Yet another blow has been dealt for the alkylating agent trabectedin in advanced ovarian cancer. The international phase III INOVATYON study found no improvement in overall or progression-free survival for trabectedin plus pegylated liposomal doxorubicin (PEG-LD) vs carboplatin/PEG-LD in patients with recurrent disease progressing 6 to 12 months after their last platinum dose.
“The study did not meet its primary endpoint. It failed to demonstrate an improvement in overall survival for trabectedin/PEG-LD followed at disease progression by platinum,” said Nicoletta Colombo, MD, PhD, of the European Institute of Oncology IRCCS and the University of Milan-Biococca, Italy, who presented the late-breaking abstract at the Europena Society for Medical Oncology (ESMO) 2020 Virtual Congress.1
As explained by Andreas du Bois, MD, PhD, Chairman of the Department of Gynecology and Gynecologic Oncology at Kliniken Essen Mitte, Germany, and Chairman of the AGO Study Group, INOVATYON sought to answer a lingering question: Does prolonging the platinum-free interval enhance the efficacy of platinum retreatment? According to Dr. du Bois, the answer is in: “Platinum-based regimens remain the standard of care in patients with recurrent ovarian cancer progressing within 6 to 12 months after their last platinum line.”
"The study did not meet its primary endpoint. It failed to demonstrate an improvement in overall survival for trabectedin/PEG-LD followed at disease progression by platinum."— Nicoletta Colombo, MD, PhD
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The study did provide some interesting hints of benefit, according to Dr. Colombo. Progression-free survival was longer with carboplatin/PEG-LD, but after subsequent therapy, it favored trabectedin/PEG-LD, particularly when that treatment was a platinum. Trabectedin/PEG-LD was the more effective treatment as well in patients who had two prior lines of treatment, suggesting this regimen may still have a role. However, based on a negative primary endpoint, she agreed with Dr. du Bois: “Platinum-based regimens remain the standard of care.”
Trabectedin has been approved by the U.S. Food and Drug Administration in the treatment of patients with soft-tissue sarcoma but not ovarian cancer. Elsewhere in the world, it has regulatory approval for platinum-sensitive ovarian cancer based on the OVA‑301 trial, a study in which the most benefit was found in those with BRCA-mutant tumors and in patients with a platinum-free interval of 6 to 12 months.2,3 The subsequent phase III OVA-3006 study failed to show a survival benefit, but it did confirm trabectedin’s benefit in BRCA-mutated cancer: a survival gain of 13 months overall (hazard ratio [HR] = 0.54) and 17 months for patients with BRCA-mutant tumors and a platinum-free interval of 6 to 12 months (HR = 0.37).4 Increased toxicity was the drug’s downside.
The international phase III INOVATYON trial was initiated in 2011, before the results of OVA-301 and OVA-3006 were known. It aimed to demonstrate an improvement in overall survival for the trabectedin/PEG-LD regimen followed upon relapse by a platinum rechallenge, as compared with carboplatin/PEG-LD, in patients with recurrent ovarian cancer. In vivo data have indicated that trabectedin may restore some sensitivity to platinum agents and may enhance the efficacy of subsequent platinum therapy, Dr. Colombo explained.
All patients in INOVATYON had a platinum-free interval of 6 to 12 months after the end of first- or second-line platinum therapy (median, 8.4 months). A total of 30% had received two prior platinum lines. BRCA status was known in only about half the patients; 13.4% of the trabectedin arm and 9.2% of the carboplatin arm were known to have BRCA-mutated tumors.
The study enrolled 617 patients from 117 European sites, randomly assigning them to trabectedin (1.1 mg/m2) plus PEG-LD (30 mg/m2) every 3 weeks or carboplatin (AUC 5) plus PEG-LD (30 mg/m2) every 4 weeks. Upon disease progression, platinum rechallenge was mandatory in the trabectedin arm but was at the physician’s discretion in the carboplatin arm. More patients completed at least six treatment cycles of carboplatin/PEG-LD, and fewer patients in that cohort discontinued treatment due to toxicity or patient refusal.
