Phase 3 innovaTV 301 Trial Shows Potential of Tisotumab Vedotin in Cervical Cancer
Tisotumab vedotin-tftv improved survival in patients with recurrent or metastatic cervical cancer with disease progression on doublet chemotherapy.
Ignace B. Vergote, MD, PhD
In the phase 3 innovaTV 301/ENGOT-cx12/GOG-3057 trial (NCT04697628), tisotumab vedotin-tftv (Tivdak) demonstrated a 30% reduction in the risk of death compared with investigator’s choice of chemotherapy when utilized in the second- or third-line for patients with recurrent or metastatic cervical cancer with disease progression on doublet chemotherapy, according to findings from a planned interim analysis presented at the 2023 ESMO Congress.1
The results showed that at a median follow-up of 10.8 months (95% CI, 10.3-11.6), the median overall survival (OS) was 11.5 months (95% CI, 9.8-14.9) with tisotumab vedotin vs 9.5 months (95% CI, 7.9-10.7) with chemotherapy (HR, 0.70, 95% CI, 0.54-0.89; P = .0038). The 12-month OS rates were 48.7% and 35.3% with tisotumab vedotin and chemotherapy, respectively.
The median progression-free survival (PFS) was 4.2 months (95% CI, 4.0-4.4) with tisotumab vedotin vs 2.9 months (95% CI, 2.6-3.1) with chemotherapy (HR, 0.67; 95% CI, 0.54-0.82; P <.0001). The 6-month PFS rates were 30.4% and 18.9% with tisotumab vedotin and chemotherapy, respectively.
“Based on these data, tisotumab vedotin should be considered a potential new standard of care for patients who have progressed after first-line systemic therapy,” lead study author Ignace B. Vergote, MD, PhD, of said in a presentation of the data. Vergote is chairman of the Leuven Cancer Institute and head of the Department of Obstetrics and Gynecology and Gynecologic Oncology at the Catholic University of Leuven in Belgium.
Poor prognosis and high mortality are hallmarks of recurrent or metastatic cervical cancer, which represents the fourth most deadly cancer in women worldwide. Although pembrolizumab (Keytruda) is approved for use in this population in the frontline setting in combination with chemotherapy, with or without bevacizumab (Avastin),2 patients who develop disease progression need improved therapeutic options.
Tisotumab vedotin is an antibody-drug conjugate composed of a tissue factor–directed human monoclonal antibody that is linked covalently to the microtubule-disrupting agent MMAE. In 2021, the FDA granted accelerated approval to the agent for patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.3 The decision was based on findings from the single-arm innovaTV 204 trial (NCT03438396), in which tisotumab vedotin led to an objective response rate (ORR) of 24% (95% CI, 15.9%-33.3%) and a median duration of response (DOR) of 8.3 months (95% CI, 4.2-not reached [NR]).4
To be eligible for enrollment in the phase 3 innovaTV 301 trial, patients had to have received a diagnosis of recurrent or metastatic cervical cancer; had documented disease progression on or after doublet chemotherapy with or without bevacizumab and an anti–PD(L)1 agent if eligible and available; measurable disease per RECIST v1.1 criteria; an ECOG performance status (PS) of 0 or 1; and exposure to no more than 2 prior lines of therapy.
Patients were randomly assigned 1:1 to 2.0 mg/kg of intravenous tisotumab vedotin every 3 weeks (n = 253) or investigator’s choice of chemotherapy (n = 249), which could have included topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed.
OS served as the primary end point. Secondary end points included PFS, ORR, and safety.
The statistical design allowed for an assumed hazard ratio of 0.7 and planned sample size of approximately 482 patients, allowing a drop-out rate of 5% per year. The sample size was powered at 90% with 336 OS events. The overall statistical level of significance was .05 (2-sided). An interim analysis was planned when 252 OS events had occurred but based on the number of events that had occurred by this point, the P value boundary was adjusted to .0226 for OS, .0453 for PFS, and .05 for ORR.
Hierarchical testing was used for OS, then PFS, and lastly ORR.
Patients were stratified by ECOG PS (0 vs 1), prior bevacizumab use (yes vs no), prior anti–PD(L)1 therapy (yes vs no), and geographic region (US, Europe, or other).
A total of 660 patients were evaluated for eligibility and 502 patients were randomized. In the tisotumab vedotin and chemotherapy arms, respectively, 250 and 239 patients received at least 1 dose of their intended treatment. The most common reason for discontinuation in the tisotumab vedotin and chemotherapy arms, respectively, was disease progression (n = 177 vs n = 193), followed by an adverse effect (AE; n = 40) in the tisotumab vedotin arm and patient decision in the chemotherapy arm (n = 17).
Only 21 patients in the tisotumab vedotin arm and 16 in the chemotherapy arm remain on study.
