Immune check-point in cervical cancer

Accepted Manuscript Title: Immune check-point in cervical cancer Authors: F. De Felice, C. Marchetti, I. Palaia, R. Ostuni, L. Muzii, V. Tombolini, P. Benedetti Panici PII: DOI: Reference:

S1040-8428(18)30118-5 https://doi.org/10.1016/j.critrevonc.2018.06.006 ONCH 2572

To appear in:

Critical Reviews in Oncology/Hematology

Received date: Revised date: Accepted date:

10-3-2018 2-6-2018 13-6-2018

Please cite this article as: De Felice F, Marchetti C, Palaia I, Ostuni R, Muzii L, Tombolini V, Benedetti Panici P, Immune check-point in cervical cancer, Critical Reviews in Oncology / Hematology (2018), https://doi.org/10.1016/j.critrevonc.2018.06.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Immune check-point in cervical cancer De Felice Fa#, Marchetti Cb#, Palaia Ib, Ostuni Rb, Muzii Lb, Tombolini Va, Benedetti Panici Pb Department of Radiotherapy, Policlinico Umberto I, “Sapienza” University of Rome, Rome, Italy b Department of Gynecological and Obstetrical Sciences and Urological Sciences, “Sapienza” University of Rome, Rome, Italy #Equal contribution a

Table of contents

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1. Introduction 2. Literature search 3. Immune check-point inhibitors 3.1 Immuno-system and immune-modulation 3.2 Ipilimumab 3.3 Pembrolizumab 3.4 Nivolumab 4. Toxicity profile 4.1 Ipilimumab 4.2 Pembrolizumab 4.3 Nivolumab 5. Clinical evidence in cervical cancer 5.1 Ipilimumab 5.2 Pembrolizumab 5.3 Nivolumab 6. Conclusion 7. References

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Correspondence to: Claudia Marchetti, Department of Gynecological and Obstetrical Sciences and Urological Sciences, Policlinico Umberto I, “Sapienza” University of Rome, Rome, Italy. Phone number: +39 064990550 Fax number : +39 064997256 E-mail : [email protected]

Immune check-point in cervical cancer Abstract Despite different treatment strategies, locally advanced cervical cancer (CC) persists as one of the most incurable cancers among women worldwide. In fact, this setting of patients are at high risk of persistent and recurrent disease. In recent years, researches

have investigated immune check-point inhibitors in hopes of determining improved response to therapy with prolongation of survival. We reviewed the published literature and conference proceedings and presented pivotal trials supporting immune check-point inhibitors use in the treatment of CC.

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Keywords Cervical cancer; immune check-point; immunotherapy; CTLA-4; PD-1; ipilimumab; pembrolizumab; nivolumab.

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1. Introduction Cervical cancer (CC) is still one of the most commonly diagnosed cancer and one of the mainly leading cause of cancer death in female population [1]. Surgery, radiation therapy, chemotherapy or a combination of these therapeutic modalities represent the classical options to CC management [2-3]. The appropriate strategy is based on tumor stage at diagnosis, but it remains dismal to improve survival in locally advanced or recurrent/metastatic disease [4]. Recent years have affirmed an exciting development of immunotherapy, especially check-point inhibitors, in different human malignancies [5-6]. Ipilimumab is an anti cytotoxic T lymphocyte associated antigen 4 (CTLA-4) antibody, whereas pembrolizumab and nivolumab are both anti-programmed death-1 (PD-1) antibody,. Firstly approved by Food and Drug Administration (FDA) for metastatic melanoma in 2011, nowadays these immunomodulatory monoclonal antibodies become standard of care also in non-small-cell lung cancer and head and neck cancer [7-10]. Due to their significant clinical impact in a growing number of tumors, this review focuses on the immune check-point inhibitors in CC. Our aim is to highlight the recent developments of ipilimumab, pembrolizumab and nivolumab in order to facilitate CC therapeutic decision making. We also describe and compare check-point inhibitors mechanism of action, as well as their main pharmacokinetics proprieties and their immune-related toxicities.

