Tisotumab Vedotin Shows Promise in Recurrent/Metastatic Cervical Cancer

In the phase 2 single-arm innovaTV 204 trial, treatment with tisotumab vedotin led to an objective response rate (ORR) of 24% (95% CI, 15.9%-33.3%) in patients with recurrent and/or metastatic cervical cancer who were previously treated with doublet chemotherapy and bevacizumab (Avastin). The encouraging result was announced during a presentation at the 2020 European Society of Medical Oncology (ESMO) Virtual Congress.¹

The ORR, assessed via an independent imaging review committee (IRC), comprised a 7% complete response rate and a 17% partial response rate, and the median duration of response (DOR) was 8.3 months (95% CI, 4.2–not reached). Most responses were rapid, with a median time to response of 1.4 months (range, 1.1-5.1), and activity was observed within the first 2 treatment cycles, explained lead study author Robert L. Coleman, MD, FACOG, FACS, in a virtual presentation during the meeting.

“Tisotumab vedotin demonstrated compelling, rapid, and durable antitumor activity with encouraging PFS and OS in women with recurrent or metastatic cervical cancer previously treated with doublet chemotherapy, with bevacizumab, if eligible,” said Coleman, who is the chief scientific officer of The US Oncology Network. “Results from this study suggest that tisotumab vedotin has the potential to be a new therapy for patients with previously treated recurrent and/or metastatic cervical cancer.”

Recurrent and/or metastatic cervical cancer remains a significant cause of mortality in women, Coleman explained, adding that there is a high unmet need following resistance to or progression on standard frontline paclitaxel with platinum/topotecan with bevacizumab, if eligible. Currently, no established second-line standard-of-care option exists for these patients. Cytotoxic therapy, given as monotherapy, is found to have a poor benefit/risk profile with limited activity; although pembrolizumab is available for patients with PD-L1–positive cervical cancer, the ORR with the agent is only 14.3%, as reported in the phase 2 KEYNOTE-158 study.²

Tisotumab vedotin is an investigational antibody-drug conjugate directed to tissue factor (TF) and is covalently linked to the microtubule-disrupting agent MMAE via a protease-cleavable linker. TF is known to be highly prevalent in cervical cancer and other solid tumors and is linked with cancer pathophysiology and poor prognosis. Additionally, it is co-opted by tumor cells to promote tumor growth, angiogenesis, and metastasis.

In normal physiology, the primary role of TF is to initiate the coagulation cascade following vascular injury. The direct cytotoxicity associated with tisotumab vedotin may be augmented by the bystander effect and multiple immune-related effects, such as immunogenic cell death, antibody-directed cellular cytotoxicity, and antibody-dependent cellular phagocytosis, Coleman added.

Previously, results from a first-in-human trial demonstrated encouraging clinical activity with tisotumab vedotin, which Coleman added was shown to have multiple antitumor effects in cervical cancer in the innovaTV 201 trial.³

In the pivotal, single-arm, multicenter, phase 2 innovaTV 204 trial, 101 patients with previously treated recurrent and/or metastatic cervical cancer were treated with tisotumab vedotin at 2.0 mg/kg intravenously every 3 weeks until either disease progression or unacceptable toxicity. Tumor responses were assessed using CT/MRI at baseline every 6 weeks for the first 30 weeks, and then every 12 weeks thereafter.

To be eligible for enrollment, patients had recurrent or extrapelvic metastatic disease, progressed during or following doublet chemotherapy with bevacizumab (if they were eligible), had received 2 or fewer prior systemic regimens, and had an ECOG performance status of 0 or 1. The primary end point of the trial was ORR per RECIST v1.1 criteria via IRC; secondary end points included investigator-assessed ORR per RECIST v1.1 criteria, OS, safety, and DOR, TTR, and PFS by both IRC and investigator. Exploratory end points were biomarkers and health-related quality of life.

The median age of participants was 50 years (range, 31-78), with 95% of patients being white, 2% being Asian, 1% being Black/African American, and 2% of patients listed as other. More than half (58%) of patients had an ECOG performance status of 0; 68% of patients had squamous cell carcinoma, followed by adenocarcinoma (27%) and adenosquamous carcinoma (5%). Ninety-four percent of patients had extrapelvic metastatic disease at baseline.

