Trabectedin Monotherapy Does Not Improve OS vs Chemotherapy in BRCA-Mutated Recurrent Ovarian Cancer

Single-agent trabectedin (Yondelis) did not provide an overall survival (OS) benefit and displayed an inferior safety profile compared with physician’s choice of chemotherapy for the treatment of patients with recurrent ovarian cancer with BRCA-mutated and/or BRCAness phenotype, according to findings from the phase 3 MITO-23 trial (NCT02903004) published in the Journal of Clinical Oncology.¹

Patients who received trabectedin (arm A; n = 122) achieved a median OS of 15.8 months (95% CI, 11.8-22.3) compared with 17.9 months (95% CI, 15.2-23.6) among patients who received chemotherapy (arm B; n = 122; HR, 1.15; 95% CI, 0.879-1.514; P = .304). Similarly, among patients in arm A (n = 45) and arm B (n = 42) who received prior PARP inhibitor therapy, the median OS was 11.6 months (95% CI, 10.0-16.4) vs 16.5 months (95% CI, 13.13-23.6), respectively (HR, 0.997; 95% CI, 0.638-1.559; P = .990).

“Trabectedin did not meet the primary end point of an OS benefit in comparison with physician's choice chemotherapy in patients with BRCA-mutated or BRCAness recurrent ovarian cancer,” the study authors wrote.

Trabectedin in combination with pegylated liposomal doxorubicin (PLD) was approved by the European Medicines Agency for the treatment of patients with platinum-sensitive recurrent ovarian cancer with a platinum-free interval of at least 6 months in 2009. Additionally, in October 2015, trabectedin was approved by the FDA for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who have received a prior anthracycline-containing regimen.^1,2

MITO-23 was a prospective, open-label trial which enrolled female patients with histologically documented invasive epithelial ovarian cancer, primary peritoneal carcinoma, or fallopian tube cancer. Eligible patients needed to have recurrent platinum-resistant disease with a platinum-free interval of less than 6 months or platinum-sensitive disease with a platinum-free interval of at least 6 months, either a BRCA1/2 mutation or BRCAness phenotype, and have responded to at least 2 prior lines of platinum-based chemotherapy or be platinum-sensitive and unable or unwilling to receive further platinum treatment(s). There were no limits regarding prior lines of chemotherapy or prior PARP inhibitor treatment; patients also needed to have an ECOG performance status of 1 or less, a life expectancy of at least 3 months, and adequate hematologic, hepatic, and renal function.¹

Patients were randomly assigned 1:1 to receive trabectedin or physician’s choice of chemotherapy, which consisted of carboplatin, gemcitabine, once-weekly paclitaxel, PLD, or topotecan. Trabectedin was given at a dose of 1.3 mg/m2 of body surface area intravenously as a 3-hour infusion once every 21 days; treatment in both arms continued until disease progression, unmanageable toxicity, withdrawal, or death. Patients were stratified by platinum-free interval (≤6 months vs >6 months), by presence vs absence of measurable disease, number of previous chemotherapy lines (<3 vs ≥3), and germline BRCA mutational status (germline BRCA1/2 mutation carriers vs BRCAness phenotype).

The primary end point was OS. Secondary end points were determined by investigator assessment and included progression-free survival (PFS), objective response rate (ORR) by RECIST 1.1, duration of response (DOR), and safety.

The baseline patient characteristics were well balanced between arm A and arm B; the median age at diagnosis was 53 years (IQR, 48-61) vs 55 years (IQR, 48-64), respectively, and the median age at enrollment was 60 years (IQR, 52-67) vs 61 years (IQR, 54-69), respectively. Most patients in both arms had the BRCAness phenotype (50.8% vs 50.8%), had an ECOG performance status of 0 (68.9% vs 65.6%), had a progression-free interval of over 6 months (55.7% vs 59.0%), had FIGO stage III disease at diagnosis (73.0% vs 77.1%), had high-grade serous and endometrioid histology (87.7% vs 83.6%), and underwent at least 3 prior lines of chemotherapy (70.5% vs 70.5%). Additionally, most patients in both arms had measurable disease (91.8% vs 94.3%) and did not undergo previous PARP inhibitor therapy (63.1% vs 65.6%).

Additional findings from MITO-23 revealed that the median PFS in arm A was 4.9 months vs 4.4 months in arm B (HR, 1.02; 95% CI, 0.787-1.314; P = .897). The median PFS among patients who received a PARP inhibitor was 3.2 months vs 2.8 months, respectively (HR, 0.889; 95% CI, 0.577-1.369; P = .592). Moreover, no superior effect with trabectedin vs chemotherapy was observed in terms of OS or PFS across BRCA mutational status, type of chemotherapy, number of previous chemotherapy lines, previous PARP inhibitor treatment, or platinum sensitivity status.

Among response-evaluable patients in arm A (n = 105) and arm B (n = 103), the respective ORRs were 17.1% (95% CI, 11.0%-25.7%) vs 21.4% (95% CI, 14.4%-30.4%); the complete response rates were 5.7% (95% CI, 2.6%-12.2%) vs 3.9% (95% CI, 1.4%-10.0%), respectively. The median DOR was 5.62 months (95% CI, 4.47-10.46) vs 5.66 months (95% CI, 3.88-8.03), respectively.

In the safety population, most patients in arm A (n = 121) and arm B (n = 118) experienced an adverse effect (AE) of any grade, at a rate of 96.7% vs 93.2%, respectively. Most patients in both arms experienced treatment-related AEs (82.0% vs 78.6%) and grade 3 or higher AEs (71.1% vs 50.0%). Serious AEs (24.8% vs 5.9%) were present in both arms; no suspected unexpected serious AEs were reported and no new or unexpected AEs nor any treatment-related deaths occurred during the trial.

“To our knowledge, MITO-23 was the first prospective, randomized phase 3 trial that specifically evaluated single-agent trabectedin in patients with recurrent ovarian cancer, primary peritoneal, or fallopian tube cancer in comparison with physician’s choice chemotherapy,” study authors wrote in conclusion. “Ongoing translational analyses [including homologous recombination deficient and homologous recombination repair evaluation, microRNA expression, and tumor microenvironment immunologic composition] will possibly help in identifying predictive biomarkers of response/resistance to trabectedin and the patients who may gain long-term benefit from the treatment.”

References

1. Lorusso D, Raspagliesi F, Ronzulli D, et al. Single-agent trabectedin versus physician's choice chemotherapy in patients with recurrent ovarian cancer with BRCA-mutated and/or BRCAness phenotype: a randomized phase III trial. J Clin Oncol. Published online February 5, 2024. doi:10.1200/JCO.23.01225
2. Trabectedin. FDA. October 23, 2015. Accessed February 9, 2024. https://wayback.archive-it.org/7993/20170111231623/http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm468914.htm