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2. Literature search A search of PubMed and Scopus databases was performed. The following combinations of keywords was used: “cervical cancer”, “immunotherapy”, “immune check-point”, “inhibitors”, “nivolumab”, “pembrolizumab”, “ipilimumab”, “PD-1”, “CTLA-4”. We provided a comprehensive picture of immune check-point inhibitors perspectives in CC using hand searching (meeting proceedings of European Society for Medical Oncology and Society of Gynecologic Oncology) and clinicaltrials.gov. Literature search strategy was performed up to December 2017. Only English written publications were selected. Titles and abstracts of search results were screened to determine eligibility in the manuscript. Additional references were selected from relevant articles. Abstract from international meetings were included only if with appropriate and sufficiently powered statistical data. 3. Immune check-point inhibitors Cancer cells have numerous mechanisms to evade local immune attack, including the up-regulation of immune check-point protein expression. The end result is the cancer progression that manifests clinically as a tumor [11]. At present, the immune checkpoint inhibitors represent the most successful immunotherapeutic approach, due to

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their peculiar ability to target lymphocyte receptors, as opposed to current target therapy, such as bevacizumab, trastuzumab and cetuximab, that act directly on the tumor cells. In fact, immune check-point proteins are physiologically expressed by activated lymphocyte and are initiated by ligand-receptor interactions. Considering that the immune system response is regulated by a balance between stimulatory and inhibitory signals, each immune check-point can be properly blocked by agonist (stimulatory signals) or antagonist (inhibitory signals) antibodies or modulated by recombinant forms of ligands or receptors [5, 12]. 3.1 Immuno-system and immune-modulation. Basic knowledge of immune system and its relationship with cancer cells should be useful to better understand immune checkpoint inhibitors properties and their effective interactions with CC microenvironment. The human immune system is divided into innate – natural killer (NK) cells, dendritic cells, macrophages and neutrophils – and adaptive – B cells and T cells, including cytotoxic (CD8+ T or CTL) cells, helper (CD4+ T) cells and NK T cells – immune components [6]. In terms of tumor immunology, host’s immune system is fundamental to prevent tumor growth and development. Basically, the innate immune system secretes cytokines that recruit immune cells and the adaptive immune system processes “non-self” cells (elimination phase). But tumor cells can express tumor antigens (TAs) able to elude immune system (equilibrium phase) and begin to grow in a dynamic and uncontrolled way (escape phase). Immuno-tolerance is mainly guaranteed by co-stimulatory pathway, including mainly the programmed death-1 receptor (PD-1) and its ligand (PD-L) and the cytotoxic T lymphocyte associated antigen 4 (CTLA-4). These signals inhibit T cell activation, proliferation and cytokine production – PD-1/PDL – or induces cell-cycle arrest and apoptosis, in Tregs and activated T cell – CTLA-4 – [5-6]. 3.2 Ipilimumab. Ipilimumab is a fully human monoclonal IgG1 antibody that antagonize the CTLA-4 immune check-point to promote antitumor immunity [13]. It binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Inhibition of CTLA-4 signaling increases T-cell activation and proliferation [13]. Ipilimumab represents the parent immune check-point inhibitor. In fact this antiCTLA-4 antibody was the first to achieve the FDA approval for first and second line treatment of unresectable or metastatic melanoma in 2011 [14]. Usually, Ipilimumab is administered at 3 mg/kg infused over 90 minutes every 3 weeks for a total of four doses in metastatic setting [13]. Steady-state concentrations are reached by the third dose; the terminal half-life (t1/2) is 15.4 days and the clearance rate is 16.8 mL/h [13]. The clearance increases with increasing body weight, supporting the recommended body weight (mg/kg) based dosing. Whereas, age, sex, performance status, baseline lactate dehydrogenase levels, previous cancer therapy, renal and mild hepatic impairment (ipilimumab has not been studied in patients with moderate or severe hepatic impairment) have no clinically important effect on the clearance of ipilimumab. 3.3 Pembrolizumab. Pembrolizumab is a humanized IgG4 monoclonal antibody against PD-1. It derives from a nonhuman species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans [11]. Pembrolizumab binds the PD-1 receptor on T cells and blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, preserving T cell proliferation and cytokine production [15]. Pembrolizumab is administered at 2 mg/kg over 30 minutes every 3 weeks until disease progression or unacceptable toxicity [15]. Steady-state concentrations are reached by 18 weeks; the mean elimination half-life (t1/2) is 26 days and the clearance rate is 9.2 mL/h. Its clearance only increases with

