Review of emerging biological therapies for recurrent and advanced metastatic cervical cancer

KEYWORDS:

• antibody drug conjugate
• biological therapy
• cervical cancer
• immune checkpoint inhibitor
• targeted therapy

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1.0 Introduction

Cervical cancer continues to be a significant cause of morbidity and mortality among women worldwide despite global efforts to increase access to care for both prevention and therapy. Cervical cancer is the fourth most common cancer in women globally and the death rate has decreased by less than 1% in the last two decades [1]. Research into the biology of solid tumors and their microenvironment during recent years has led to investigation of novel therapies. The resulting clinical trials have yielded approval of several classes of targeted therapies for solid tumors including antiangiogenic agents, immune checkpoint inhibitors (ICI) and antibody-drug conjugates (ADC). These groundbreaking therapeutic agents have shifted the existing treatment paradigms for cervical cancer, particularly for those patients diagnosed with recurrent or metastatic cervical cancer (rmCC). This paper will focus on current and evolving treatment standards as well as the significance of a more novel therapy, tisotumab vedotin (TV), an ADC comprised of an anti-tissue factor antibody and a microtubule inhibitor.

2.0 Current treatment standards in recurrent and advanced metastatic cervical cancer

The pharmacologic standard of care (SOC) for rmCC was platinum-based chemotherapy until 2014, when the US Food and Drug Administration (FDA) approved the addition of bevacizumab, an antiangiogenic agent targeting vascular endothelial growth factor (VEGF), to SOC cytotoxic chemotherapy for patients with persistent or rmCC. This approval was based on results from the phase III randomized, controlled trial (RCT), Gynecologic Oncology Group (GOG)-240 (NCT 00803062) showing benefit in both progression free survival (PFS) and overall survival (OS) (8.2 vs 5.9 months; hazard ratio (HR) = 0.67; 95% confidence interval (CI) 0.54-0.82; p= 0.0002 and 16.8 vs 13.3 months; HR 0.77 95% CI 0.62-0.95; p=0.007, respectively) [2]. Based on these findings and the growing understanding of the role of the immune system in solid tumors, other novel therapies were investigated. Pembrolizumab, an ICI with action against programmed cell death protein 1 (PD-1), was investigated in the phase II clinical trial, Keynote-158 (NCT 02628067). The study assessed the safety and efficacy of pembrolizumab monotherapy in the second line (2L) management of solid tumors. The clinically meaningful and durable survival benefits observed in this study allowed for accelerated FDA approval [3]. The phase III, confirmatory RCT, Keynote-826 (NCT 03635567), investigated the addition of pembrolizumab to platinum-based chemotherapy with or without bevacizumab in first line (1L) management of rmCC. Survival benefit was seen in a subset of patients that received pembrolizumab and had a programmed death ligand-1 (PD-L1) combined positive score (CPS) of ≥1. Data showed a statistically significant difference in PFS (10.4 versus 8.2 months; HR= 0.62; 95% CI= 0.5-0.77; p=<0.001) and OS (53.0% versus 41.7%; HR= 0.64; 95% CI= 0.5-0.81; p=<0.001) [4]. This regimen was approved by the FDA on October 13, 2021, for patients with persistent or rmCC with a PD-L1 CPS ≥1 and has since become the SOC [5]. The role of pembrolizumab in earlier disease has also been investigated. Keynote-A18 (NCT 04221945), a phase III RCT of concurrent chemoradiotherapy (CRT) with or without pembrolizumab in patients with high-risk, locally advanced cervical cancer (LACC) showed an improvement in PFS with the addition of pembrolizumab compared to CRT alone (67.8% versus 57.3% at 24 months (HR= 0.70; 95% CI 0.55-0.89). This resulted in accelerated FDA approval on January 12, 2024, demonstrating pembrolizumab’s potential to shift the landscape of treatment for these patients as well [6].

2.1 Cemiplimab as an acceptable option for 2L management

FDA approval of pembrolizumab in the 1L and 2L management of rmCC met a significant clinical need for patients with PD-L1 positive tumors. Under concurrent investigation was the PD-1 inhibitor, cemiplimab, in the EMPOWER trial (NCT 03257267) which showed survival benefit for patients receiving cemiplimab monotherapy in 2L compared to chemotherapy (OS 12.0 versus 8.5 months; HR, 0.69; 95% CI, 0.56-0.84; two-sided P<0.001) [7]. Based on these results, cemiplimab has been included as an acceptable option for 2L management according to National Comprehensive Cancer Network (NCCN) guidelines [8].

