Tisotumab vedotin in Japanese patients with recurrent/metastatic cervical cancer: Results from the innovaTV 206 study

Abstract New treatments, particularly second‐line options, are needed to improve outcomes for patients with recurrent/metastatic cervical cancer (r/mCC). Tisotumab vedotin (TV) is an antibody–drug conjugate directed to tissue factor, a transmembrane protein commonly expressed in cancer cells, to deliver cytotoxic monomethyl auristatin E. This single‐arm, open‐label phase 1/2 trial evaluated the consistency of safety and efficacy outcomes of TV in Japanese patients with r/mCC to bridge the current findings with those reported in previous trials in non‐Japanese patients in the United States and Europe. In part 1 (dose escalation; N = 6), patients with advanced solid tumors received TV 1.5 or 2.0 mg/kg once every 3 weeks to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Part 2 (dose expansion; N = 17) evaluated the RP2D in r/mCC patients with 1–2 prior lines of therapy. In part 1, no dose‐limiting toxicities were observed, the MTD was not reached, and TV 2.0 mg/kg was established as the RP2D. In part 2, the most common treatment‐emergent adverse events were anemia (58.8%), nausea (58.8%), alopecia (47.1%), epistaxis (47.1%), and diarrhea (35.3%); adverse events of special interest were bleeding (76.5%), ocular events (35.3%), and peripheral neuropathy (17.6%), and were mostly grade 1/2. In part 2, confirmed objective response rate was 29.4%, median duration of response was 7.1 months, and median time to response was 1.2 months. In Japanese patients with r/mCC, TV demonstrated a manageable and tolerable safety, pharmacokinetics, and efficacy profile consistent with that observed in non‐Japanese patients.


| INTRODUC TI ON
Cervical cancer is both the fourth most prevalent and the fourth deadliest cancer globally, with more than 500,000 new cases diagnosed each year that account for 7.5% of cancer-related deaths in women. 1,2 In Japan, an estimated 34,000 new patients were diagnosed with cervical cancer in 2016; contrary to the global trend, recent studies suggest that the incidence of cervical cancer has been increasing in Japan over the past 2 decades. [3][4][5][6] Until recently, the preferred first-line systemic options for the treatment of recurrent/ metastatic cervical cancer (r/mCC) were a taxane (eg, paclitaxel, topotecan), a platinum-containing agent (eg, cisplatin, carboplatin), and bevacizumab. [7][8][9] Pembrolizumab was recently approved by the US Food and Drug Administration (FDA) as a single agent or in combination with chemotherapy, with or without bevacizumab, for patients with persistent, recurrent, or metastatic cervical cancer whose tumors express programmed death-ligand 1 (as expressed by a combined positive score ≥ 1). [10][11][12] However, there remains a need to establish effective second-line treatments for patients who progress on first-line treatment or who are unable to tolerate first-line treatment. Accordingly, second-line treatments for r/mCC are being explored in Japan and globally.
Tisotumab vedotin (TV) is an antibody-drug conjugate (ADC) in clinical development for the treatment of several solid tumors. [13][14][15][16] The antibody is directed to tissue factor (TF), a transmembrane protein whose primary role is to initiate the coagulation cascade. TF has also been shown to play a role in the tumor growth, angiogenesis, and metastasis of cancer, 17 and is highly prevalent in cervical cancer, including squamous and adenocarcinoma histological subtypes. 18,19 The antibody moiety of TV is conjugated to monomethyl auristatin E (MMAE) via a valine citrulline linker, which is proteolytically cleaved and released following internalization of TV into cancer cells expressing TF. 15,16 MMAE is a microtubule disruptor and kills actively dividing cancer cells that have internalized TV. 15 TV has antitumor activity on multiple tumor types and kills target cells by direct cytotoxicity, bystander cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and immunogenic cell death. 13 Previously, a phase 1/2 trial (innovaTV 201; NCT02001623) of TV monotherapy in US and European patients reported a confirmed objective response rate (ORR) of 22% (95% CI,  as assessed by independent review in the cohort of patients with previously treated r/mCC (N = 55). 20 More recently, a pivotal phase 2, single-arm, openlabel study (innovaTV 204; NCT03438396) evaluating TV monotherapy in a larger cohort of women with r/mCC (N = 101) in the United States and Europe reported a confirmed ORR as assessed by independent review of 24% (95% CI, 16-33), with a median duration of response (DOR) of 8.3 months. 21 The median progression-free survival (PFS) and overall survival (OS) in this study were 4.2 and 12.1 months, respectively. The most common treatment-related adverse events (AEs) were alopecia, epistaxis, nausea, conjunctivitis, fatigue, and dry eye, and most (65%) were mild to moderate (grade 1-2) in severity. It was this pivotal innovaTV 204 study that led to accelerated approval of the use of TV monotherapy in adult patients with previously treated r/mCC with disease progression on or after chemotherapy by the US FDA. 22 TV monotherapy has been shown to provide clinically meaningful and durable antitumor activity with a manageable safety profile in women with previously treated r/mCC.
Here, we performed a single-arm phase 1/2 trial (innovaTV 206) to evaluate the safety, pharmacokinetics, and efficacy of TV in Japanese patients with solid tumors (part 1) and r/mCC (part 2).