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increasing body weight. Pembrolizumab has not been studied in patients with moderate or severe hepatic impairment [15]. 3.4 Nivolumab. Nivolumab is a fully human IgG4 monoclonal antibody that targets PD-1. Its mechanism of action is similar to pembrolizumab. It binds to the PD-1 receptor, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response [16]. Nivolumab is administered at 3mg/kg intravenously over 60 minutes every 2 weeks until disease progression or unacceptable toxicity [16]. Steady-state concentrations are reached by 12 weeks; the mean elimination half-life (t1/2) is 26.7 days and the clearance rate is 9.5 mL/h. Its clearance only increases with increasing body weight [16]. The clearance increases with increasing body weight supporting a weight-based dose. Other factors, including age, gender, race, baseline lactate dehydrogenase levels, PD-L1 expression, tumor type, tumor size, renal impairment and mild hepatic impairment, have no clinically important effect on nivolumab clearance. The effect of hepatic impairment on the clearance has not been studied in patients with moderate or severe alteration [16].

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4. Toxicity profile The adverse-event (AE) profile of immune check-point inhibitors is consistent with their mechanism of action. Thus, different AE pattern exists between CTLA-4 and PD-1 targeting agents. Generally, PD-1 blockade seems to be better tolerated and has a lower AE frequency than CTLA-4 blockade. CTLA-4-related AEs increase with increasing dose, whereas PD-1-related AE do not appear to be dose related. AEs affect over 2/3 of patients. But severe immune-related AEs occur in 10% to 20% of cases treated with CTLA-4 inhibitors, whereas its frequency is lower (1% to 2%) in those patients treated with PD-1 inhibitors. The most common AEs include dermatologic, gastro-intestinal, hepatic and endocrine events, as well as fatigue and injection-site reactions. For both CTLA-4 and PD-1 agents, dermatologic toxicity – it mainly consists of erythematous rash on the extremities and trunk – is the most frequent and earliest AE. Diarrhea and proctocolitis also represent a relevant AE and usually occur 6 weeks after the start of treatment. Immune check-point inhibitors may also determine endocrinopathies affecting the pituitary, adrenal and thyroid glands, that should required hormone-replacement therapy [11]. Mucositis, dry mouth and transaminitis more common with CTLA-4 inhibition than with PD- 1 inhibition (10% versus rare). A positive correlation between AEs occurrence/severity and therapeutic response seems to be possible [17]. For clarity, AEs also depend on tumor-related factor, such as primary site. Moreover, it should be noticed that the following AE descriptions came from each immune check-point inhibitor prescribing information. 4.1 Ipilimumab. Most common AEs (≥ 5%) are fatigue, diarrhea, pruritus, rash and colitis [13]. Additional common adverse reactions at the 10 mg/kg dose (≥ 5%) include nausea, vomiting, headache, weight loss, pyrexia, decreased appetite and insomnia [13]. 4.2 Pembrolizumab. Most common AEs (reported in ≥ 20% of patients) include fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia and diarrhea [15]. 4.3 Nivolumab. Most common AEs (≥20%) in patients are fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection and pyrexia [16]. 5. Clinical evidence in cervical cancer

