Tisotumab Vedotin in Previously Treated Recurrent or Metastatic Cervical Cancer Free

This article is featured in Highlights of This Issue, p. 1201

Cervical cancer is a common cancer in women, with an estimated 570,000 new cases globally in 2018, and represents the third leading cause of cancer-related death in women worldwide (1). Approximately 15,500 and 61,000 new cases of cervical cancer were estimated in North America and in Europe in 2018, respectively, resulting in approximately 5,800 and 25,800 deaths (2). Recurrent or metastatic cervical cancer has a poor prognosis, with a 5-year survival rate of 17% (3). Bevacizumab and doublet chemotherapy (paclitaxel and cisplatin or paclitaxel and topotecan) were adopted as first-line (1L) standard-of-care therapy for recurrent or metastatic cervical cancer in the past 5 years (4–6). However, nearly all patients relapse after 1L treatment, and single-institution experiences indicate that the percentage of patients who receive a second-line (2L) therapy varies (30%–70%) as many patients die before receiving treatment (7, 8).

Available 2L+ therapies for recurrent or metastatic cervical cancer are characterized by low response rates (5, 6). Before adoption of bevacizumab plus doublet chemotherapy in 1L, therapies administered in the 2L+ setting reported response rates in the range of 4.5% to 15%, with median survival of <8 months (9–15). Data in the post–bevacizumab plus chemotherapy setting are limited, with a single-institution study showing single-digit response rates (0%–6%) for 2L treatment (7), suggesting that prior vascular endothelial growth factor inhibition may negatively impact subsequent treatment response. Data in the third-line setting are further limited, with approximately 60% of patients not receiving third-line treatment and, when treated, response rates of 3% (8). Recently, pembrolizumab (anti–programmed death 1) was granted accelerated approval in the United States for the 2L+ treatment of patients with programmed death-ligand 1 (PD-L1)-positive (combined positive score ≥1%) recurrent or metastatic cervical cancer (16). However, only a fraction of these patients respond [objective response rate (ORR): 14%; ref. 16]. In addition, efficacy in nonsquamous recurrent or metastatic cervical cancer is not yet known as 92% of the patients studied had squamous histology (16). These data underscore the high and immediate need for effective therapies that provide clinical benefit in a broader patient population.

Tisotumab vedotin is a first-in-class investigational antibody–drug conjugate (ADC) comprising a tissue factor (TF)-specific, fully human monoclonal antibody conjugated to the clinically validated microtubule-disrupting agent monomethyl auristatin E (MMAE) using a protease-cleavable linker (17, 18). Under normal physiologic conditions, TF is central to the coagulation pathway (19). In oncogenesis, TF plays a role in tumor-associated angiogenesis, progression, and metastasis (20–23). Tissue factor is aberrantly expressed across many solid tumors, including cervical cancer (20, 24–26), and has been associated with poor clinical outcomes (20). The expression of TF across tumor types and its role in oncogenesis make it an appealing therapeutic target.

Tisotumab vedotin delivers MMAE to TF-expressing cells to induce direct cytotoxicity and bystander killing of neighboring cells (17, 18). In vitro studies demonstrated that tisotumab vedotin induces immunogenic cell death and efficiently engages with immune cells to promote tumor cell death through Fcγ receptor–mediated effector functions, such as antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis (18, 27). Moreover, tisotumab vedotin was found to inhibit TF-activated factor VII (FVIIa)–dependent intracellular signaling while minimally impacting procoagulant activity (18). To our knowledge, tisotumab vedotin is the first drug to successfully target TF.

innovaTV 201 (NCT02001623) is a phase I/II dose escalation and expansion trial evaluating tisotumab vedotin in patients with previously treated locally advanced or metastatic solid tumors. In the dose escalation phase, tisotumab vedotin showed a manageable safety profile, and 2.0 mg/kg every 3 weeks was established as the recommended phase II dose (28). Here, we report the safety and antitumor activity of tisotumab vedotin in the cervical cancer expansion cohort.

Genmab A/S sponsored the study, provided study drug, and collaborated with academic investigators on study design, data analysis/interpretation, and manuscript writing. The trial was conducted in accordance with the International Conference on Harmonization Good Clinical Practice Guidelines, Declaration of Helsinki, and all applicable regulatory requirements. The trial protocol was approved by an independent ethics committee or institutional review board prior to initiation. All patients gave written informed consent. All authors confirm the accuracy of the data and adherence of the trial to the protocol.

innovaTV 201 is an open-label, multicohort, phase I/II dose escalation and expansion study of tisotumab vedotin for the treatment of locally advanced and/or metastatic solid tumors known to express TF.