| Study population and design
The innovaTV 206 trial (GCT1015-06, NCT03913741) was a singlearm, open-label phase 1/2 trial designed to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of intravenous TV in Japanese patients with advanced solid malignancies. The trial was conducted in compliance with the protocol ICH Good Clinical Practice E6 (R2) and applicable regulatory requirements.
The study consisted of two parts: Part 1, which enrolled patients with solid tumors in sequential dose escalation cohorts, sought to determine the maximum tolerated dose (MTD) and establish the recommended phase 2 dose (RP2D). Part 2 was an expansion phase designed to assess the safety and antitumor activity of TV in Japanese patients with r/mCC at the RP2D of TV determined in part 1.

| Study procedures
For parts 1 and 2, patients were given one 30-min intravenous infusion of TV every 3 weeks (Q3W) until disease progression or unacceptable toxicity. Thus, each cycle was 21 days in duration. For part 1, dose escalation was performed according to a 3 + 3 design.
Initially, three patients were given TV 1.5 mg/kg intravenously and monitored carefully for dose-limiting toxicities (DLTs) during the first cycle. Following the absence of DLTs, three additional patients were given TV 2.0 mg/kg and similarly monitored. The MTD was considered to be the dose below the lowest dose that caused a DLT in at least one-third of patients. Patients were followed for ≥2 cycles before the RP2D was defined. For part 2, patients were given TV 2.0 mg/kg Q3W, which was determined to be the RP2D.
AEs were graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 5.0) and monitored throughout treatment and for 30 days after treatment ended.
Treatment to prevent ocular AEs was mandated for all study patients and consisted of the use of preservative-free lubricating eye drops throughout the study, steroid eye drops (first dose was given before start of infusion and for the first 3 days of each treatment cycle), a local ocular vasoconstrictor before TV infusion, and eye-cooling pads during infusion. Laboratory tests for hematology, biochemistry, and coagulation assessments were performed within 5 days before the first cycle and within 24 hours before TV infusion for each cycle beginning with cycle 2. For pharmacokinetics assessments, blood sampling was performed before infusion; at the end of infusion; and at 2, 5, 12, 24 (day 2), 72 (day 4), 168 (day 8), and 336 (day 15) hours after infusion for cycles 1 and 2; before infusion for cycle 3 and for every fourth cycle beginning with cycle 7; at the end of treatment; and at follow-up visits. These samples were collected during cycles 1 and 2 to characterize the pharmacokinetics profile for TV (ADC), and free MMAE, and to compare the pharmacokinetics of these analytes in this Japanese population with Western populations in other trials. Plasma concentrations of ADC were determined using a validated enzyme-linked immunosorbent assay. 20 Plasma concentrations of MMAE were determined using a validated liquid chromatography method with tandem mass spectrometric detection. 20 Computed tomography was the preferred modality for the acquisition of tumor images. Contrast-enhanced magnetic resonance imaging was used when computed tomography with iodinated contrast is contraindicated or when mandated by local practice. Tumor imaging assessments were performed during the screening period (≤28 days before cycle 1 day 1), every 6 weeks beginning with the first dose until 30 weeks, and every 12 weeks thereafter. Tumor response was determined based on RECIST v1.1 criteria. Objective response (ie, complete response [CR] or partial response [PR]) was confirmed by a repeat imaging assessment ≥4 weeks after the first observed indication of a response. In the case of stable disease (SD), the measurement must have been performed at least 5 weeks after the first dose of study treatment to meet the criterion for SD.
For antidrug antibody (ADA) assessments, sampling was performed before infusion for cycles 1-3, at every fourth cycle beginning with cycle 7, at the end of treatment, and at follow-up visits.
Serum samples were screened for antibodies binding to TV, and the titer of confirmed positive samples was determined.
Biopsies provided at screening were retrospectively analyzed for TF expression (on the cell surface or membrane) using an analytically validated immunohistochemistry assay. A TF histology score (H-score) was calculated to combine both expression and intensity of staining as described previously. 20 Tumor cells with any proportion of TF expression were considered positive.

