Investigators determined the feasibility, safety, and tolerability of new combinations of tisotumab vedotin (Tivdak; TV) and bevacizumab (Avastin) or pembrolizumab (Keytruda) or carboplatin in a 2-part multicohort, phase 1b/2 trial (ENGOT-cx8/GOG-3024/innovaTV 205; NCT03786081). TV is an investigational antibody- drug conjugate directed at tissue factor, which is highly expressed in many solid tumors, particularly cervical cancer. The 3 combination agents have nonoverlapping mechanisms of action and are known to be active in cervical cancer.
The primary objective of the study was to determine the maximum tolerated dose, as well as recommend a phase 2 dose (RP2D) for TV combined with bevacizumab, pembrolizumab, or carboplatin. Secondary objectives were to evaluate the safety and tolerability, antitumor activity, and durability of tumor response of the TV combinations.
Bradley Monk, MD, FACOG, FACS, presented the dose-binding portion of the study, which led to the recommended RP2D, during the International Gynecologic Cancer Society 2021 Annual Global Meeting.1
“Baseline demographics were representative of the patient mix as seen in the clinic,” Monk, medical director of gynecologic oncology research at The US Oncology Network, and professor, clinical scholar track, University of Arizona College of Medicine in Phoenix, said. “The majority of patients had either failed first-line or second-line treatment for metastatic disease,” he continued.
At data cutoff on March 1, 2021, the median duration of follow-up was 8.6 months (range, 5-20) for the TV plus bevacizumab arm, 16.0 months (range, 0-22) for the TV plus pembrolizumab arm, and 12.5 months (range, 0-20) for the TV plus carboplatin arm. Monk noted that disease progression was the most common reason for discontinuation of study treatment for all patients in the TV plus bevacizumab arm. In both the TV plus pembrolizumab and TV plus carboplatin arms, 61.5% of patients discontinued because of disease progression, reported investigators. Discontinuation of treatment due to adverse events (AEs) was rare, with no patients in the TV plus bevacizumab arm and 15.4% of patients for both the pembrolizumab and carboplatin arms.
“There were no instances of dose-limiting toxicities in any of the cohorts based on review by the data monitoring committee,” Monk said. “We never reached a maximum tolerated dose. [This means] that it’s possible to combine full-dose TV with full-dose bevacizumab, pembrolizumab, or carboplatin,” Monk continued.
The maximum planned dose level was determined to be the RP2D in each study arm, which was TV 2 mg/kg plus bevacizumab at 15 mg/kg, carboplatin area under the curve 5, or pembrolizumab 200 mg once every 3 weeks. No fatal AEs related to TV were reported, and common grade 3 or higher AEs related to TV included anemia (30.8%) and thrombocytopenia (15.4%) in the TV plus carboplatin arm and peripheral sensory neuropathy (15.4%) in the TV plus pembrolizumab arm (TABLE). Prespecified AEs of interest included ocular AEs, bleeding, and peripheral neuropathy, but these were mostly grade 1 or 2.
For all combinations, the majority of patients demonstrated a decrease in tumor burden from baseline, with more than half of the patients showing greater than 30% reduction at the respective RP2Ds for each arm.
“Five patients in the TD plus bevacizumab arm had a confirmed objective response, and that included 1 complete response and 4 partial responses,” Monk said. “In the other arms, 2 of 11 patients in the pembrolizumab arm and 4 of 12 patients in the carboplatin arm had partial responses,” he said.
Monk noted that a previous pivotal phase 2 single-arm study2 showed that single-agent TV had durable and clinically meaningful activity with a 24% response rate (95% CI, 15.9%-33.3%) and 7% complete response rate in patients with metastatic or recurrent cervical cancer. Additionally, 49% of patients had stable disease.
These findings led to the FDA approval of TV monotherapy for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. TV is the first and only approved antibody-drug conjugate for this indication.3
Monk said the findings from innovaTV 205 show that the maximum planned dose of TV and the combination agents were feasible and considered to be the RP2D. “All combinations showed some promising but preliminary antitumor activity. I think we’d all agree that these data are encouraging. We’re excited for dose-expansion cohorts,” he concluded.
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: International Gynecologic Cancer Society 2021 Annual Global Meeting; August 30-September 2, 2021; virtual.
2. Coleman RL, Lorusso D, Gennigens C, et al. Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021;22(5):609- 619. doi:10.1016/S1470-2045(21)00056-5
3. Seagen and Genmab announce FDA accelerated approval for Tivdak™ (tisotumab vedotin-tftv) in previously treated recurrent or metastatic cervical cancer. News release. Seagen, Inc. September 20, 2021. Accessed September 20, 2021. https://bwnews.pr/3hSbILN