Tisotumab Vedotin–Based Combos Demonstrate Antitumor Activity in Recurrent/Metastatic Cervical Cancer

Bradley J. Monk, MD, FACOG, FACS

Treatment with the antibody-drug conjugate tisotumab vedotin in combination with bevacizumab (Avastin), pembrolizumab (Keytruda), or carboplatin was tolerable and elicited encouraging preliminary antitumor activity in patients with recurrent or metastatic cervical cancer, according to the dose-escalation results of the phase 1b/2 innovaTV 205 study (NCT03786081) presented during the 2021 International Gynecologic Cancer Society Annual Global Meeting.¹

Moreover, the maximum planned dose of tisotumab vedotin and the combination agents was feasible and was confirmed to be the recommended phase 2 dose (RP2D) in each treatment arm: 2.0 mg/kg of tisotumab vedotin plus 15 mg/kg of bevacizumab, 200 mg of pembrolizumab, or carboplatin at an area under the curve (AUC) of 5, all given every 3 weeks.

“We developed a very conservative and safe plan to show that the RP2D for these 3 doublets is full dose. These combinations were adequately tolerated, had an acceptable safety profile, with the majority of [adverse effects] being grade 1 or 2,” said lead study author Bradley J. Monk, MD, FACOG, FACS, a professor in the Division of Gynecologic Oncology at Arizona Oncology, the University of Arizona College of Medicine, Creighton University School of Medicine at St. Joseph’s Hospital, and medical director of the Gynecologic Program at the US Oncology Research Network.

“Acknowledging the limited sample size, all combinations showed some promising, although preliminary, antitumor activity in this group of recurrent or metastatic cervical cancer in the second-line [setting] and beyond,” Monk added.

Although frontline platinum-taxane doublets plus bevacizumab have improved survival for eligible patients with recurrent or metastatic cervical cancer, more effective and better tolerated treatment options are needed, Monk explained.

In April 2021, the FDA granted a priority review designation for a biologics license application for tisotumab vedotinfor patients with recurrent or metastatic cervical cancer with progressive disease on, or following, chemotherapy.² The FDA action data is set for October 10, 2021.

The application is based on findings from the phase 2 innovaTV 204 trial, in which single-agent tisotumab vedotin elicited an objective response rate of 24% in patients with recurrent or metastatic cervical cancer who had prior doublet chemotherapy and bevacizumab.³

“In this study, we evaluated the feasibility of new combinations. [We sought to] combine tisotumab vedotin with other agents with nonoverlapping mechanisms of action, which are known to be active in cervical cancer [to try] to improve activity in a safe way,” Monk said.

Eligible patients were 18 years of age or older and had recurrent or metastatic cervical cancer and measurable disease at baseline per RECIST v1.1 criteria. Patients had to have progressed on or after, were ineligible for, or intolerant of standard therapy. Patients had to have an ECOG performance status (PS) of 0 or 1 and a life expectancy of at least 3 months.

The median age was 46 years (range, 30-62) in the tisotumab vedotin/bevacizumab cohort (n = 15), 45 years (range, 32-75) in the tisotumab vedotin/pembrolizumab cohort (n = 13), and 52 years (range, 35-65) in the tisotumab vedotin/carboplatin cohort (n = 13). Across arms, most patients had an ECOG PS of 0 and had not received bevacizumab plus a chemotherapy doublet as first-line therapy.

Most patients had either squamous or adenocarcinoma histology and had received 1 to 2 prior lines of therapy in the recurrent or metastatic setting, with some patients having received up to 4 prior lines of treatment.

In the tisotumab vedotin/bevacizumab cohort, dose-level 1 (DL1) consisted of 1.3 mg/kg of tisotumab vedotin plus 7.5 mg/kg of bevacizumab (n = 3), dose-level 2 (DL2) consisted of 1.3 mg/kg of tisotumab vedotin plus 15 mg/kg of bevacizumab (n = 3), and dose-level 3 (DL3) consisted of 2.0 mg/kg of tisotumab vedotin plus 15 mg/kg of bevacizumab (n = 9).

In the tisotumab vedotin/pembrolizumab cohort, DL1 consisted of 1.3 mg/kg of TV plus 200 mg of pembrolizumab (n = 6), and DL2 consisted of 2.0 mg/kg of tisotumab vedotin plus 200 mg of pembrolizumab (n = 7).

In the tisotumab vedotin/carboplatin cohort, DL1 consisted of 1.3 mg/kg of tisotumab vedotin plus carboplatin AUC 5 (n = 6), and DL2 consisted of 2.0 mg/kg of tisotumab vedotin plus carboplatin AUC 5 (n = 7).