The dose escalation phase of the innovaTV 201 study followed a standard 3 + 3 design to evaluate tisotumab vedotin at doses of 0.3 mg/kg up to 2.2 mg/kg administered intravenously every 3 weeks. The dose of tisotumab vedotin used in the expansion cohort was based on the safety and efficacy data from the dose escalation phase (28).

The expansion phase included patients with locally advanced and/or metastatic cervical, ovarian, prostate, bladder, esophageal, endometrial, and non–small cell lung cancer who have progressed on or are ineligible for standard treatments (28). The cervical and ovarian cancer cohorts were expanded from the initial 14 patients to approximately 30 patients each based on preliminary clinical activity and safety observed. After an amendment to the protocol, up to an additional 25 patients could be enrolled in the cervical cancer cohort for a maximum of 55 patients in total.

Eligible patients had measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients with known coagulation defects, ongoing major bleeding, or Common Toxicity Criteria for Adverse Events (CTCAE) grade ≥2 neuropathy were excluded. A protocol amendment allowed for enrollment of patients on anticoagulants. Patients in the cervical cancer cohort had recurrent/metastatic disease, progressed on a platinum-based regimen, and received ≤4 prior treatments for advanced disease.

Patients in the cervical cancer cohort received tisotumab vedotin 2.0 mg/kg intravenous infusion every 3 weeks for four cycles. Patients with clinical benefit (stable disease or better) at the end of four cycles had the option to continue treatment for an additional eight cycles (up to 12 cycles total), or until disease progression or unacceptable toxicity. After 12 cycles, patients with clinical benefit could continue in an extension study (NCT03245736).

Safety was monitored throughout the study and for up to 30 days after the last dose. Adverse events (AE) were graded according to the National Cancer Institute CTCAE v4.03 and coded according to Medical Dictionary for Regulatory Activities (MedDRA) v17.0. Adverse events of special interest (AESI) that were identified during the dose escalation phase of the study and for which pooled standardized MedDRA queries were applied included neuropathies (known MMAE-related AEs), bleeding-related events (because of TF's role in coagulation), and ocular events (e.g., conjunctivitis, conjunctival ulceration, keratitis, symblepharon).

Protocol amendments implementing additional exclusion criteria and mitigation measures to reduce the risk for ocular events were introduced throughout the study. Patients with active ocular surface disease at baseline or a history of cicatricial conjunctivitis were excluded. Mitigation strategies included the application of preservative-free lubricating eye drops from the start of study treatment until the end of treatment, administration of local ocular vasoconstrictor eye drops immediately prior to the start of infusion, cooling eye pads worn during infusion, and application of steroid eye drops for 3 days beginning on the day of infusion. Furthermore, the use of contact lenses was avoided, and stricter dose modification guidance for ocular events was provided.

Tumor responses were assessed by investigator and independent review committee (IRC) using magnetic resonance imaging or computed tomography at baseline and every 6 weeks during the study. Responses were confirmed by subsequent repeat imaging performed ≥4 weeks after initial response.

Tumor biopsies were requested upon enrollment in the study. Fresh biopsies were requested, but the most recent archived sample could be used. If no archived biopsies were available, a fresh biopsy was taken prior to dosing. Biopsy samples were retrospectively assessed for membrane and cytoplasmic TF tumor expression in a central laboratory using an analytically validated immunohistochemistry assay. TF histology score (H-score) was calculated based on the percentage of tumor tissue that had membrane or cytoplasmic TF expression intensity of low (1+), intermediate (2+), and high (3+) on evaluable samples using the following equation: H-score = [1 × (% cells 1+)] + [2 × (% cells 2+)] + [3 × (% cells 3+)].

The primary objective of this study was to evaluate the safety and tolerability of tisotumab vedotin. Key secondary endpoints included ORR [defined as complete response (CR) or partial response (PR) as assessed by the investigator or IRC], duration of response (DOR), and progression-free survival (PFS) per RECIST v1.1.

