Targeting cervical cancer with anti-PD-1 antibodies: what is new?

KEYWORDS:

• cervical cancer
• gynecologic malignancy
• PD-1

1. Introduction

In 2023, it is estimated that there will be approximately 13,960 new cases of invasive cervical cancer diagnosed in the United States, of which 4,310 women will die due to their disease [1]. Worldwide, cervical cancer poses an even greater threat, with an estimated 604,000 new cases and 342,000 deaths annually [2]. This makes cervical cancer the fourth most common cancer in women, with 90% of these cases occurring in low- and middle-income countries [2]. Even among patients adequately treated, in the presence of locally advanced or recurrent disease, outcomes tend to be poor. Given the high mortality rate in locally advanced and recurrent cases, the development of effective therapies for cervical cancer is imperative.

One of the most promising strategies for cancer in general, and specifically in cervical cancer, is suppression of immune checkpoint inhibitors, especially targeting the immune checkpoint programmed cell death protein-1 (PD-1). Features of cervical cancer, including high expression of PD-L1, a moderate-to-high tumor mutation burden (TMB), and microsatellite instability (MSI), make it an excellent target for immunotherapy [3]. Additionally, because the majority of cervical cancer cases are driven by HPV infection, viral proteins may act as strong immune stimulants, making this disease more responsive to immunotherapy than other malignancies [4]. Although PD-L1 expression tends to be upregulated in HPV-related cervical cancers, the use of immunotherapy to reverse effector T cell suppression is not an HPV specific strategy and can be used among all cervical cancer histologies, including more rare cervical melanomas and lymphomas [5]. PD-1 binds its ligand PD-L1 to down regulate T-cell activation and cytotoxicity, preventing T-cell proliferation and facilitating immune evasion [6]. Accordingly, monoclonal antibodies to PD-1 blocking inhibitory signals may restore and augment cytotoxic T-cell responses against cervical tumors. Here, we will review the latest recommendations as well as recent and ongoing clinical trials that are anticipated to change the landscape of cervical cancer treatment.

2. Current treatment recommendations

The use of anti-PD-1 inhibitors for cervical cancer was first introduced in the setting of recurrent and metastatic disease. Table 1 summarizes the key trials leading to current treatment recommendations. The phase 2 trial, KEYNOTE-158, studied pembrolizumab, an anti-PD-1 inhibitor, as monotherapy in patients with previously treated, metastatic, or unresectable cervical cancer with known programmed death-ligand 1 (PD-L1) expressing tumors [8]. Patients treated with pembrolizumab had an ORR of 12.2% and prolonged overall survival, demonstrating the antitumor activity of the anti-PD-1 antibody, while maintaining a manageable safety profile [8]. This successfully led to the approval of pembrolizumab monotherapy for PD-L1 positive recurrent or metastatic cervical cancer.

Table 1. Summary of published clinical trials evaluated anti-PD-1 inhibitors for cervical cancer.

Trial	Phase	Setting	Drug	Primary Endpoint	Key Study Findings
Keynote 028 (Frenel et al. 2017) [7]	IB	Locally advanced, Reucrrent	Pembrolizumab	ORR	17% Overall Response Rate
Keynote 158 (Chung et al. 2019) [8]	II	Recurrent	Pembrolizumab	ORR	12.2% Objective Response Rate 14.6% ORR in PD-L1-positive tumors
Keynote 826 (Colombo et al. 2021) [9]	III	Recurrent, Metastatic	Pembrolizumab with platinum-based chemotherapy ± bevacizumab	PFS, OS	PFS 10.4 months vs. 8.2 months in placebo OS 53% vs. 40.4% in placebo group
NRG-GY002 (Santin et al. 2020) [10]	II	Persistent, Recurrent	Nivolumab	ORR	4% Partial Response Rate Median PFS 3.5 months Median OS 14.5 months
Checkmate 358 (Naumann et al. 2019) [11]	I/II	Recurrent, Metastatic	Nivolumab	ORR	26.3% Objective Response Rate Median OS 21.9 months
O’Malley et al. 2020 [12]	II	Recurrent, Metastatic	Balstilimab with zalifrelimab	ORR	14% Objective Reponse Rate with Balstilimab, 22% Objective Response Rate combined Balstilimab with zalifrelimab
CLAP (Lan et al. 2020) [13]	II	Recurrent, Metastatic	Camrelizumab with apatinib	ORR	55.6% ORR Median PFS 8.8 months OS not reached

ORR: objective response rate; PFS: Progression-free survival; OS: overall survival.