At a median follow-up of 44 months, median overall survival was 21.5 months with trabectedin/PEG-LD and 21.3 months with carboplatin/PEG-LD (HR = 1.10; P = .284). Median progression-free survival was 7.5 and 9.0 months, respectively (HR = 1.26; P = .005), significantly favoring carboplatin/PEG-LD. Subgroup analyses did not identify any subsets who clearly benefited from trabectedin.
Three-quarters of each arm went on to subsequent therapy; for 63% of the trabectedin arm, this was platinum-based treatment, as mandated by the protocol, vs 18% of the carboplatin arm; it was a poly (ADP-ribose) polymerase (PARP) inhibitor for 15% of the trabectedin arm and 11% of the carboplatin arm.
“Platinum-based regimens remain the standard of care in patients with recurrent ovarian cancer progressing within 6 to 12 months after their last platinum line.”— Andreas du Bois, MD, PhD
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Other Findings of Note
“The assumption of INOVATYON was that trabectedin could enhance the efficacy of subsequent platinum, and we did see a trend for longer progression-free survival in the trabectedin/PEG-LD arm,” stated Dr. Colombo. “This became statistically significant when platinum was used as subsequent treatment, according to the protocol.”
After the start of subsequent therapy, median progression-free survival was 7.4 months with trabectedin/PEG-LD, vs 5.7 months with carboplatin/PEG-LD (HR = 0.84; P = .086). When treatment was with a platinum, median progression-free survival was 7.6 months and 5.7 months, respectively (HR = 0.80; P = .028).
There was also an interesting interaction between treatment and the number of prior lines of therapy, with hazard ratios going in the opposite direction favoring carboplatin/PEG-LD after one line of therapy (HR = 1.22) and trabectedin/PEG-LD after two lines (HR = 0.87).
Grades 3 to 5 adverse reactions occurred in 69% of the trabectedin arm and 36% of the carboplatin arm (P < .001). Most serious adverse events were hematologic, and they were more frequent with trabectedin, as were gastrointestinal and hepatic toxicities and asthenia. Neurotoxicity of any grade was observed in 18% of both arms. By numerous quality-of-life measures (on functional and symptom scales), there was worsening with trabectedin/PEG-LD.
DISCLOSURE: Dr. Colombo reported financial relationships with Roche, PharmaMar, AstraZeneca, Clovis, Tesaro/GSK, Amgen, Pfizer, MSD, BioCad, Immunogen, Takeda, and Advaxis. Dr. du Bois reported financial relationships with AstraZeneca, BioCad, Clovis Oncology, Doxolipad, Genmab, Ingress Health, Roche/Genentech, and Tesaro.
1. Colombo N, Gadducci A, Sehouli J, et al: INOVATYON study: Randomized phase III international study comparing trabectedin/PLD followed by platinum at progression vs carboplatin/PLD with recurrent ovarian cancer progressing within 6-12 months after last platinum line. ESMO Virtual Congress 2020. Abstract LBA30. Presented September 19, 2020.
2. Poveda A, Vergote I, Tjulandin S, et al: Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer: Outcomes in the partially platinum-sensitive (platinum-free interval 6-12 months) subpopulation of OVA-301 phase III randomized trial. Ann Oncol 22:39-48, 2011.
3. Kaye SB, Colombo N, Monk BJ, et al: Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer delays third-line chemotherapy and prolongs the platinum-free interval. Ann Oncol 22:49-58, 2011.
4. Monk BJ, Herzog TJ, Triantos S, et al: A randomized, open-label study comparing trabectedin and pegylated liposomal doxorubicin with pegylated liposomal doxorubicin alone for the treatment of advanced-relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer (ET743-OVC-3006). 2019 Society for Gynecologic Oncology Annual Meeting. Abstract 20. Presented March 16, 2019.
The invited discussant of the phase III INOVATYON trial was Andreas du Bois, MD, PhD, Chairman of the Department of Gynecology and Gynecologic Oncology at Kliniken Essen Mitte, Germany, and Chairman of the AGO Study Group. As Dr. du Bois explained, the study “dealt with an old question: Does...