Considering Tisotumab Vedotin for Recurrent/Metastatic Cervical Cancer

Bradley J. Monk, MD, FACS, FACOG

As the first and only approved antibody-drug conjugate for the treatment of recurrent or metastatic cervical cancer with disease progression on or after chemotherapy, tisotumab vedotin (TV; Tivdak) filled an unmet need. The drug continues to show encouraging antitumor activity and tolerable safety both alone and in combination with other therapies, according to experts.¹

Results from the phase 2 innovaTV 204/GOGO-3023/ENGOT-cx6 clinical trial (NCT03438396) were the basis for the FDA’s accelerated approval of TV in recurrent or metastatic cervical cancer.² In the study of 102 patients with previously treated recurrent, or metastatic cervical cancer were followed for a median of 10.0 months (interquartile range, 6.1-13.0 months), and TV achieved an objective response rate (ORR) of 24% (95% CI, 16%-33%).

The activity of TV in the study included complete responses (CRs) in 7% of patients, and partial responses in 17%, demonstrating a disease control rate of 72% (95% CI, 63%-81%). The median duration of response (DOR) shown with the agent was 8.3 months (95% CI, 4.3 months to not reached). The median time to response (TTR) observed was 1.4 months (95% CI, 1.3-1.5 months).³

The most common treatment-related adverse events (TRAEs) among patients who received TV in the innovaTV 204 study were alopecia (38%), epistaxis (30%), nausea (27%), conjunctivitis (26%), and fatigue (26%). Grade 3 or higher TRAEs occurred in 28% of patients, and serious TRAEs occurred in 13%. The most common of the serious TRAES were peripheral sensorimotor neuropathy (2%), and pyrexia (2%). There was 1 death in the study that resulted from septic shock and deemed to be related to study treatment. There were also 3 deaths that were unrelated to treatment.

“The innovaTV-201 and innovaTV-204/GO30xx/ENGOT-cx6 trials showed that TV has clinically meaningful and durable antitumor activity in pretreated patients with recurrent or metastatic cervical cancer,” Bradley J. Monk, MD, FACS, FACOG told Targeted Oncology™, in an interview.

Proof-of Concept

Although the efficacy and safety of TV in patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy has yet to be confirmed for continued FDA approval, the utility of anti-PD-L1 therapies, like TV in this patient population, has been illustrated in previous trials.

KEYNOTE-826

In KEYNOTE-826 (NCT03635567), a double-blind, phase 3 trial, the anti-PD-L1 agent pembrolizumab (Keytruda) demonstrated improvements in progression-free survival (PFS) and overall survival (OS) in patients with persistent, recurrent, or metastatic cervical cancer who were also being treated with chemotherapy with or without bevacizumab (Avastin).⁴

“This is a transformational result. This is not changing a CAT scan, what we call progression-free survival. This is changing a woman's life. The more intensive therapy helps her live 12.1 months longer with a hazard ratio of 0.60, and doesn't decay her quality-of-life,” said Monk, professor, division of gynecologic oncology, University of Arizona College of Medicine, Creighton University School of Medicine, director, principal investigator, community research development, HonorHealth Research Institute, vice president and member board of directors GOG-Foundation, co-director GOG-partners, in the interview.

A total of 548 patients in KEYNOTE-826 had a PD-L1 combined positive score of 1 or higher. Among them, the median among patients who did not receive chemoradiation PFS observed with pembrolizumab was 10.4 months compared with 8.2 months in the placebo group (HR, 0.62; 95% CI, 0.50-0.77; P <.001). In patients with a PD-L1 combined positive score of 10 or higher, the median PFS was 10.4 months with pembrolizumab compared with 8.1 months in the placebo group (HR, 0.58; 95% CI, 0.44 to 0.77; P <0.001).

The PFS in this group was consistent with the intent-to-treat (ITT) population. The OS rate at 24 months was 53.5% with pembrolizumab vs 39.4% with placebo (HR, 0.60; 95% CI, 0.49-0.74; P <.0001), among patients with a PD-L1 combined positive score of 1 or more. In the ITT population, the 24-month OS rate was 50.4% in the pembrolizumab arm compared with 40.4% in the placebo arm (HR, 0.67; 95% CI, 0.54 to 0.84; P<0.001). In patients with a PD-L1 combined positive score of 10 or higher, the OS rate at 24 months was 54.4% with pembrolizumab vs 44.6% with placebo (HR, 0.61; 95% CI, 0.44 to 0.84; P =0.001).

Safety results showed that the profiles of pembrolizumab and bevacizumab in the study were consistent with the known profiles of each agent individually. Adverse events (AEs) of any grade occurred in 99.3% of patients in the pembrolizumab group and 99.4% of patients in the placebo group. The most common AEs of any grade in the pembrolizumab arm vs the placebo arm were anemia (61.2% v 53.4.8%), alopecia (56.4% v 57.9%), nausea (39.7% v 43.7%), and diarrhea (35.5% v 29.8%).

Investigators noted that by the month 3 of treatment with the anti-PD-1 agent, the survival curves started to separate, and this benefit continued as the trial went on. The survival benefit of pembrolizumab over placebo was also consistent in prespecified subgroups of patients, including those with a PD-L1 combined positive score of 1 or more.