Recognition on the utility of pembrolizumab in cervical cancer subsequently led to further studies. KEYNOTE-826 was a phase III trial investigating the use of pembrolizumab plus chemotherapy with or without bevacizumab compared to chemotherapy plus or minus bevacizumab in persistent, recurrent, or metastatic cervical cancer [9]. The addition of pembrolizumab led to a reduced hazard of disease progression, decreased risk of death, prolonged progression-free survival, and overall survival across all subgroups [9]. The findings of this landmark clinical trial were reflected in a change to NCCN guidelines, with the addition of pembrolizumab to the preferred regimen of cisplatin/paclitaxel or carboplatin/paclitaxel with or without bevacizumab in PD-L1 positive, TMB-H, or MSI/dMMR recurrent tumors [14]. These data recently changed the standard of care which was previously set as platinum-based paclitaxel chemotherapy with or without bevacizumab for recurrent disease.

Unlike KEYNOTE-826 which required a PD-L1 score of at least 1%, in GOG Protocol 3016 and ENGOT Protocol En-Cx9, use of Cemiplimab, an alternative PD1-blocking antibody, was evaluated in patients with progression following first-line platinum containing chemotherapy, regardless of PD-L1 status [15]. Among women that received Cemiplimab, an ORR of 16.4% was achieved compared to an ORR of 6.3% in the chemotherapy alone group [15]. These findings highlight a survival benefit of significant magnitude in women treated with Cemiplimab and led to its approval as a second-line monotherapy for recurrent disease [15]. While evidence is limited, preliminary findings also suggest activity of Cemiplimab in PD-L1-negative patients [15].

3. Future directions

Given the proven utility of anti-PD-1 antibodies in recurrent cervical cancer, current studies are exploring the efficacy and safety of pembrolizumab for primary treatment of locally advanced cervical cancer. Table 2 includes active clinical trials. KEYNOTE-A18/ENGOT-cx11/GOG-3047 extrapolates lessons learned from trials in the recurrent setting to test the hypothesis if pembrolizumab plus concurrent chemoradiotherapy is superior to chemoradiotherapy alone for the initial treatment of locally advanced cervical cancer. It was recently announced that results show a statistically significant and meaningful progression-free survival in patients that received pembrolizumab with concurrent chemoradiotherapy [16]. The trial is ongoing, with data on overall survival as another primary endpoint maturing [16]. If future results continue to trend in the same direction, this study has the potential to dramatically shift the standard of care by recommending a change in the use of pembrolizumab from the recurrent setting to upfront treatment.

Table 2. Summary of active* clinical trials targeting PD-1 inhibition in cervical cancer.

Clinicaltrials.gov identifiers	Phase	Trial Status	Drug	Drug Class	Study population
NCT04221945	III	Active, not recruiting	Pembrolizumab + cisplatin + EBRT + brachytherapy	Anti-PD-1 and chemoradiotherapy	Locally advanced cervical cancer
NCT04483544	II	Recruiting	Pembrolizumab + Olaparib	Anti-PD-1 and PARPi	Recurrent cervical cancer with low potential for cure with radiation and surgery alone
NCT03228667	IIb	Active, not recruiting	N-803 + PD-1/PD-L1 inhibitor	IL-15 agonist and Anti-PD-1/Anti-PD-L1	Recurrent or metastatic cervical cancer on or following pembrolizumab
NCT03236935	Ib	Active, not recruiting	Pembrolizumab + NG-monomethyl-L-arginine (L-NMMA)	Anti-PD-1 and nitric oxide synthase inhibitor	MSI-H, dMMR, or TMB-H unresectable or metastatic solid tumors
NCT06022757	Ib/II	Not yet recruiting	XNW5004 + Pembrolizumab	Ehnancer of zeste homolog 2 (EZH2) inhibitor and Anti-PD-1	Recurrent or metastatic cervical cancer progression after standard therapy
NCT04651127	Ib/II	Unknown	Toripalimab + Chidamide	Anti-PD-1 and histone deacetylase (HDAC) inhibitor	Metastatic, recurrent, or persistent cervical cancer not amenable to curative treatment with surgery or radiation
NCT03827837	II	Recruiting	Cemrelizumab + Famitinib	Anit-PD-1 and multikinase inhibitor	Advanced squamous cell carcinoma of the cervix after failure of first-line treatment
NCT05824468	II	Not yet recruiting	Zimberelimab + Lenvatinib	Anti-PD-1 and tyrosine kinase inhibitor (TKI)	Cervical cancer progression following use of prior immune checkpoint inhibitor
NCT03544623	II	Unknown	Adenoviral p53 + physician’s choice anti-PD-1/PD-L1	Ad-p53 + Anti-PD-1/PD-L1	Progressive solid tumor with p53 wild type profile
NCT05824494	II	Not yet recruiting	Cadonilimab + Abraxane	Anti-PD-1/CTLA-4 and nab-Paclitaxel	Recurrent cervical cancer previously treated with immune checkpoint inhibitor
NCT0515149	II	Not yet recruiting	Carilizumab + Cisplatin or Carboplatin	Anti-PD-1 + chemoradiotherapy	Locally advanced PD-L1 positive cervical cancer
NCT05180788	I/II	Recruiting	BA3071 + Nivolumab	CTLA-4 inhibitor and Anti-PD-1	Advanced solid tumors
NCT05887392	I/II	Recruiting	TNG260 + Pembrolizumab	CoREST inhibitor and Anti-PD-1	Locally advanced or metastatic solid tumors with known STK11 mutation

