FDA Grants Priority Review to Tisotumab Vedotin sBLA for Recurrent or Metastatic Cervical Cancer

The FDA has granted priority review to a supplemental biologics license application (sBLA) seeking to convert the accelerated approval of tisotumab vedotin-tftv (Tivdak) to a full approval for the treatment of patients with recurrent or metastatic cervical cancer whose disease progresses on or following frontline therapy.¹

The sBLA is based on findings from the phase 3 innovaTV 301 trial (NCT04697628), in which the antibody-drug conjugate (ADC) significantly improved overall survival (OS), progression-free survival (PFS), and confirmed investigator-assessed overall response rate (ORR) vs chemotherapy in this population.²

The median OS achieved with tisotumab vedotin (n = 253) was 11.5 months (95% CI, 9.8-14.9) vs 9.5 months (95% CI, 7.9-10.7) with investigator’s choice of chemotherapy (n = 249), translating to a 30% reduction in the risk of death (HR, 0.70; 95% CI, 0.54-0.89; stratified log-rank P = .0038), meeting the study’s primary end point. The 12-month OS rates were 48.7% and 35.3%, respectively. The median investigator-assessed PFS with the ADC was 4.2 months (95% CI, 4.0-4.4) 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%, respectively. The confirmed ORRs achieved with tisotumab vedotin and chemotherapy were 17.8% (95% CI, 13.3%-23.1%) and 5.2% (95% CI, 2.8%-8.8%), respectively (OR, 4.0; 95% CI, 2.1-7.6; P < .0001).

Under the Prescription Drug User Fee Act, the regulatory agency will decide on the application by May 9, 2024.¹

“The phase 3 innovaTV 301 trial demonstrated a favorable benefit/risk profile, including improvement in overall survival, and adds to the overall data supporting Tivdak as a treatment option for people with recurrent and metastatic cervical cancer who have limited treatment options,” Roger Dansey, MD, chief development officer of oncology at Pfizer, stated in a press release. “The FDA acceptance of our sBLA for review is important progress toward continuing to offer an option that can extend the lives of more adults with cervical cancer.”

In September 2021, the FDA granted accelerated approval to tisotumab vedotin for use in adult patients with recurrent or metastatic cervical cancer with disease progression on or following chemotherapy.³ The decision was based on findings from the phase 2 innovaTV 204 trial (NCT03438396). Data indicated that the ORR achieved with the ADC was 24% (95% CI, 15.9%-33.3%) by independent review committee assessment and RECIST v1.1 criteria in this population.4 Notably, patients had previously received doublet chemotherapy and bevacizumab (Avastin).

The confirmatory randomized, open-label, phase 3 innovaTV 301 trial enrolled patients with recurrent or metastatic cervical cancer who experienced disease progression on or following doublet chemotherapy with or without bevacizumab and an anti–PD-1/PD-L1 agent if eligible and available. They must have received at least 2 lines of treatment. Patients needed to have measurable disease by RECIST v1.1 criteria and an ECOG performance status of 0 or 1.

Study participants were randomly assigned 1:1 to 2.0 mg/kg of intravenous (IV) tisotumab vedotin every 3 weeks or investigator’s choice of chemotherapy. Those in the chemotherapy arm could have received IV topotecan at 1 or 1.25 mg/m2 on days 1 to 5 every 21 days, IV vinorelbine at 30 mg/m2 on days 1 and 8 every 21 days, IV gemcitabine at 1000 mg/m2 on days 1 and 8 every 21 days, IV irinotecan at 100 or 125 mg/m2weekly for 28 days every 42 days, or IV pemetrexed at 500 mg/m2 on day 1 every 21 days.

Randomization was stratified by performance status (0 vs 1), previous receipt of bevacizumab (yes vs no), prior exposure to anti­–PD-1/PD-L1 therapy (yes vs no), and geographic region (United States vs Europe vs other).

In addition to OS serving as the trial’s primary end point, key secondary end points included PFS, ORR, and safety.