The primary objective of the study was to establish the maximum-tolerated dose (MTD) and RP2D of tisotumab vedotin plus bevacizumab or pembrolizumab or carboplatin. Secondary objectives included evaluation of safety and tolerability, antitumor activity, durability of tumor response, clinical efficacy, and pharmacokinetics and immunogenicity.

The median follow-up at the time of data cutoff was 8.6 months with tisotumab vedotin/bevacizumab (range, 5-20), 16.0 months with TV/pembrolizumab (range, 0-22), and 12.5 months with TV/carboplatin (range, 0-20).

Sixty percent (n = 9) of patients receiving bevacizumab, 7.7% (n = 1) of patients receiving pembrolizumab, and 15.4% (n = 2) of patients receiving carboplatin had ongoing treatment at the time of the data cutoff.

Disease progression was the most common cause of treatment discontinuation. In the bevacizumab-containing cohort, 40% of patients (n = 6) discontinued treatment because of radiographical progressive disease (PD). In the pembrolizumab-containing cohort, 92.3% of patients (n = 12) discontinued treatment; reasons for discontinuation included radiographical PD (53.8%; n = 7), clinical PD (7.7%; n = 1), death (7.7%; n =1), adverse events (AEs; 15.4%; n = 2), or withdrawn consent (7.7%; n = 1). In the carboplatin-containing cohort, 84.6% of patients (n = 11) discontinued treatment; reasons for discontinuation included radiographical PD (61.5%; n = 8), death (7.7%; n = 1), or AEs (15.4%; n = 2).

Regarding safety, no dose-limiting toxicities were observed with any of the tisotumab vedotin–based regimens and the MTD was not reached.

All patients who received any of the 3 regimens experienced at least 1 treatment-emergent AE. Moreover, 100% of patients who received tisotumab vedotin/bevacizumab, 92.3% of patients who received tisotumab vedotin/pembrolizumab, and 92.3% of patients who received tisotumab vedotin/carboplatin experienced an AE related to TV.

Grade 3 or higher AEs were observed in 33.3% of patients with tisotumab vedotin/bevacizumab, 92.3% of patients with tisotumab vedotin/pembrolizumab, and 61.5% of patients with tisotumab vedotin/carboplatin. Grade 3 or higher AEs related to tisotumab vedotin were observed in 13.3%, 61.5%, and 53.8% of patients, respectively.

Serious AEs were observed in 20%, 61.5%, and 38.5% of patients, respectively. Of these, 0%, 23.1%, and 23.1%, respectively, were found to be related to tisotumab vedotin.

Notably, no fatal AEs related to tisotumab vedotin were reported with any of the 3 combinations. Common grade 3 or higher AEs that occurred in at least 10% of patients included anemia (30.8%) and thrombocytopenia (15.4%) with the carboplatin-containing regimen, and peripheral sensory neuropathy (15.4%) in the pembrolizumab-containing arm.

Prespecified AEs of special interest included ocular toxicities, bleeding events, and peripheral neuropathy. In all arms, these toxicities consisted of mostly grade 1 or 2 events, with some grade 3 or higher events observed with the bevacizumab- or pembrolizumab-containing regimens.

Finally, the majority of patients experienced a decrease in their tumor burden from baseline, and more than half of patients demonstrated a reduction of more than 30% at the respective RP2Ds for each arm. There were 5 confirmed responses with tisotumab vedotin/bevacizumab, 2 confirmed responses with tisotumab vedotin/pembrolizumab, and 4 confirmed responses with tisotumab vedotin/carboplatin.

“These data are encouraging, and we are excited for dose-expansion cohorts. [This research] is ongoing and will be presented at an upcoming meeting,” Monk concluded.

References

1. Monk BJ, Van Gorp T, Lorusso D, et al. Tisotumab vedotin + bevacizumab or pembrolizumab or carboplatin in recurrent/metastatic cervical cancer: phase 1b/2 ENGOT-Cx8/GOG-3024/innovaTV 205 study dose-escalation results. Presented at: 2021 IGCS Annual Global Meeting; August 30-September 2, 2021; virtual. Plenary 5.
2. Seagen and Genmab announce US FDA filing acceptance for priority review of tisotumab vedotin biologics license application for patients with recurrent or metastatic cervical cancer. News release. Seagen. April 9, 2021. Accessed September 7, 2021. https://bit.ly/3s6I7AL
3. 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