FDA Approves Tisotumab Vedotin-tftv for Recurrent or Metastatic Cervical Cancer

FDA

The FDA has granted an accelerated approval to tisotumab vedotin (Tivdak) for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.¹

The regulatory decision is based on data from phase 2 innovaTV 204 trial (NCT03438396), in which the antibody-drug conjugate elicited an objective response rate (ORR) of 24% (95% CI, 15.9%-33.3%) per independent review committee using RECIST v1.1 criteria in patients with recurrent or metastatic cervical cancer who received prior doublet chemotherapy and bevacizumab (Avastin).²

Among those who responded to treatment, 7% experienced a complete response and 17% had a partial response. The median duration of response with tisotumab vedotin was 8.3 months (95% CI, 4.2–not reached). The median time to response (TTR) with the ADC was 1.4 months (range, 1.1-5.1), and activity was noted within the first 2 treatment cycles.

“Once recurrent or metastatic cervical cancer progresses, there is a need for more options for these patients,” said Robert L. Coleman, MD, chief scientific officer, US Oncology Research and lead investigator of the innovaTV 204 clinical trial, stated in a press release. “This is an important development for patients with recurrent or metastatic cervical cancer.”

The single-arm, multicenter, phase 2 innova TV 204 trial enrolled a total of 101 previously treated patients with recurrent and/or metastatic cervical cancer who were intravenously administered tisotumab vedotin at a dose of 2.0 mg/kg every 3 weeks until disease progression or unacceptable toxicity.

To be eligible for enrollment, patients had to have recurrent or extrapelvic metastatic disease, experienced disease progression during or after doublet chemotherapy with bevacizumab (if eligible), had received 2 or fewer prior systemic therapies, and have had an ECOG performance status of 0 to 1.

The primary end point of the trial was ORR per RECIST v1.1 criteria and independent imaging review committee (IRC) assessment. Secondary end points included ORR per investigator assessment and RECIST criteria, overall survival (OS), and safety.

DOR, TTR, and progression-free survival (PFS) per IRC and investigator, served as additional end points. Investigators also evaluated biomarkers and health-related quality of life with the treatment.

The median age of study participants was 50 years, 95% were White, and 58% had an ECOG performance status of 0. Moreover, 68% of patients had squamous cell carcinoma, 27% had adenocarcinoma, and 5% had adenosquamous carcinoma. Almost all patients, or 94%, had extrapelvic metastatic disease at baseline.

Fifty-four percent of participants had received prior cisplatin plus radiation therapy and 70% had received 1 prior line of systemic treatment for recurrent or metastatic disease. Additionally, 63% of patients received prior bevacizumab and doublet chemotherapy as first-line treatment and 56% did not respond to their last systemic treatment received.

Patients received treatment for a median duration of 4.2 months at a median of 6 doses; a high dose intensity of 95.9% was reported with the agent. Four patients continued to receive treatment; 65% of patients discontinued because of radiographic progression. Thirteen percent of patients discontinued treatment because of toxicities, 8% due to clinical progression, 5% due to withdrawn consent, 4% because of death, and 1% per investigator decision.

Additional data presented during the 2020 ESMO Virtual Congress demonstrated that 4% of those who received the ADC achieved disease stability while 24% experienced disease progression per IRC. Seventy-nine percent of participants also experienced a reduction in target lesions.

Notably, clinically meaningful responses were experienced irrespective of tumor histology, lines of previous treatment, responses to previous systemic treatment, and whether frontline bevacizumab/doublet chemotherapy was received. Responses were also observed irrespective of membrane TF expression level.

The median PFS reported with the ADC was 4.2 months, while the OS was 12.1 months. The PFS rate at 6 months was 30%, while the OS rate at this time point was 79%.

The ADC had a manageable safety profile. The prescribing information for the agent includes a boxed warning for ocular toxicity, as well as warning for peripheral neuropathy, hemorrhage, pneumonitis, and embryo-fetal toxicity.

The adverse effects most frequently reported with tisotumab vedotin included hemoglobin decreased (52%), fatigue (50%), lymphocytes decreased (42%), nausea (41%), peripheral neuropathy (39%), alopecia (39%), epistaxis (39%), conjunctival adverse reactions (37%), hemorrhage (32%), leukocytes decreased (30%), creatinine increased (29%), dry eye (29%), prothrombin international normalized ratio increased (26%), activated partial thromboplastin time prolonged (26%), diarrhea (25%), and rash (25%).

“[Tisotumab vedotin's] approval as a monotherapy in the United States is an important milestone for women with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy, as they are in need of a new treatment option and we look forward to making it available to them,” Jan van de Winkel, PhD, chief executive officer at Genmab, stated in a press release. “The journey toward the approval of [tisotumab vedotin] started nearly 2 decades ago with innovative research by scientists at Genmab and Seagen and reflects on our purpose of making an impact in the lives of cancer patients and their families. Today’s announcement marks Genmab’s evolution into a fully integrated biotechnology company and we would like to thank patients, caregivers, investigators and our collaborators for their participation in our clinical studies.”

References

1. Seagen and Genmab announce FDA accelerated approval for TIVDAK (tisotumab vedotin-tftv) in previously treated recurrent or metastatic cervical cancer. News release. Seagen Inc. and Genmab A/S. September 20, 2021. Accessed September 20, 2021. https://bit.ly/3lJOwAI
2. 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