2.2 Accelerated FDA approval of tisotumab vedotin

InnovaTV-204 (NCT 03438396) (Figure 1A), the phase II trial investigating the ADC, tisotumab vedotin (TV), in pre-treated rmCC patients, showed a clinically meaningful antitumor response (objective response rate (ORR) 24%; 95% CI= 15.9%-33.3%, p=0.0002) [9]. These findings led to the accelerated FDA approval of TV for pretreated patients with rmCC on September 20, 2021 [10]. The ongoing confirmatory trial, InnovaTV-301 (NCT 04697628), will be discussed in a subsequent section of this paper. While FDA approval of pembrolizumab in 2L is restricted to patients with PD-L1 positive tumors, the accelerated FDA approval of TV has no such biomarker restrictions and therefore offers a 2L option for those patients with PD-L1 negative tumors or those with progression despite prior ICI in the 1L.

Figure 1: Schema for innova tisotumab vedotin trials.

3.0 Treatment related adverse events of TV

TV is a microtubule inhibitor, similar to the cytotoxic chemotherapeutic agent, paclitaxel. Despite sharing the same intracellular target, studies investigating paclitaxel and those investigating TV have highlighted differing toxicities. As a microtubule stabilizer, paclitaxel is strongly associated with peripheral neuropathy, affecting up to 90% of treated patients to varying degrees across studies [11]. Conversely, a lower overall incidence has been reported in TV clinical trials affecting 42% of participants [9]. Additionally, the profound dose-limiting neutropenia affecting patients treated with paclitaxel (≥grade 3, 52%) has not been observed in studies investigating TV (≥grade 3, 3%). Furthermore, while alopecia is frequently observed in clinical trials investigating paclitaxel (87%), its occurrence is notably less common in studies assessing TV (38%) [9], [11].

3.1 Unique toxicology profile of TV

A unique toxicity of bleeding events has been reported with TV and is inherent to one of its cellular targets, tissue factor (TF). TF, also known as thromboplastin, is a protein found on the surface of cells, most notably those within blood vessels but also can be overexpressed in certain cancers. This overexpression allows for TV to directly bind these cancer cells. However, the interaction between TV and TF can also affect normal blood vessels. Blood exposure of TF is the initial step in the extrinsic pathway of the clotting cascade in response to vascular endothelial injury and, as such, is vital in hemostasis efforts. By targeting TF, TV may interfere with this process, potentially leading to a disruption in the body’s ability to form blood clots effectively. Bleeding events were therefore a prespecified adverse event in the innovaTV-204 investigation of TV and occurred in 39% of patients in the experimental arm; most were grade 1 and 2 treatment-related adverse events (TRAE). These bleeding events did not have a substantial impact on the clinical management of these patients and the most common events included epistaxis (30%), vaginal hemorrhage (7%) and hematuria (3%) [9].

3.2 Mitigation strategy for ocular toxicity

Another unique toxicity reported with TV use is ocular toxicity that was observed even during the phase I/II clinical trials. Given these findings, there have been management strategies implemented to mitigate these effects. The most frequent ocular TRAE reported were conjunctivitis (26%), dry eye (23%) and Keratitis (11%). Most events were mild to moderate, reported as grade 1 or 2 [9], [12]. The manufacturer released an eye care checklist involving resources and materials for providers and patients undergoing treatment with TV. This plan includes access to an eye care provider, premedication with eye drops, and cold packs for use during infusion. Dose modifications, when necessary, may also mitigate these TRAE [12]. Patient education is important regarding the potential occurrence of these TRAE, signs and symptoms to look for while undergoing therapy, and management strategies. A detailed discussion with patients is a vital component of shared decision making and should occur prior to initiating therapy with TV.

4.0 Expert opinion

4.1 Role of tissue factor as a prognostic biomarker in cervical cancer

TF as discussed above is one of the cellular targets of TV and is also related to hemostasis given its expression on endothelial cells. In recent years, TF overexpression has also been noted on malignant tumor cells and is thought to play a role in solid tumor angiogenesis and metastasis. In some cervical tumors, upregulation of TF expression has been noted to be directly proportionate to increasing clinical stage and TF is therefore theorized to be a potential biomarker for cervical cancer [13]. The FDA’s accelerated approval of TV, as a result of findings from the InnovaTV-204 trial, is noteworthy for its biomarker-unrestricted approach and differs from pembrolizumab’s approval, which was limited to patients positive for the PD-L1 biomarker. InnovaTV-204 showcased TV’s anti-tumor activity in patients with rmCC, irrespective of TF status. Although TF positivity was not a prerequisite for TV approval, the observed upregulation of TF in some cervical tumors suggests its potential as a biomarker for treatment response in those expressing the protein.