Data from the planned interim analysis of the trial were shared during the 2023 ESMO Congress. The median patient age across the arms was 50.5 years (range, 26-80). Slightly more than half of patients in the ADC and chemotherapy arms had an ECOG performance status of 0 (54.2% vs 54.6%, respectively). Just under half of patients were from Europe (41.9% vs 41.8%) and 33.6% vs 35.3% of patients, respectively, were from Asia. Most patients had squamous cell carcinoma histology (63.2% vs 63.1%), and 10.7% vs 9.6% of patients, respectively, had pelvic recurrence only.

More than half of patients received 1 prior line of systemic treatment (62.8% vs 59.8%) and 36.8% vs 40.2% of patients had 2 prior lines. More than half of patients had prior bevacizumab (64.8% vs 63.1%), and less than one-third of patients received prior immunotherapy (28.1% vs 26.9%). The majority of patients received prior radiation for their cancer (81.0% vs 81.5%).

Additional data showed that the OS and PFS benefits derived with the ADC over chemotherapy were generally consistent across the key subsets that were analyzed.

Among those who responded to tisotumab vedotin, 2.4% achieved a complete response, 15.4% experienced and partial response, and 58.1% had stable disease; 18.2% experienced progressive disease and 5.9% were not evaluable for response. The disease control rate achieved with the ADC was 75.9% (95% CI, 70.1%-81.0%) vs 58.2% (95% CI, 51.8%-64.4%) with chemotherapy. The median duration of response was 5.3 months (95% CI, 4.2-8.3) in the ADC arm vs 5.7 months (95% CI, 2.8-not reached) in the chemotherapy arm.

Regarding safety, grade 1 or 2 treatment-related adverse effects (TRAEs) occurred in 58.4% of those given tisotumab vedotin vs 40.2% of those who received chemotherapy; TRAEs were grade 3 or greater in 29.2% and 45.2% of patients, respectively. Grade 5 TRAEs were reported in 0.8% of those in the ADC arm vs 0.4% of those in the chemotherapy arm.

The most common TRAEs reported with the ADC were conjunctivitis (30.4%), nausea (29.2%), peripheral sensory neuropathy (26.8%), alopecia (24.4%), epistaxis (22.8%), reduced appetite (18.0%), diarrhea (16.0%), keratitis (15.6%), anemia (12.8%), and neutropenia (6.4%).

The most common toxicities of special interest observed with tisotumab vedotin were ocular (grade 1/2, 47.2%; grade ≥3, 3.2%), peripheral neuropathy (30.4%; 5.2%), and bleeding (26.8%; 0.8%). No grade 4 or 5 adverse effects of special interest were experienced. Ocular and peripheral neuropathy events resulted in dose discontinuation for 5.6% of those in each arm.

References

1. Tivdak supplemental biologics license application accepted for priority review by FDA for patients with recurrent or metastatic cervical cancer. News release. Pfizer. January 9, 2024. Accessed January 9, 2024. https://www.pfizer.com/news/press-release/press-release-detail/tivdakr-supplemental-biologics-license-application-accepted
2. Vergote IB, Martin AG, Fujiwara K, et al. LBA9 innovaTV 301/ENGOT-cx12/GOG-3057: a global, randomized, open-label, phase III study of tisotumab vedotin vs investigator’s choice of chemotherapy in 2L or 3L recurrent or metastatic cervical cancer. Ann Oncol. 2023;34(suppl 2):S1276-S1277. doi:10.1016/j.annonc.2023.10.029
3. Genmab and Seagen announce FDA accelerated approval for Tivdak (tisotumab vedotin-tftv) in previously treated recurrent or metastatic cervical cancer. News release. Genmab A/S and Seagen Inc.. September 20, 2021. Accessed January 8, 2024. https://ir.genmab.com/news-releases/news-release-details/genmab-and-seagen-announce-fda-accelerated-approval-tivdaktm
4. Coleman RL, Lorusso D, Gennigens C, et al. Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer: results from the phase 2 innovaTV 204/GOG-3023/ENGOT-cx6 study. Ann Oncol. 2020;31(suppl 4):S1162-S1163. doi:10.1016/j.annonc.2020.08.2262