Margaret von Mehren

Large-Scale Multiomic Analysis Identifies Anatomic Differences and Immunogenic Potential in Subtypes of Leiomyosarcoma

Abstract Purpose: Comprehensive molecular profiling was used to define the genomic and immune landscapes of leiomyosarcomas (LMS) by anatomic subtypes, which have not been completely characterized. Experimental Design: A total of 1,115 LMS samples, categorized into uterine LMS (uLMS), retroperitoneal LMS, or other LMS (oLMS), underwent DNA/RNA sequencing (Caris Life Sciences). Genomic/transcriptomic profiles were compared across subtypes. Immune profiling was compared with melanoma (n = 1,255), an immunogenic tumor. Insurance claims data were used to infer real-world outcomes with immune checkpoint inhibitors (ICI) in LMS. Results: uLMSs (n = 701) were molecularly distinct from retroperitoneal LMSs (n = 166) and oLMSs (n = 248). RB1 mutations and MAP2K4 copy-number amplification were more common in non-uLMS. MED12 mutations were almost exclusive to uLMS. Traditional ICI response biomarkers (i.e., PD-L1) did not vary by anatomic site. Non-uLMS demonstrated upregulated immune-related gene sets, including IFN and inflammatory response pathways, and higher immune cell infiltration, especially CD8+ T cells and B cells (>2-fold increase, P < 0.0001). LMS had lower immune cell abundance and T cell–inflamed scores (TIS) compared with melanoma, though 11% of oLMS samples had high TIS scores. In a real-world cohort (n = 138), 29% of patients with LMS receiving ICI were treated >6 months, indicating potential clinical benefit. Conclusions: Comprehensive profiling suggested that uLMS represents a molecularly distinct disease from non-uLMS. Although traditional ICI response biomarkers were similar across anatomic subtypes, uLMSs were immune cold compared with non-uLMS. Signals for ICI responsiveness, such as high TIS and immune cell abundance, in some tumors suggest that further research into immunotherapies for LMS is warranted.

Cardiac safety of trabectedin monotherapy or in combination with pegylated liposomal doxorubicin in patients with sarcomas and ovarian cancer

AbstractBackgroundAs with other alkylating agents, cardiac dysfunction can occur with trabectedin therapy for advanced soft tissue sarcomas (STS) or recurrent ovarian cancer (ROC) where treatment options for advanced disease are still limited. Cardiac safety for trabectedin monotherapy (T) for STS or in combination with pegylated liposomal doxorubicin (T+PLD) for ROC was evaluated in this retrospective postmarketing regulatory commitment.MethodsPatient data for multiple cardiac‐related treatment‐emergent adverse events (cTEAEs) were evaluated in pooled analyses of ten phase 2 trials, one phase 3 trial in STS (n = 982), and two phase 3 trials in ROC (n = 1231).ResultsMultivariate analyses on pooled trabectedin data revealed that cardiovascular medical history (risk ratio [RR (95% CI)]: 1.90 [1.24‐2.91]; p = 0.003) and age ≥65 years (RR [95% CI]: 1.78 [1.12‐2.83]; p = 0.014) were associated with increased risk for cTEAEs. Multivariate analyses showed increased risk of experiencing cTEAEs with T+PLD compared to PLD monotherapy (RR [95% CI]: 2.70 [1.75‐4.17]; p < 0.0001) and with history of prior cardiac medication (RR [95% CI]: 1.88 [1.16‐3.05]; p = 0.010).ConclusionsFor patients with STS or ROC who still have limited treatment options, trabectedin may be initiated after carefully considering benefit versus risk.Trial Registration (ClinicalTrials.gov): NCT01343277; NCT00113607; NCT01846611.

A Study Comparing the Combination of Trabectedin (YONDELIS) and DOXIL/CAELYX With DOXIL/CAELYX for the Treatment of Advanced-Relapsed Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

The purpose of this study is to assess the efficacy and safety of trabectedin+DOXIL as a third-line chemotherapy regimen (treatment) in patients with platinum-sensitive advanced-relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer who received 2 previous lines of platinum-based chemotherapy.

An Efficacy and Safety Study for Yondelis (Trabectedin) in Patients With Advanced Relapsed Ovarian Cancer

The purpose of the study is to compare the progression-free survival (PFS) of the combination of trabectedin + DOXIL with DOXIL monotherapy in patients with ovarian cancer.