy compared to rates expected with surgery alone, based on historical controls, in a patient population that typically has very high recurrence rates,” said Emily Keung, MD, Assistant Professor of Surgical Oncology at The University of Texas MD Anderson Cancer Center and lead author of the study. “Previous studies assessed immune checkpoint blockade in heavily pretreated patients with advanced unresectable or metastatic soft-tissue sarcoma, so it’s encouraging to see these results in patients with earlier-stage, operable disease.”
Approximately 13,000 new cases of soft-tissue sarcoma are diagnosed each year and, with dozens of different histologies, each one is a rare cancer. DDLPS and UPS are two of the most common types of soft-tissue sarcoma. For patients with resectable soft-tissue sarcoma, surgery is the only potentially curable treatment option, but many patients with UPS or DDLPS see their cancer return within 5 years.
Study Details
The single-institution study enrolled 17 patients with DDLPS and 10 patients with UPS amenable to surgical resection. In both cohorts, the median age was 68 years, and most patients were male (88% DDLPS and 60% UPS) and White (94% DDLPS and 100% UPS). At enrollment, 65% of patients with DDLPS and 10% of patients with UPS had recurrent disease. Patients were randomly assigned to receive nivolumab monotherapy or nivolumab/ipilimumab combination therapy, followed by surgery. Patients with UPS received concurrent neoadjuvant radiation therapy.
At the time of surgery, pathologic response was 90% in patients with UPS and 18% in patients with DDLPS, which is consistent with early results from the study presented during the 2020 ASCO Virtual Scientific Program. Historically, pathologic responses to neoadjuvant chemotherapy and radiation therapy were 20% to 30% at the time of surgery. However, pathologic responses to immunotherapy did not predict overall survival, underscoring the need for biomarkers of response.
Toxicities were manageable and there were no new safety concerns compared to known safety profiles for nivolumab and ipilimumab. Fatigue, diarrhea, and rash were the most common side effects. Seven patients (25.9%) experienced grade 3 treatment-related adverse events, with colitis being the most common grade 3 event.
BCR Repertoire in Tumor Microenvironment
Co–principal investigators Christina Roland, MD, Associate Professor of Surgical Oncology at MD Anderson, and Neeta Somaiah, MD, Associate Professor of Sarcoma Medical Oncology at MD Anderson, designed the clinical trial with multiple blood, tumor, and stool sample collections before, during, and after treatment to enable correlative studies on biomarkers for response.
After noticing trends in T- and B-cell populations and treatment response, which were presented at the Society for Immunotherapy of Cancer (SITC) 36th Annual Meeting, the research team performed bulk tumor RNA sequencing. They found that both diversity and clonality of BCR repertoire in the tumor microenvironment at baseline was associated with a trend for improved progression-free survival and a significant association with overall survival.
“We’re excited to introduce a novel biomarker for response to immune checkpoint blockade in sarcoma. We and others previously reported the prognostic impact of B-cell infiltration, but the BCR repertoire had not yet been characterized in soft-tissue sarcomas,” Dr. Keung said. “The study design allowed us to learn a lot from a small group of patients with a rare disease, where it’s not possible to enroll large cohorts. We’re grateful to the patients who participated and are looking forward to continuing our work evaluating novel approaches, including neoadjuvant studies, to treat and improve outcomes for our patients with rare cancers.”
Disclosure: The study was supported by Bristol Myers Squibb, Fondation pour la Recherche Médicale, Nuovo-Soldati Foundation for Cancer Research, American College of Surgeons, and the Paul Calabresi Career Development Award for Clinical Oncology (K12). For full disclosures of the study authors, visit coi.asco.org.
