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Using Tumor Genomic Profiling to Guide Treatment Selection Extends Survival in Advanced Sarcoma

The results of a new study, underscoring the value of precision medicine in advanced sarcoma, showed that patients with heavily pretreated sarcoma who received treatment in accord with their mutational profile attained better outcomes than patients who did not (Abstract 11018). Most notably, median overall survival reached 22.1 months for patients treated with agents targeting mutations identified by genomic profiling, compared with 15.5 months for patients who received treatment unguided by genomic profiling (HR 0.70, 95% CI [0.50, 0.98]; p = 0.031).

“Drug development in sarcomas remains challenging, with few effective U.S. Food and Drug Administration–approved therapies,” lead investigator Shiraj Sen, MD, PhD, of the Sarah Cannon Research Institute, said. “Fortunately, recent genomic analyses have revealed many potentially actionable mutations across sarcoma subtypes. However, the actionability of these potential driver mutations remains unclear, and whether patients enrolled on genomically matched early-phase trials have improved outcomes over patients enrolled on nongenomically matched trials remains unknown.”

To clarify the value of genomic profiling in sarcoma, the investigators leveraged clinical data and next-generation sequencing information for 406 patients with advanced disease who were treated within phase I trials at The University of Texas MD Anderson Cancer Center over a 12-year period (2006 to 2018). Patients had received a median of three prior lines of therapy (range, 0 to 9) before being enrolled in a phase I trial, and collectively they featured a diverse array of soft tissue sarcomas (e.g., leiomyosarcoma, 16%; liposarcoma, 13%; gastrointestinal stromal tumor, 11%; and synovial sarcoma, 3%) and bone sarcomas (e.g., osteosarcoma, 8%; chondrosarcoma, 7%; and Ewing sarcoma, 6%).

Within the 406-patient cohort, 23% of patients had potentially actionable alterations identified through next-generation sequencing and were enrolled in clinical trials of genomically matched therapies. The remaining 77% of patients who participated in nongenomically matched trials served as the comparator group.

The results revealed no difference in the objective response rate for patients who were and were not matched to treatment based on their genomic profile (11% vs. 6%, respectively; odds ratio [OR] 1.97, 95% CI [0.88, 4.44]; p = 0.10). However, significant differences favoring the genomically matched group over the unmatched group were observed for the clinical benefit rate (41% vs. 19%, respectively; OR 2.91, 95% CI [1.77, 4.80]; p < 0.0001), the median time to progression (3.7 vs. 2.7; HR 0.72, 95% CI [0.57, 0.91]; p = 0.0048), and median overall survival (22.1 vs. 15.5 months; HR 0.70, 95% CI [0.50, 0.98]; p = 0.031).

“In our study, while response rates in genomically matched trials were low (11%), occasional responses were seen with experimental therapies targeting alterations such as NTRK, LRRC15, cMET, mTOR, VEGF, MDM2, and FGFR. This suggests that molecular profiling should be considered in metastatic, refractory sarcomas and clinical trial enrollment should be considered for these patients,” Dr. Sen said.

Kara Nyberg, PhD