All patients who received at least one dose of tisotumab vedotin were included in the safety and antitumor activity analyses. Objective response rate was determined with a corresponding two-sided 95% exact binomial confidence interval (CI). Independent review committee assessment utilized a two readers plus adjudication method. Agreement between investigator and IRC assessment with respect to confirmed objective response was determined using Cohen's kappa coefficient. Median PFS and DOR were determined using the Kaplan–Meier method and were presented with a two-sided 95% CI. Prespecified subgroup factors included TF expression. Association between TF expression and response was analyzed using analysis of variance with Tukey multicomparison post hoc test.

Between November 2015 and April 2018, 55 patients were enrolled into the cervical cancer expansion cohort of the innovaTV 201 study (Supplementary Fig. S1). The demographics and baseline disease characteristics are presented in Table 1. Most patients had ECOG performance status of 1 (73%). Fifty-one percent of the patients had squamous cell carcinoma and 35% had adenocarcinoma. Fifty-one percent received ≥2 prior lines of treatment. Four patients did not receive 1L standard-of-care therapy because they were refractory to treatment for early-stage disease (concurrent chemoradiation or neoadjuvant therapy) and were considered as having zero prior lines of treatment in the recurrent setting. Prior systemic therapies received included taxanes (91%) and bevacizumab plus doublet chemotherapy (67%). Tissue factor expression (≥1%) was confirmed in the majority of evaluable patients (membrane expression, 100%; cytoplasmic expression, 95%).

At data cutoff (September 30, 2018), the median follow-up was 3.5 months (range: 0.6–11.8). The median number of doses of tisotumab vedotin received was 4.0 (range: 1.0–14.0). Ten patients (18%) discontinued treatment due to an AE, the most common of which was peripheral neuropathy (9%). Seven patients (13%) had an AE leading to dose reduction (Supplementary Table S1).

Treatment-emergent AEs regardless of causality and of any grade were reported in all patients, and AEs of grade ≥3 were reported in 31 patients (56%; Table 2). The most common AEs were epistaxis (51%), fatigue (51%), nausea (49%), conjunctivitis (42%), and alopecia (40%; Table 2). Of these, most were grade 1/2. The most common grade ≥3 AEs were anemia (11%), fatigue (9%), and vomiting (7%). Twenty-nine patients (53%) had serious AEs (Supplementary Table S2), the most common of which were vomiting (7%) and constipation (5%). Two fatal events occurred while on treatment, both due to disease progression, and were assessed as unrelated to treatment by investigator and study sponsor. No treatment-related deaths were observed.

No grade ≥4 AESIs were observed. Neuropathy AESIs occurred in 30 patients (55%); six of the AESIs (11%) were grade 3, and the most common was peripheral neuropathy (all grades: 36%; grade 3: 4%; Table 2, additional information on neuropathy AESIs is summarized in Supplementary Table S3). Seventeen patients (31%) had neuropathy at baseline. Bleeding-related AESIs occurred in 40 patients (73%) and most were grade 1/2, with 3 patients (5%) experiencing a grade 3 bleeding-related event (two with vaginal hemorrhage and one with hematuria; Table 2, additional information on bleeding-related AESIs is summarized in Supplementary Table S4). The most common bleeding-related event was epistaxis (51%); all were grade 1 except for one grade 2. Ocular AESIs of any type occurred in 36 patients (65%), and the most common were conjunctivitis (42%) and dry eye (24%; Table 2, additional information on ocular AESIs is summarized in Supplementary Table S5). The incidence of ocular events was reduced from 80% in patients enrolled prior to the implementation of mitigation measures (n = 15) to 60% in patients enrolled after implementation (n = 40). The rates of conjunctivitis were reduced from 80% to 28% (Fig. 1).

The investigator-assessed confirmed ORR was 24% (95% CI: 13%−37%; Table 3). Maximum changes in target lesion size from baseline are shown in Fig. 2A. The median time to response was 2.6 months (range: 1.1−3.9) and the median DOR was 4.2 months (range: 1.0⁺−9.7; Table 3). Four patients experienced a confirmed PR for ≥8 months (Fig. 2B). The median PFS was 4.2 months (95% CI: 2.1−5.3), and the 6-month PFS rate was 29% (95% CI: 17%−43%; Table 3; Supplementary Fig. S2).

