TTFields/Paclitaxel Fails to Boost OS in Platinum-Resistant Ovarian Cancer But Shows Potential in Key Subgroup

Platinum-Resistant Ovarian Cancer
| Image Credit:© Dr_Microbe
- stock.adobe.com

Although the addition of tumor treating fields (TTFields) to paclitaxel did not lead to a statistically significant improvement in overall survival (OS) vs paclitaxel alone in patients with platinum-resistant ovarian cancer in the final analysis of the phase 3 INNOVATE-3 trial (NCT03940196), findings from an exploratory post hoc analysis showed a potential survival benefit for the combination in patients naive to pegylated liposomal doxorubicin (PLD).

Findings from the final analysis of the study published in the European Journal of Cancer showed that in the intent-to-treat (ITT) population, patients treated with TTFields and paclitaxel (n = 280) experienced a median OS of 12.2 months (95% CI, 10.3-13.8) at a median follow-up of 10.7 months compared with a median OS of 11.9 months (95% CI, 10.8-13.6) in patients treated with paclitaxel alone (n = 278) at a median follow-up of 9.9 months (HR, 1.01; 95% CI, 0.83-1.24; P = .89).

“In the overall ITT population of [INNOVATE-3] study, the addition of TTFields therapy did not improve OS vs paclitaxel,” lead study author Ignace B. Vergote, MD, PhD, of the Division of Gynecological Oncology at University Hospitals Leuven, KU Leuven, and the Luxembourg Gynaecological Oncology Group in Belgium, and colleagues wrote in the publication. “While unexpected, this is not uncommon in the [patient population with] platinum-resistant ovarian cancer. [Respective patients] have limited available therapies and are often heavily pretreated.”

Data from the post hoc analysis showed that among patients who were PLD-naive, the median OS was 16.0 months (95% CI, 13.6-19.0) vs 11.7 months (95% CI, 10.1-14.2) in those treated with TTFields plus paclitaxel (n = 113) vs paclitaxel alone (n = 88), respectively (HR, 0.67; 95% CI, 0.49-0.94; P = .003).

“Surprisingly, prior PLD use was the only independent factor identified via multivariable analyses to predict outcomes in this study, apart from the well-established prognostic factors ECOG performance status and ascites,” study authors wrote. “Results from these exploratory post hoc analyses may be explained by the known tumor microenvironment alteration, such as increases in regulatory T cells and macrophage-inflammatory-protein-1-beta following PLD administration.”

INNOVATE-3 Background and Design

The randomized, open-label, multicenter study evaluated TTFields in combination with paclitaxel vs paclitaxel alone in patients at least 18 years of age with a confirmed diagnosis of epithelial ovarian cancer, including serous, endometrioid, mucinous, clear cell, mixed, undifferentiated, and other histologies, who had platinum-resistant disease. Patients included in the study experienced disease progression within 6 months of platinum-based treatment; had evaluable disease per RECIST 1.1 criteria; received 5 or fewer previous lines of therapy; underwent 2 or fewer prior lines of therapy after platinum resistance; and had an ECOG performance status of 0 or 1.

Patients were randomly assigned 1:1 to TTFields plus paclitaxel or paclitaxel alone. Those in the experimental arm received TTFields at 22 kHz continuously using the NovoTFF-200(O) system, along with a recommended device to be worn for at least 18 hours per day on a monthly average. Intravenous paclitaxel was administered at 80 mg/m2 weekly for 8 weeks and then on days 1, 8, and 15 in a 28-day cycle in both arms.

Patients in the overall population were stratified based on prior lines of therapy after platinum resistance, prior use of bevacizumab (Avastin), and BRCA mutation status.

The primary end point was OS; secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.

Baseline Patient Characteristics

In the ITT population, baseline characteristics were well balanced. Between the arms, the median age was 62 years (range, 22–91), most patients had serous histology (88.7 %), and most had an ECOG performance status of 0 (60.2 %). Additionally, 24.4 % of patients received at least 4 prior lines of therapy, and 40.7 % were given at least 1 line of therapy after platinum-resistance. Prior therapies included taxanes (99.5 %), bevacizumab (65.9 %), and anthracyclines (64.0 %). Of patients who received a prior anthracycline, 93% received PLD, and the remainder were given a non-specified doxorubicin formulation.

The PLD-naive subgroup included 201 patients, which comprised 36% of the ITT population. In the PLD-naive subgroup, patients in the TTFields/paclitaxel (n = 113) and paclitaxel alone (n = 88) arms, the median ages were 62 years (range, 26-78) and 63 years (range, 25-80), respectively. Patients had an ECOG performance status of 0 (TTFields/paclitaxel, 58.4%; paclitaxel alone, 65.9%) or 1 (41.6%; 34.1%).

The most common primary tumor type was ovarian cancer (TTFields/paclitaxel, 87.6%; paclitaxel, 80.7%), and the most common histology at diagnosis was serous (85%; 94.3%). Number of prior lines of therapy included 1 (26.5%; 25.0%), 2 (38.1%; 36.4%), 3 (27.4%; 27.3%), 4 (7.1%; 5.7%), and 5 (0.9%; 4.5%). The number of prior lines of systemic therapies for platinum-resistant ovarian cancer included 0 (78.8%; 76.1%), 1 (16.8%; 19.3%), and 2 (4.4%; 4.5%). BRCA status included mutated (13.3%; 14.8%) and wild-type or unknown (86.7%; 85.2%). Prior systemic agents included bevacizumab (58.4%; 60.2%).

Additional Efficacy and Safety Data

In the PLD-naive subgroup, median PFS was not significantly different between the TTFields/paclitaxel and paclitaxel alone groups. Specifically, data showed a median PFS of 5.4 months (95% CI, 3.9-5.9) vs 5.1 months (95% CI, 3.8-5.6) in the TTFields/paclitaxel and paclitaxel alone arms, respectively. The ORR was 43.6% vs 41.7% in the respective arms.

Adverse effects (AEs) were reported in 99.3% and 97.2% of patients in the safety-evaluable portion of the ITT population treated with TTFields/paclitaxel (n = 268) and paclitaxel alone (n = 251), respectively. Of note, AEs were similar between the treatment arms; common any-grade AEs included leukopenia (TTFields/paclitaxel, 44.0%; paclitaxel alone, 42.6%), anemia (47.8%, 51.8%), and fatigue (47.0%, 51.0%). Grades 3 to 5 AEs were reported in 60.1% of patients, regardless of treatment. The most frequent grade 3 to 5 AEs included hematologic and lymphatic system disorders with TTFields/paclitaxel (29.5%) and paclitaxel alone (31.1%). Treatment discontinuations due to AEs occurred in 25.7% and 18.7% of patients in the respective arms, and AEs leading to death occurred in 12 and 13 patients, respectively.

Reference

Vergote I, Copeland LJ, Van Gorp T, et al. Tumor treating fields therapy in platinum-resistant ovarian cancer: results of the ENGOT-ov50/GOG-3029/INNOVATE-3 pivotal phase 3 randomized study. Eur J Cancer. 2025;219:115306. doi:10.1016/j.ejca.2025.115306