*Active based on information provided on ClinicalTrials.gov (accessed October 13, 2023).

The addition of pembrolizumab in advanced or recurrent disease has finally added a new option in place of traditional chemotherapy and offers hope to women suffering from cervical cancer. This has prompted investigation into alternative anti-PD-1 agents, such as nivolumab in the phase I/II CheckMate 358 study, which overall shows promising efficacy when used as monotherapy [11]. However, despite this progress, further treatment options in advanced and recurrent disease remain needed as a large population of cervical cancer patients fail to respond to treatment and ultimately will die from their disease. An area of exploration is the combination of anti-PD-1 antibodies with a second cytotoxic agent in order to utilize distinct but complementary mechanisms to improve outcomes. Combined treatments are a mainstay in oncology, and this also applies to immunotherapy.

A phase II open-label study using dual-checkpoint blockage with balstilimab (anti-PD-1) and zalifrelimab (CTLA-4-targetings monoclonal antibody) in previously treated, recurrent, and metastatic cervical cancer demonstrated impressive clinical activity reflected in the PRR, with an enhanced benefit among patients with PD-L1 expression [12]. The combination of an anti-PD-1 with CTLA-4 inhibitor demonstrated a significantly enhanced anti-tumor activity, reflected in a higher objective response rate and partial response rate [12,17]. A higher number of side effects were reported with this antibody combination; however, these events appeared manageable with appropriate supportive care, corticosteroids, or withholding treatment.

The combined effect of an anti-PD1-antibody with a vascular endothelial growth factor receptor (VEGFR) inhibitor was studied using camrelizumab plus apatinib in recurrent cervical cancer. In the phase II CLAP trial, patients that received the combined therapy achieved an ORR of 55.6%, with responses observed regardless of PD-L1 expression, although PD-L1 tumors had a greater PFS [13]. The combination activity was superior to either anti-PD-1 or VEGF monotherapy alone, supporting an additive effect of the combined regimen.

4. Conclusions

In the last few years, anti-PD-1 immune checkpoint antibodies have emerged as a promising treatment in both locally advanced and recurrent cervical cancer. Cervical cancer is still commonly diagnosed at advanced stages in many women, creating a major challenge to successfully treating these patients. Given that many women with advanced disease often do not respond to available treatments, the need for novel, effective targeted treatment is imperative. Anti-PD-1 therapies show substantial promise and accordingly, the treatment of cervical cancer has already begun its transformation with the approval of anti-PD-1 antibodies to NCCN guidelines. Anti-PD1 antibodies have the potential to improve survival outcomes and enhance quality of life. However, additional studies are required to investigate effectiveness in combination with other validated cervical cancer therapeutics. We anticipate anti-PD-1 antibodies to play an increasing role in the treatment of cervical cancer in the years to come.

Declaration of interest

AD Santin reports grants from Puma, grants from Immunomedics, grants from Gilead, grants from Synthon, grants and personal fees from Merck, grants from Boehringer-Ingelheim, grants from Genentech, grants and personal fees from Tesaro and grants and personal fees from Eisai and R-Pharm U.S.A. The other authors declare no conflict of interest. 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 funded in part by grants from NIH U01 CA176067-01A1, the Deborah Bunn Alley Foundation, the Domenic Cicchetti Foundation, the Discovery to Cure Foundation, and the Guido Berlucchi Foundation to AD Santin. This investigation was also supported by NIH Research Grant CA-16359 from NCI and Standup-to-cancer (SU2C) convergence grant 2.0 to AD Santin.