The IRC-assessed confirmed ORR was 22% (95% CI: 12%−35%; Table 3), which included one patient who had a CR by IRC assessment. Four patients were refractory to prior treatment for early-stage disease and did not receive standard of care (doublet chemotherapy ± bevacizumab) for 1L treatment of recurrent or metastatic disease. In these patients (n = 51), the IRC-assessed confirmed ORR was 24% (95% CI: 13%–38%). The overall agreement between investigator and IRC assessment with respect to ORR was 95% (Cohen's kappa = 0.84). The median IRC-assessed DOR was 6.0 months (range: 1.0⁺−9.7), and the 6-month PFS rate was 40% (95% CI: 24%−55%; Table 3; Supplementary Fig. S3).

Fig. 2C shows the target and nontarget lesion baseline and follow-up scans of a 43-year-old female patient with squamous cell carcinoma previously treated with paclitaxel plus carboplatin. This patient achieved PR after 16 weeks of treatment and discontinued tisotumab vedotin due to an AE at that time. The decreased target lesion size persisted after treatment discontinuation up to week 47.

Investigator-assessed responses with tisotumab vedotin were observed across histologic types [squamous cell carcinoma ORR, 29% (8/28 patients); adenocarcinoma ORR, 16% (3/19 patients)] and for patients who received zero [25% (1/4 patients)], one [22% (5/23 patients)], two [35% (6/17 patients)], or three or four [9% (1/11 patients)] prior lines of therapy (Fig. 3A). Patients who previously received bevacizumab plus doublet chemotherapy demonstrated a similar ORR to the overall population [22% (8/37 patients)].

Tissue factor expression in relation to clinical response was evaluable in tissue samples from 44 of the 55 patients (80%), as three patients had no biopsy, four were not evaluable for response by RECIST v1.1, and five had insufficient tumor material (one patient not evaluable for response also had insufficient tumor material). Of the evaluable cases, 37 patients (84%) had archival biopsies and seven (16%) had fresh biopsies. Seventeen of the 37 patients (46%) with archived tissue had no prior treatment at the time of biopsy. There was no statistically significant difference in TF expression between biopsy samples taken with no prior treatment compared with recurrent cervical cancer biopsy samples (data not shown). Twenty-seven biopsies (61%) were from primary tumors and 17 (39%) were from metastatic lesions. Membrane and cytoplasmic TF expression (H-score) were comparable across histologic types (Fig. 3B and C). Investigation of membrane or cytoplasmic TF expression did not show a statistically significant association with investigator-assessed best overall confirmed response (Fig. 3D and E).

In patients with advanced recurrent or metastatic cervical cancer, tisotumab vedotin, a first-in-class ADC designed to target TF, demonstrated a manageable safety profile and encouraging antitumor activity in a patient population for which no standard-of-care therapy exists. To our knowledge, tisotumab vedotin is the first ADC to successfully demonstrate meaningful clinical activity specifically targeting TF, a novel target overexpressed in many solid tumors associated with poor outcomes.

The safety profile of tisotumab vedotin was generally consistent with other MMAE-based ADCs, except for epistaxis and conjunctivitis (29, 30). Almost all epistaxis events were grade 1, and none required clinical intervention. Moreover, as TF is highly expressed in the nasal epithelium (31), this observation may reflect a local disruption of the nasal mucosa rather than an underlying treatment-induced coagulopathy. The incidence of other bleeding-related events was consistent with the expected incidence observed in patients with advanced cervical cancer. Most ocular events were grade 1/2, except for one patient with grade 3 conjunctivitis. The incidence of ocular events, including conjunctivitis, was reduced in the patients enrolled after implementation of mitigation measures. Although the mechanism of the ocular events is not known, TF expression has been demonstrated in the ocular epithelium (32, 33), which may result in treatment-emergent toxicity in these cells. The understanding of TF-related epistaxis and ocular events is continuing to evolve, and further studies are needed to optimize mitigation strategies, as well as to assess the long-term effects of tisotumab vedotin, the duration of these AESIs, and the mechanisms by which they occur.

The ORR observed with tisotumab vedotin across histologies, line of therapy, and prior treatments, including bevacizumab plus doublet chemotherapy, is clinically important in a patient population that lacks effective therapies. Tisotumab vedotin demonstrated a notable response rate (24% by investigator assessment) and meaningful 6-month PFS rate in this previously treated patient population with advanced cervical cancer, including in patients with adenocarcinoma histology. In contrast, an ORR of 14% was observed in patients with PD-L1−positive cervical cancer treated with pembrolizumab (16). The efficacy of pembrolizumab in patients with nonsquamous histology has not been well established as most patients (92%) enrolled in the clinical trial of pembrolizumab had squamous cell carcinoma (16), and although the median DOR was not reached, meaningful PFS benefit was not observed (34).