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At the time of publication, all three immune check-point inhibitors are not approved for the treatment of CC. But all three immune check-point inhibitors are currently being investigated in several ongoing CC clinical trials. Details are listed in Table 1. Recently three studies have been presented at the 2017 American Society of Clinical Oncology meeting and preliminary results seem to be promising. These are the first trials investigating the safety and tolerability of each immune check-point inhibitor in CC patients. Here we extrapolated the main characteristics and briefly described the results. 5.1 Ipilimumab. Lheureux et al performed a multicenter phase I/II trial in order to assess the safety and antitumor activity of ipilimumab in recurrent and metastatic CC [18]. In total, 42 women, given prior pelvic radiotherapy and platinum-based chemotherapy, were enrolled. Of 34 patients evaluated for best response, one patient had partial response and 10 had stable disease. Median progression-free survival (PFS) and overall survival (OS) rates were 2.5 months and 8.5 months, respectively. Even if ipilimumab as monotherapy did not demonstrate significant benefit in this setting of patients, the safety and tolerability of treatment was established, indicating its feasibility in further therapeutic strategies. The GOG 9929 is the first phase I study that examined the safety, tolerability and efficacy of sequential ipilimumab after radiotherapy plus concomitant platinum-based chemotherapy (cisplatin 40 mg/mq) in lymph node positive CC patients [19]. Ipilimumab was given 2-6 weeks after the end of chemoradiotherapy in case of no disease progression. Primary endpoints were the ipilimumab maximum tolerated dose and the dose-limiting toxicities. Secondary endpoints were disease-free survival (DFS) at 1 year. A total of 34 patients were enrolled, but only 19 patients were evaluable for the analysis (to note, 14 patients went off study to unrelated-ipilimumab reasons). The ipilimumab maximum tolerated dose was 10 mg/kg. Severe hepatic and dermatologic toxicity was recorded in 16% of cases (n = 3). The 1-year DFS rate was 74%. Results suggest a valid radioimmunotherapy combination. 5.2 Pembrolizumab. Frenel et al presented the CC results from the phase Ib KEYNOTE-028 trial [20]. Patients with advanced CC received pembrolizumab 10 mg/kg every 2 weeks for up to 24 months. The primary end point was overall response rate (ORR). In total, 24 patients were enrolled; the majority of patients (n = 22) had received prior radiation therapy, as well as two or more lines of therapy (n = 15). Median follow-up was 11 months. ORR was 17%. Four patients achieved a confirmed partial response and 3 had stable disease. The main toxicity were rash (n = 5) and pyrexia (n = 4). Five patients experienced severe treatment-related adverse events, including one case each of rash, colitis, Guillain- Barré syndrome and pyrexia. No treatment-related mortality occurred. Median PFS and OS rates were 2 months and 9 months, respectively. 5.3 Nivolumab. The CheckMate 358 trial investigated the safety and effectiveness of nivolumab in recurrent or metastatic human papilloma virus associated gynecological cancers [21]. Patients were eligible to receive nivolumab 240 mg every 2 weeks until progression or unacceptable toxicity if they had performance status 0-1 and ≤ 2 prior systemic therapies for recurrent or metastatic disease. Primary end-points were ORR and safety; secondary end-points were duration of response, PFS and OS. In total 24 patients were treated and the vast majority (n = 19) had CC at diagnosis. Globally, ORR was 20.8%; median PFS was 5.5 mo, whereas median OS was not reached in the study group. Interestingly, if only CC patients are considered, ORR rate raised to 26.3%. Severe toxicity was recorded in 12.5% of cases. Updated clinical and biomarker data will be presented shortly.