| Endpoints
The primary endpoints were assessment of AEs (with laboratory tests, electrocardiogram, and vital signs), DLTs, ADAs, and pharma-

| Sample size considerations
For part 1, the sample size was based on the standard 3 + 3 design.
For part 2, the sample size was based on the following considera-

| Statistical analyses
All analyses were based on patients who received ≥1 dose of TV.
Safety assessments included AEs, DLTs, and laboratory assessments and were summarized by dose for each trial part. Pharmacokinetics parameters and ADA assessments were summarized by descriptive statistics by trial part and dose. Confirmed and confirmed/unconfirmed ORRs, by dose and trial part, were estimated with exact 95% CIs calculated by the Clopper-Pearson method. DOR, TTR, PFS, and OS were analyzed using the Kaplan-Meier method, and medians were estimated with 95% CIs, where possible.
Baseline demographics and disease characteristics of the 17 patients with r/mCC enrolled in part 2 are shown in Table 2. Most patients were aged <50 years (58.8%), and similar proportions had adenocarcinoma (47.1%) or squamous cell carcinoma (52.9%), one (47.1%) or two (52.9%) previous lines of therapy, and first-line bevacizumab in combination with chemotherapy doublet treatment (47.1%) or not (52.9%). Patients in part 2 received a median of five cycles, and the median duration of exposure was 3.7 months (Table S2).
This exposure to TV was consistent with the previous innovaTV 204 study. 21

| Pharmacokinetics assessments
Pharmacokinetics data for part 1 and part 2 are shown in Figure 1, Table S4, and Table S5. geometric means for free plasma MMAE was 42.0 day ng/ml and 36.0 day ng/ml, respectively (Table S5). Exposures in Japanese patients enrolled in parts 1 and 2 were consistent with exposure in non-Japanese patients.

| Efficacy
Of the 17 patients enrolled in part 2, the confirmed best overall response of CR, PR, SD, PD, and not evaluable occurred in zero, five  available postbaseline scans is shown in Figure 2.
As assessed by the independent review, the median TTR was 1.2 months (range, 1.1-2.7 months), and the median DOR was 7.1 months (range, 3.1 months to not reached). The TTR and DOR for the five patients who achieved a PR is shown in Figure 3.

| ADA
No patients were positive for treatment-emergent ADAs in part 1.  Figure 4); however, the analysis of association between TF expression and response was limited by the small sample size. Tissue factor expression was assessed in biopsy specimens from patients before TV treatment. All 17 evaluable biopsy specimens showed TF expression on the cell membrane of tumor cells. Taken together with other studies in which comparable distribution of TF expression was observed among different response groups, 20,21 the totality of data suggests that a response to TV occurs regardless of membrane TF expression-levels in r/mCC. The data potentially reflect that the binding of TV may be sufficient to initiate target cell killing regardless of surface TF expression levels due to its multimodal mechanisms of action, which include direct and bystander cytotoxicity of actively dividing tumor cells, ADCC, ADCP, and immunogenic cell death. 10,11,21 Limitations of this open-label phase 2 study include that it had only one treatment group, making it difficult to fully assess the ef- In conclusion, results from this study were consistent with data from trials enrolling US and European women in that TV was similarly tolerable and showed comparable efficacy in Japanese and Western women. These results support the continued development of TV as a viable second-line systemic option for Japanese patients with r/mCC with disease progression during or after chemotherapy.

ACK N OWLED G M ENTS
We thank the patients and their families and caregivers for participating in this study and all site personnel. This study was funded and sponsored by Genmab A/S (Copenhagen, Denmark) and Seagen Protocols were approved by appropriate institutional review boards.

CO N S E NT
Written informed consent was provided by all participants.