Similar survival benefit was demonstrated with cemiplimab (Libtayo) in the phase 3 EMPOWER Cerival-1/GOG-3016/ENGOT-cx9 study (NCT03257267), according to experts.¹

EMPOWER-Cervical 1

Compared with single-agent chemotherapy, cemiplimab significantly prolonged survival in patients with recurrent or metastatic cervical cancer in the EMPOWER Cerival-1 study. In the overall population of 608 patients, the median OS was 12.0 months (95% CI, 10.3-13.5 months) with cemiplimab compared with 8.5 months (95% CI, 7.5-9.6 months) with single-agent chemotherapy (HR, 0.69; 95% CI, 0.56-0.84; 2-sided P <.001).The OS benefit of cemiplimab was irrespective of histology.⁵

“The controversy is, what about PD-L1 status? You can't know. EMPOWER was not designed to test that. As a result of that, the primary end point in EMPOWER was squamous cell tumors, because we thought that there was more PD-L1 expression in squamous tumors, and we thought that the activity would be better. Well, the reality is that some cemiplimab works regardless of PD-L1 status in both squamous tumors, and adenocarcinomas,” explained Monk.

The median PFS in the overall population of EMPOWER-Cervical 1 was 2.8 months (95% CI, 2.6-3.9 months) with cemiplimab vs 2.9 months (95% CI, 2.7-3.4 months) with the control (HR, 0.75; 95% CI, 0.63-0.89; 2-sided P <.001).

AEs were observed in 88.3% of the cemiplimab arm compared with 91.4% of the chemotherapy arm, and these AEs were high-grade in 45.0% vs 53.4 %, respectively. The most common AEs observed were anemia (12.0% v 16.9%), urinary tract infection (5.0% v 2.8%), and neutropenia (1.0% v 9.0%).

Although cemiplimab is no longer being developed for recurrent or metastatic cervical cancer. Monk explained that it is one of the use cases for immunotherapy in high-risk patients.

“Locally advanced cervical cancer is defined as those cancers that cannot be surgically resected because the cancer is spreading outside the cervix, and they are treated with chemotherapy and radiation and that global standard was established in 1999. In fact, it was so dramatic that the National Cancer Institute issued a clinical alert, and here we are. It hasn't changed, but we’ve tried. In 2021 during an ASCO plenary session, there was a study called OUTBACK [NCT01414608], where additional cycles of platinum and taxane were added to the standard cisplatin chemotherapy and radiation, and there was no difference. But the hope for patients is that immune therapy can be given to patients at high-risk for death, and those are patients with unresectable, locally advanced cervical cancer,” said Monk.

Whether TV will continue to be option patients with recurrent or metastatic cervical cancer will depend on the results of the innovaTV-205 study (NCT03786081).¹

Confirmatory Research

The efficacy and safety of TV in recurrent/metastatic cervical cancer is being confirmed in innovaTV-205, which is expected to enroll 214 patients in the phase 1/2 portion. Based on interim findings from the study, investigators are encouraged.⁶

In 33 patients with recurrent or metastatic cervical cancer, TV added to pembrolizumab demonstrated antitumor activity and treatment was manageable. The confirmed ORR was 35% (95% CI, 20%-54%), with CRs in 6% of patients and partial responses in 29%. The median DOR was not evaluable (NE), and the median TTR was 1.4 months (range, 1.3-5.8 months).

In terms of survival, TV showed a median PFS of 5.6 months (95% CI, 2.7-9.6 months).

In another cohort of the study, patients received TV plus chemotherapy. In this cohort, the ORR was 55% (95% CI, 36%-72%) with CRs in 6% of patients, and PRs in 48%. The median DOR was 5.6 months (range, 2.7-NE), and the median TTR was 1.4 months (range, 1.1-4.4 months). Tisotumab vedotin plus chemotherapy also demonstrated median PFS of 6.9 months (95% CI, 3.9-NE months).

Interim safety findings show that the AEs of interest were ocular AEs, peripheral neuropathy, and bleeding events. No TRAEs occurred in either group.

“The phase 1b/2 trial ENGOT Cx8/GOG 3024/innovaTV-205 is testing other possible combination between TV and other treatments. TV is characterized by a promising antitumor activity and an acceptable safety profile. Moreover, the preliminary data highlighted the feasibility of using TV in the first-line,” said Monk.

_REFERENCES:

_{1. Bogani G, Coleman RL, Vergote I, et al. Tisotumab vedotin in recurrent or metastatic cervical cancer. Curr Probl Cancer. 2023;47(3):100952. doi:10.1016/j.currproblcancer.2023.100952}

_{2. 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 July 24, 2023. https://bwnews.pr/3hSbILN}

_{3. 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}

_{4. Colombo a, dubot c, lorusso d, et al. pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385:1856-1867
doi:10.1056/NEJMoa2112435}

_{5. Tweari KS, Monk BJ, Vergota I, et al. Survival with cemiplimab in recurrent cervical cancer. N Engl J Med 2022; 386:544-555. doi:10.1056/NEJMoa2112187}

_{6. VErgote IB. O’Ceatbhaill Re, Nicacio LV, et al. 723MO Tisotumab vedotin (TV) + carboplatin (Carbo) in first-line (1L) or + pembrolizumab (Pembro) in previously treated (2L/3L) recurrent or metastatic cervical cancer (r/mCC): Interim results of ENGOT-Cx8/GOG-3024/innovaTV 205 study. Ann Oncol. 2021;32(suppl 5):S726-S727. doi:10.1016/j.annonc.2021.08.1166}