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6. Conclusion Taken together, these preliminary results of the phase I/II studies demonstrate the value of immune check-point inhibitors in CC and further support their promising antitumor activity in that context. Although the data are immature, these three immune checkpoint inhibitors seem to be an attractive therapeutic strategy that could be added to the arsenal for the treatment of CC in the near future. Maybe the combination of CTLA-4 and PD-1 agents, as well as association with radiotherapy would generate a synergistic anticancer effects. Further trials are needed to test new alternative treatment combination that should be well tolerated and that may significantly improve clinical outcomes.

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Funding Sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors’ contributions Conception and design: XXX Collection and assembly of data: XXX Data analysis and interpretation: XXX Manuscript writing: XXX Final approval of manuscript: All authors

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Conflict of interest statement The authors declare that they have no competing interests.

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Acknowledgement None.

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7. References [1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7-30. [2] National Comprehensive Cancer Network Guidelines Cervical Cancer Version 1.2018. [http://www.nccn.org/] [3] Marchetti C, De Felice F, Di Pinto A, Romito A, Musella A, Palaia I, Monti M, Tombolini V, Muzii L, Benedetti Panici P. Survival Nomograms After Curative Neoadjuvant Chemotherapy and Radical Surgery for Stage IB2-IIIB Cervical Cancer. Cancer Res Treat. 2017. [Epub ahead of print] [4] Pfaendler KS, Tewari KS. Changing paradigms in the systemic treatment of advanced cervical cancer. Am J Obstet Gynecol. 2016;214(1):22-30. [5] De Felice F, Musio D, Cassese R, Gravina GL, Tombolini V. New Approaches in Glioblastoma Multiforme: The Potential Role of Immune-check Point Inhibitors. Curr Cancer Drug Targets. 2017;17(3):282-289. [6] De Felice F, Marchetti C, Palaia I, Musio D, Muzii L, Tombolini V, Panici PB. Immunotherapy of Ovarian Cancer: The Role of Checkpoint Inhibitors. J Immunol Res. 2015;2015:191832. [7] Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong

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Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122-33. [8] Wolchok JD. PD-1 Blockers. Cell. 2015;162(5):937. [9] Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Iglesias Docampo LC, Haddad R, Rordorf T, Kiyota N, Tahara M, Monga M, Lynch M, Geese WJ, Kopit J, Shaw JW, Gillison ML. Nivolumab for Recurrent SquamousCell Carcinoma of the Head and Neck. N Engl J Med. 2016;375(19):1856-1867. [10] Chow LQ, Haddad R, Gupta S, Mahipal A, Mehra R, Tahara M, Berger R, Eder JP, Burtness B, Lee SH, Keam B, Kang H, Muro K, Weiss J, Geva R, Lin CC, Chung HC, Meister A, Dolled-Filhart M, Pathiraja K, Cheng JD, Seiwert TY. Antitumor Activity of Pembrolizumab in Biomarker-Unselected Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results From the Phase Ib KEYNOTE-012 Expansion Cohort. J Clin Oncol. 2016. pii: JCO681478. [11] La-Beck NM, Jean GW, Huynh C, Alzghari SK, Lowe DB. Immune Checkpoint Inhibitors: New Insights and Current Place in Cancer Therapy. Pharmacotherapy. 2015;35(10):963-76. [12] Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-64. [13] Bristol-Myers Squibb. Yervoy (ipilimumab) package insert. Princeton, NJ; 2013. [14] Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-23. [15] Merck and Co., Inc. Keytruda (pembrolizumab) package insert. Whitehouse Station, NJ; 2014. [16] Bristol-Myers Squibb. Opdivo (nivolimab) package insert. Princeton, NJ; 2015. [17] Postow MA, Callahan MK, Wolchok JD. Immune Checkpoint Blockade in Cancer Therapy. J Clin Oncol. 2015;33(17):1974-82. [18] Lheureux S, Butler MO, Clarke B, Cristea MC, Martin LP, Tonkin K, Fleming GF, Tinker AV, Hirte HW, Tsoref D, Mackay H, Dhani NC, Ghatage P, Weberpals J, Welch S, Pham NA, Motta V, Sotov V, Wang L, Karakasis K, Udagani S, Kamel-Reid S, Streicher HZ, Shaw P, Oza AM. Association of Ipilimumab With Safety and Antitumor Activity in Women With Metastatic or Recurrent Human Papillomavirus-Related Cervical Carcinoma. JAMA Oncol. 2017. [Epub ahead of print] [19] Mayadev J, Brady WE, Lin YG,Da Silva DM, Lankes HA, Fracasso PM. A phase I study of sequential ipilimumab in the definitive treatment of node positive cervical cancer: GOG 9929. J Clin Oncol. 2017;35(15):5526-5526. [20] Frenel JS, Le Tourneau C, O'Neil B, Ott PA, Piha-Paul SA, Gomez-Roca C, van Brummelen EMJ, Rugo HS, Thomas S, Saraf S, Rangwala R, Varga A. Safety and Efficacy of Pembrolizumab in Advanced, Programmed Death Ligand 1Positive Cervical Cancer: Results From the Phase Ib KEYNOTE-028 Trial. J Clin Oncol. 2017. [Epub ahead of print]