4.2 Future directions for TV therapy

The landscape for initial therapy of women with International Federation of Gynecology and Obstetrics (FIGO) stage III/IVA may be shifting to pembrolizumab with concurrent CRT based on the preliminary data from the Keynote-A18 study and resulting accelerated FDA approval. If this treatment regimen were to be adopted as SOC, then patients with prior ICI exposure that subsequently develop recurrent disease will be ineligible for the current standard 1L regimen proposed by Keynote-826 (platinum-based chemotherapy plus pembrolizumab with or without bevacizumab) [4]. The ongoing phase III RCT, innovaTV-301 (NCT 04697628) (Figure 1B) is the confirmatory trial for innovaTV-204 and is assessing the efficacy and tolerability of TV in pre-treated rmCC patients [14]. If the antitumor activity and tolerability mirror the outcomes observed in InnovaTV-204, the prospect of full FDA approval for TV in 2L management of rmCC is encouraging. Additionally, the phase Ib/II trial, InnovaTV-205 (NCT 03786081) (Figure 1C), assessed 1L TV in combination with either bevacizumab, carboplatin or pembrolizumab and showed survival benefit with tolerable side effect profiles for these combination therapies [15]. Therefore, TV could potentially emerge as a 1L option for rmCC patients as well. Subject to full approval, TV presents a prospective therapeutic avenue for patients experiencing recurrence after receiving initial ICI treatment, as per the proposed Keynote-A18 regimen [6] (Table 1).

Table 1: Progression of Pharmacologic Management for Recurrent and Metastatic Cervical Cancer

Trial, Drug	GOG-240, Bevacizumab (n= 452)	Keynote-158, Pembrolizumab (n=107)	Keynote-826, Pembrolizumab (n=617)	EMPOWER, Cemiplimab (n=608)	InnovaTV-204, Tisotumab Vedotin (n=101)	InnovaTV-205, Tisotumab Vedotin (n=159)	Keynote-A18, Pembrolizumab (n=980)	InnovaTV-301, Tisotumab Vedotin (n=502)
Phase	III	II	III	II	II	Ib/II	?	III
Population	Persistent or rmCC	Advanced solid tumors that progressed following prior treatment	Persistent or rmCC	rmCC following prior treatment with platinum therapy	rmCC following prior treatment with platinum therapy	rmCC previously untreated or following prior treatment with platinum therapy	Previously untreated locally advanced cervical cancer	rmCC following prior treatment with platinum therapy
Treatment Arms	A. Control: Cisplatin + paclitaxel + placebo B. Experimental: cisplatin + paclitaxel + bevacizumab C. Topotecan + paclitaxel + placebo bevacizumab D. Topotecan + paclitaxel + bevacizumab	A. Pembrolizumab monotherapy	A. Experimental: Chemotherapy + pembrolizumab B. Control: Chemotherapy + Placebo	A. Experimental: Cemiplimab monotherapy B. Active comparator: Investigator’s choice chemotherapy	A. TV monotherapy	A. TV+ bevacizumab B. TV + pembrolizumab C. TV + carboplatin D. 1L TV + carboplatin E. 1L TV + pembrolizumab F. 2L/3L TV + pembrolizumab G. TV monotherapy H. TV + pembrolizumab ± bevacizumab	A. Experimental: CRT + pembrolizumab B. Control: CRT + placebo	A. Experimental: TV monotherapy B. Active comparator: investigator’s choice chemotherapy
Primary Endpoint	OS	ORR	PFS, OS	OS	ORR	ORR for arm D,E,F	PFS	OS
HR	0.77	30.8%	PFS: 0.62; OS: 0.64	0.75	24%	D: 54.5%; E:40.6%; F:35.3%	0.54	0.70
95% CI	0.62-0.95	25.8-36.2	PFS: 0.50-0.77; OS: 0.50-0.81	0.63-0.89	15.9-33.3	D: 36.4-71.9; E: 23.7-59.4; F: 19.7-53.5	0.41-0.71	0.54-0.89
P value	<0.007	-	PFS, OS: 0.0001	0.0005	0.0002	-	<0.001	0.004

Abbreviations: rmCC: recurrent/metastatic cervical cancer, HR: hazard ratio, 95% CI: 95% confidence interval, OS: overall survival, ORR: objective response rate, PFS: progression free survival, TV: Tisotumab vedotin, 1L: first line, 2L: second line, 3L: third line, CRT: chemoradiotherapy

List of abbreviations

1L	=	first line
2L	=	second line
3L	=	third line
ADC	=	Antibody Drug Conjugate
AE	=	adverse event
CI	=	confidence interval
CPS	=	combined positive score
CRT	=	chemoradiotherapy
DLT	=	dose limiting toxicity
DOR	=	duration of response
ECOG PS	=	Eastern cooperative oncology group performance status
FDA	=	Food and Drug Administration
FIGO	=	international federation of gynecology and obstetrics
GOG	=	gynecologic oncology group
HR	=	Hazard ratio
IRC	=	independent review committee
ORR	=	Objective response rate
OS	=	Overall survival
PD-1	=	Programmed cell death protein 1
PD-L1	=	Programmed cell death ligand 1
PFS	=	Progression Free Survival
RCT	=	Randomized controlled trial
rmCC	=	Recurrent/metastatic cervical cancer
SOC	=	Standard of care
TF	=	Tissue factor
TRAE	=	treatment-related adverse event
TTR	=	time to response
TV	=	Tisotumab Vedotin
VEGF	=	Vascular endothelial growth factor

Declaration of interest

K Tewari has acted as a consultant for Merck, Pfizer, Genmab and Seagen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.