The antitumor activity of tisotumab vedotin is further supported by the concordance between the investigator- and IRC-assessed ORR and prolonged responses. The durability of response with tisotumab vedotin is highlighted by the 4 patients with response >8 months and the patient case demonstrating persistent PR despite tisotumab vedotin discontinuation. The durable responses observed may be indicative of the multiple proposed mechanisms of action of tisotumab vedotin, including direct cytotoxicity, bystander killing, and immunogenic cell death induced by MMAE, as well as Fcγ receptor–mediated effector functions and inhibition of TF/FVIIa signaling (17, 18, 27).

Most biopsies of patients with cervical cancer had detectable TF expression. Both membrane and cytoplasmic levels of TF expression were comparable across various cervical cancer histologic types. Although median membrane and cytoplasmic TF H-score were higher in patients who achieved PR and stable disease than those with progressive disease, there was no statistically significant association with best confirmed response. That said, the majority of samples were from archival tissue, and the effect of previous lines of therapy on TF expression has yet to be explored. Further studies evaluating TF expression and other potential predictive biomarkers that associate with antitumor activity will be explored to determine whether certain patient populations may benefit more from tisotumab vedotin.

This study demonstrated the antitumor activity of tisotumab vedotin in patients with advanced, previously treated recurrent or metastatic cervical cancer. However, overall survival was not a specified endpoint, and thus further studies are needed to establish the impact of tisotumab vedotin on survival in these patients. The ongoing phase II innovaTV 204 study (NCT03438396; ENGOT-cx6; GOG-3032) is investigating the antitumor activity and safety of tisotumab vedotin in approximately 100 patients with previously treated recurrent or metastatic cervical cancer. In addition, the phase I/II innovaTV 205 study (NCT03786081; ENGOT-cx8; GOG-3024) is investigating the combination of tisotumab vedotin with pembrolizumab, bevacizumab, or carboplatin in the 1L and 2L+ settings in patients with recurrent or metastatic cervical cancer.

Recurrent or metastatic cervical cancer is a serious, life-threatening disease. The lack of effective treatments, high relapse risk, and low survival after 1L treatment demonstrate the need for novel, safe, and effective therapies that improve clinical benefit. The results of this study cohort have demonstrated the manageable safety profile and encouraging antitumor activity of tisotumab vedotin, supporting the further clinical development of this first-in-class ADC targeting the novel therapeutic target TF in patients with previously treated recurrent or metastatic cervical cancer.