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[21] Hollebecque A, Meyer T, Moore KN, Machiels JPH, De Greve J, LópezPicazo JM. An open-label, multicohort, phase I/II study of nivolumab in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in recurrent or metastatic (R/M) cervical, vaginal, and vulvar cancers. J Clin Oncol. 2017;35(15):5504-5504.

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Short biography Claudia Marchetti was born in Rome in 1981. She graduated from the Faculty of Medicine of the University of Rome “Sapienza” in 2006. She obtained the license to practice medicine in Italy in 2007. She was specialized in Gynecological and Obstetrical Sciences at the University of Rome “Sapienza” in 2012. She is author of several indexed papers, all in the field of clinical and experimental gynecological oncology.

Table 1. Immune check-point inhibitors ongoing trials in cervical cancer

Patient population

N planned

Treatment

Primary outcome

NCT02635360

II

advanced CC

88

Pembrolizumab 200 mg day 1-21 for 3 months following or concurrent to chemoradiotherapy

DLT; immunologic markers

NCT03367871

II

recurrent, persistent or metastatic CC

39

3 cycles of cisplatin (50 mg/mq), paclitaxel (175-135 mg/mq), pembrolizumab (200 mg), day 1-21

CR; PR; SD

NCT03144466

I

locally advanced CC

26

Pembrolizumab in combination with chemoradiotherapy

MTD; efficacy

NCT03192059

II

advanced/refractory CC, endometrial carcinoma, uterine sarcoma

43

Immunomodulatory cocktail, pembrolizumab (200 mg) day 1-21 combined with radiation

ORR

NCT03298893

I

locally advanced CC

21

Nivolumab (40 mg/,mq) concurrent and following chemoradiotherapy

DLT

NCT02257528

II

recurrent, persistent or metastatic CC

NCT01693783

II

recurrent or metastatic HPV-related CC

NCT02488759

I/II

HPV-positive and HPVnegative solid tumors*

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Phase

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Nivolumab every 2 weeks for a maximum of 46 doses

CR; PR; SD; AEs

44

Ipilimumab every 21 days for 4 courses, maintenance ipilimumab every 12 weeks for 4 courses

AEs; ORR

500

Metastatic nivolumab monotherapy; neoadjuvant nivolumab; nivolumab plus ipilimumab

AEs; ORR

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* Anal canal cancer, cervical cancer, epstein barr virus positive gastric cancer, human papilloma virus positive and negative squamous cell cancer of the head and neck, merkel cell cancer, nasopharyngeal cancer, penile cancer, vaginal and vulvar cancer N: number; CC: cervical cancer; DLT: dose limiting toxicities; CR: complete response; PR: partial response; SD: stable disease; MTD: maximum tolerated dose; ORR: objective response rate; AEs: adverse events; HPV: human papilloma virus;