Baseline patient and disease characteristics were “very well balanced,” Ignace said, noting that most patients in the tisotumab vedotin and chemotherapy arms, respectively, had squamous cell carcinoma (63.2% vs 63.1%), extrapelvic metastatic disease (89.3% vs 90.4%), 1 prior line of systemic therapy (62.8% vs 59.8%), prior bevacizumab (64.8% vs 63.1%), and prior radiation therapy (81.0% vs 81.5%). Moreover, approximately one-third of patients were enrolled in Asia and received prior anti–PD-(L)1 therapy. Of the approximate 80% of patients who had an evaluable biopsy, more than 90% had positive membrane TF expression.
Additional findings indicated that the ORR was 17.8% (95% CI, 13.3%-23.1%) with tisotumab vedotin vs 5.2% (95% CI, 2.8%-8.8%) with chemotherapy. Best overall responses in the tisotumab vedotin arm included complete response (CR; 2.4%), partial response (PR; 15.4%), stable disease (SD; 58.1%), and progressive disease (PD; 18.2%); 5.9% of patients were not evaluable (NE). In the chemotherapy arm, best responses included only PR (5.2%), SD (53.0%), and PD (29.7%); 12.0% of patients were NE.
The disease control rate was 75.9% (95% CI, 70.1%-81.0%) with tisotumab vedotin vs 58.2% (95% CI, 51.8%-64.4%) with chemotherapy. The median DOR was 5.3 months (95% CI, 4.2-8.3) and 5.7 months (95% CI, 2.8-NR) with tisotumab vedotin and chemotherapy, respectively.
Vergote noted that the OS and PFS benefit was generally consistent across key subgroups, although lack of prior bevacizumab appeared to negate the benefit of tisotumab vedotin for both PFS (HR, 0.83; 95% CI, 0.59-1.16) and OS (HR, 1.00; 95% CI, 0.66-1.50).
The agent was well tolerated with a median relative dose intensity of 96.1% vs 90.0% with chemotherapy. Any-grade treatment-related AEs (TRAEs) occurred in 87.6% of patients in the tisotumab vedotin arm (grade 1/2, 58.4%; grade ≥3, 29.2%) and 85.4% of patients in the chemotherapy arm (grade 1/2, 40.2%; grade ≥3, 45.2%). Two patients in the tisotumab vedotin arm and 1 patient in the chemotherapy died due to TRAEs.
The most common TRAEs with tisotumab vedotin and chemotherapy, respectively, were anemia (12.8% vs 43.9%), nausea (29.2% vs 36.0%), conjunctivitis (30.4% vs 0%), peripheral sensory neuropathy (26.8% vs 2.1%), alopecia (24.4% vs 2.9%), epistaxis (22.8% vs 2.1%), neutropenia (6.4% vs 21.8%), decreased appetite (18.0% vs 10.0%), diarrhea (16.0% vs 8.8%), and keratitis (15.6% vs 0%).
Regarding AEs of special interest for tisotumab vedotin, only grade 1 to 3 events occurred, although the rates were significantly higher than with chemotherapy. These included ocular events (grade 1/2, 47.2%; grade 3, 3.2% vs grade 1/2, 2.5% for chemotherapy), peripheral neuropathy (grade 1/2, 30.4%; grade 3, 5.2% vs grade 1/2, 2.5% for chemotherapy), and bleeding (grade 1/2, 26.8%; grade 3, 0.8% vs grade 1/2, 2.9% for chemotherapy). Dose discontinuation due to ocular and peripheral neuropathy events were reported in 5.6% of patients in the tisotumab vedotin and chemotherapy arms, respectively.
Further breakdown of each category of event included reports of conjunctivitis (30.4%), keratitis (15.6%), dry eye (13.2%), peripheral sensory neuropathy (26.8%), paresthesia (2.8%), muscular weakness (2.4%), peripheral sensorimotor neuropathy (2.4%), epistaxis (22.8%), hematuria (3.2%), and vaginal hemorrhage (3.2%).
“The safety profile of tisotumab vedotin was manageable and tolerable, and consistent with previous experience,” Vergote concluded.
Disclosures: Dr Vergote declared consulting or advisory roles with Agenus, Akesobio, Amgen (Europe), AstraZeneca, Bristol Myers Squibb, Carrick Therapeutics, Clovis Oncology, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, F. Hoffmann-La Roche, Genmab, GSK, Immunogen, Jazzpharma, Karyopharm, Mersana, Millenium Pharmaceuticals, Molecular Partners, MSD, Novocure, Novartis, Oncoinvent, Regeneron, Seagen, Sotio, Verastem Oncology, and Zentalis; research funding from Amgen and Roche; and other relationships with Oncoinvent and Genmab contracted research (via KULeuven).