D.S. Hong is a paid consultant for Alpha Insights, Amgen, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Prime Oncology, Seattle Genetics, Takeda, Trieza Therapeutics, and WebMD; reports receiving commercial research grants from AbbVie, Adaptimmune, Aldi-Norte, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, Medimmune, Mirati, MiRNA, Molecular Templates, Mologen, Novartis, Pfizer, Seattle Genetics, Takeda, and Turning Point; holds ownership interest (including patents) in Molecular Match, OncoResponse, and Presagia; and reports receiving other remuneration from Genmab, AACR, ASCO, and SITC. I. Vergote is a paid consultant for Roche NV and Genmab. J.S. de Bono reports receiving speakers bureau honoraria from Seattle Genetics and Genmab, and reports receiving other remuneration from AstraZeneca, SanofiAventis, Merck Serono, Bayer, MSD, Pfizer Oncology, Roche/Genentech, Janssen, Astellas, and Daiichi Sankyo. B.M. Slomovitz is a paid consultant for Genmab, GlaxoSmithKline, Clovis, AstraZeneca, and Genentech. Y. Drew reports receiving honoraria for participating in advisory board speakers meeting held at ASCO 2018. H.-T. Arkenau is an employee of HCAHealthcare UK/Sarah Cannon and reports receiving speakers bureau honoraria from Pierre Fabre, Guardant, BeiGene, and Roche. J.-P. Machiels is a paid advisory board member for Pfizer, Roche, AstraZeneca, Bayer, Innate, Merck Serono, Bristol-Myers Squibb, Novartis, Janssen, Incyte, Cue Biopharma, ALX Oncology, Debio, and Nanbiotix; is an unpaid consultant/advisory board member for MSD; and reports receiving other remuneration from Amgen. R. Jones reports receiving commercial research grants from Merck and reports receiving speakers bureau honoraria from Roche. M.L. Johnson reports receiving commercial research grants from BerGenBio, Lilly, EMD Serono, Mirati Therapeutics, Genmab, Janssen, Pfizer, AstraZeneca, Genentech/Roche, Stemcentrx, Novartis, Checkpoint Therapeutics, Array Biopharma, Regeneron, Apexigen, AbbVie, Tarveda, Adaptimmune, Syndax, Neovia, Boehringer Ingelheim, Sanofi, Hengrui Therapeutics, Merck, Daiichi-Sankyo, Lycera, G1 Therapeutics, Dynavax, LOXO, CytomX, BeiGene, Birdie, Corvus, Incyte, Genocea, Gritstone, Amgen, Bristol-Myers Squibb, Kadmon, Clovis, Acerta, OncoMed, Guardant Health, Takeda, Shattuck Labs, and GlaxoSmithKline; is an unpaid consultant/advisory board member for Genentech/Roche, Celgene, Boehringer Ingelheim, Sanofi, Mirati, LOXO, Calithera, AstraZeneca, Merck, Araxes Pharma, Mersana Therapeutics, BeiGene, Incyte, Pfizer, Guardant Health, Bristol-Myers Squibb, and Ribon Therapeutics; and reports receiving other remuneration from AbbVie, Astellas, AstraZeneca, Boehringer Ingelheim, Clovis, Daiichi Sankyo, EMD Serono, Bristol-Myers Squibb, Exelixis, Genentech, Incyte, Merck, Pfizer, Sysmex Inostics, and Vapotherm. F.C. Thistlewaite is a paid consultant for Novartis, GlaxoSmithKline, and Bristol-Myers Squibb and reports receiving commercial research grants from Novartis. R.A. Rangwala is an employee of Genmab and is an unpaid consultant/advisory board member for International AIDS Vaccine Initiative. S. Ghatta is an employee of Genmab. K. Windfeld is an employee of Genmab. J.R. Harris is an employee of Genmab. R.L. Coleman is a paid consultant for AstraZeneca, Roche, Matea, Merch, and Genmab; reports receiving commercial research grants from Merck, Clovis, Roche, AstraZeneca, and Janssen; and reports receiving other commercial research support from V-Foundation and Gateway Foundation. No potential conflicts of interest were disclosed by the other authors.

Conception and design: D.S. Hong, J.S. de Bono, H.-T. Arkenau, R.A. Rangwala, S. Ghatta, U.N. Lassen

Development of methodology: I. Vergote, J.S. de Bono, R.A. Rangwala, U.N. Lassen

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): D.S. Hong, N. Concin, I. Vergote, J.S. de Bono, B.M. Slomovitz, Y. Drew, H.-T. Arkenau, J.-P. Machiels, J.F. Spicer, R. Jones, M.D. Forster, C. Gennigens, M.L. Johnson, F.C. Thistlethwaite, R.A. Rangwala, U.N. Lassen, R.L. Coleman

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): D.S. Hong, I. Vergote, J.S. de Bono, Y. Drew, J.-P. Machiels, J.F. Spicer, M.D. Forster, M.L. Johnson, R.A. Rangwala, S. Ghatta, K. Windfeld, J.R. Harris, U.N. Lassen, R.L. Coleman

Writing, review, and/or revision of the manuscript: D.S. Hong, N. Concin, I. Vergote, J.S. de Bono, B.M. Slomovitz, Y. Drew, H.-T. Arkenau, J.-P. Machiels, J.F. Spicer, R. Jones, M.D. Forster, N. Cornez, C. Gennigens, M.L. Johnson, F.C. Thistlethwaite, R.A. Rangwala, S. Ghatta, J.R. Harris, U.N. Lassen, R.L. Coleman

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): J.S. de Bono, Y. Drew

Study supervision: D.S. Hong, I. Vergote, J.S. de Bono, H.-T. Arkenau, R.A. Rangwala

The authors thank the patients and their families and caregivers for participating in this study as well as all site personnel. The authors thank Freddy de Bree at Genmab for his contribution to biomarker data analysis. This study was funded by Genmab A/S. Tisotumab vedotin is being developed in collaboration with Seattle Genetics, Inc. Medical writing assistance was provided by Emily C. Casey, PhD, of the ApotheCom Genmab Team (San Francisco) and was funded by Genmab A/S.

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