A total 54% of patients had received prior cisplatin plus radiation therapy, which was not considered a systemic therapy; 70% of patients had received 1 previous line of systemic therapy for recurrent/metastatic disease. Sixty-three percent of patients had prior bevacizumab plus doublet chemotherapy as frontline therapy, and 56% of patients did not respond to their last systemic treatment. While not an eligibility requirement, Coleman noted that 96% of patients’ tumors were positive for membrane TF expression.

The median duration of treatment was 4.2 months (range, 1-16), with a median 6 doses (range 1-21) of tisotumab vedotin received and a high dose intensity was observed (95.9%). Four patients had treatment ongoing, and the majority of patients discontinued therapy due to radiographic disease progression (65%), followed by adverse effects (AEs; 13%), clinical progression (8%), withdrawal of consent (5%), death (4%), and investigator decision (1%). Thirty-three percent of patients remain in follow-up for survival.

At a median follow-up of 10.0 months (range, 0.7-17.9), additional findings showed that 49% of patients achieved stable disease and 24% of patients had progressive disease; 4% of patients were not evaluable, all via IRC. Moreover, target lesions were reduced in 79% of patients with 1 or more post-baseline scan.

Clinical meaningful responses were also observed regardless of tumor histology (squamous, 23%; nonsquamous, 25%), lines of prior therapy (1, 28%; 2, 13%), responses to prior systemic treatment (responded, 26%; did not respond, 21%), and whether or not they received frontline doublet chemotherapy with bevacizumab (yes, 19%; no, 32%).

“Of note, the ORR in patients with nonsquamous histology, 25%, and [in those] previously treated with bevacizumab, 19%, are encouraging, as only limited data currently exist in these populations,” Coleman said.

Moreover, responses to tisotumab vedotin were observed regardless of membrane TF expression level. Seventy-six of the 80 patients for whom TF expression data were available were also available for response, and a similar distribution of TF expression was observed between the various response groups.

Additional results showed that the median PFS was 4.2 months and OS was 12.1 months with the approach. Moreover, the 6-month PFS and OS rates were 30% and 79%, respectively.

Regarding safety, tisotumab vedotin showcased a manageable and tolerable safety profile, with no new safety signals identified. The most common treatment-related AEs (TRAEs) with a 10% or higher incidence rate included alopecia (38%), epistaxis (30%), nausea (27%), conjunctivitis (26%), fatigue (24%), dry eye (23%), myalgia (15%), anemia (12%), asthenia (12%), arthralgia (12%), decreased appetite (11%), keratitis (11%), and pruritis (10%). Most of these were grade 1/2, but grade 3/4 TRAEs occurred in 28% of patients. Of the 4 patients who died, 1 was due to septic shock that was considered to be treatment related.

Coleman noted that prespecified AEs of interest with the agent, including ocular toxicity (grade 1/2, 52%; grade 3, 2%), bleeding (grade 1/2, 37%; grade 3, 2%) and peripheral neuropathy (grade 1/2, 26%; grade 3, 7%) were generally mild and effectively managed with the use of an eye care plan and dose modifications for the ocular toxicity and peripheral neuropathy, respectively.

The time to onset of ocular, bleeding, and peripheral neuropathy TRAEs were 1.4 months, 0.3 months, and 3.1 months, respectively. Eighty-six percent, 90%, and 21% of events resolved in 0.7 months, 0.5 months, and 0.6 months, respectively. The lower resolution rate with peripheral neuropathy could be attributed to in part to the protocol-defined follow-up period for AEs of 30 days, Coleman concluded.

_References

_{1. 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. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract LBA32.}

_{2. Chung HC, Ros W, Delord J-P, et al. Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2019;37(17):1470-1478. doi:10.1200/JCO.18.01265}

_{3. Hong DS, Concin N, Vergote I, et al. Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer. Clin Cancer Res. 2020;26(6):1220-1228. doi:10.1158/1078-0432.CCR-19-2962}