Five new therapies for the treatment of patients with cervical cancer are in late-stage development that could potentially change clinical practice and set the stage for 2021 to be a banner year for FDA approvals for this malignancy, according to Robert L. Coleman, MD. 

“This is going to be really exciting,” said Coleman, noting that there have been only 2 new drug approvals for cervical cancer in recent years: bevacizumab (Avastin) plus chemotherapy in 2014 and pembrolizumab (Keytruda) for PD-L1 positive disease in 2018.

 award winner in the gynecologic malignancies category, identified the following therapies as among the most promising in the cervical cancer pipeline: lifileucel; balstilimab as a single agent and in combination with zalifrelimab; tisotumab vedotin; cemiplimab-rwlc (Libtayo); and pembrolizumab (Keytruda) in combination with chemotherapy (

Table. Emerging Therapies for Cervical Cancer

®, Coleman discussed key data for these therapies and touched on emerging developments concerning new therapies in ovarian and endometrial cancers. Coleman, a longtime clinical investigator and leader of the Gynecologic Oncology Group Foundation, became chief scientific officer of The US Oncology Network in March 2020.

Lifileucel, formerly known as LN-145, uses autologous tumor-infiltrating lymphocytes (TILs) harvested from tumor fragments to create a patient-specific immunotherapy. In November 2020, Iovance Biotherapeutics, Inc, which is developing the adoptive cell transfer therapy, said the last patient has been dosed in the pivotal cohort of the phase 2 C-145-04 trial (NCT03108495) in patients with recurrent, metastatic, or persistent cervical cancer. The company is discussing assays to define TILs with the FDA and plans to submit a biologics license application (BLA) to the agency this year.

In early findings from the pivotal trial, lifileucel demonstrated a 44% objective response rate (ORR) among 27 patients, including 3 complete responses (11%) and 9 partial responses (33.3%), for an 85% disease control rate, according to data presented at the 2019 American Society of Clinical Oncology Annual Meeting.

 TIL persistence was observed at 6 months in the peripheral blood mononuclear cells of 20 participants available for analysis, suggesting that memory T cells in the TIL therapy can be long lived, investigators said in a poster presented at the European Society for Medical Oncology Virtual Congress 2020 (ESMO 2020).

Another treatment moving forward in the regulatory process is balstilimab, an anti– PD-1 monoclonal antibody. In September 2020, Agenus Inc, the drug’s developer, started a rolling BLA with the FDA for use of balstilimab in recurrent or metastatic cervical cancer based on findings from a single-arm phase 2 trial (NCT03104699).

 The study enrolled patients with squamous cell, adenosquamous, or adenocarcinoma of the cervix who had relapsed or progressed on or after platinum-based treatment.

Balstilimab monotherapy resulted in a 14% ORR among 160 patients in the intentionto-treat population, with a median duration of response (DOR) of 15.4 months (range, 1.1+ to 15.4), according to findings presented at ESMO 2020. The ORR was 19% among participants with PD-L1–positive tumors (19 of 99 patients).

In a separate phase 2 trial (NCT03495882), balstilimab administered in combination with zalifrelimab, a CTLA-4 inhibitor, resulted in an ORR of 22% among 143 patients, with the median DOR not reached (range, 1.3+ to 16.6+ months). The ORR was 27% among those with PD-L1–positive disease (21 of 79 patients).

 The combination is being developed under an FDA fast track designation.

Tisotumab vedotin, another therapy on the horizon, is an antibody-drug conjugate that targets tissue factor, part of the coagulation network, which is highly prevalent in cervical cancer and other solid tumors. Coleman and colleagues presented data at ESMO 2020 from the phase 2 innovaTV 204 trial (NCT03438396) evaluating tisotumab vedotin as monotherapy, if appropriate, in patients with recurrent or extrapelvic metastatic cervical cancer that progressed during or after doublet chemotherapy with bevacizumab.

The ORR was 24% (95% CI, 15.9-33.3) among 101 patients who received tisotumab vedotin, including 7 patients (7%) with a complete response and 17 patients (17%) with a partial response. After a median follow-up of 10 months, the median DOR was 8.3 months (95% CI, 4.3-not reached). The median time to response was 1.4 months (range, 1.1-5.1), with activity generally observed within the first 2 treatment cycles.

Plans call for the phase 3 innovaTV 301 trial (NCT04697628) to start enrolling patients in January 2021. The study will evaluate tisotumab vedotin monotherapy versus physician’s choice of 1 chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed) as second- or third-line treatment for patients with recurrent or metastatic cervical cancer. The trial aims to enroll 482 participants.

Several immune checkpoint inhibitors approved in other indications also are being investigated for cervical cancer. Cemiplimab, a PD-1 inhibitor approved for patients with metastatic or locally advanced cutaneous squamous cell carcinoma, is being evaluated in a phase 3 trial (NCT03257267) as monotherapy versus physician’s choice of chemotherapy in patients with recurrent or metastatic platinum-refractory cervical cancer with squamous cell histology.

In November 2020, investigators reported data from expansion cohorts from a phase 1 trial (NCT02383212) that evaluated cemiplimab as a monotherapy or in combination with hypofractionated radiation therapy in patients with recurrent or metastatic cervical cancer. One of the 10 patients in each cohort achieved a partial response for an ORR of 10% (95% CI, 0.3%-44.5%); both responders had squamous histology. The DOR was 11.2 months and 6.4 months in the monotherapy and combination cohort, respectively.

“In cervix cancer recurrence, if the cemiplimab trial is positive, that would replace chemotherapy with an immune checkpoint inhibitor. We’re monitoring these phase 3 studies that could be reporting in 2021,” Coleman said.

These studies include the phase 3 KEYNOTE-826 trial (NCT03635567), which is testing the PD-1 inhibitor pembrolizumab in combination with investigator’s choice of chemotherapy (paclitaxel plus either cisplatin or carboplatin) with bevacizumab, if appropriate, versus chemotherapy with bevacizumab alone as first-line treatment for patients with persistent, recurrent, or metastatic cervical cancer. Pembrolizumab currently is approved for PD-L1–positive recurrent or metastatic cervical cancer that has progressed on or after chemotherapy.

In the ovarian cancer space, Coleman said, the results of the TRUST trial (NCT02828618) could be practice changing. The trial is comparing primary debulking surgery followed by 6 cycles of standard chemotherapy versus 3 cycles of neoadjuvant chemotherapy followed by interval debulking surgery in patients with newly diagnosed invasive stage IIIB to IVB epithelial ovarian cancer. The study, which is designed for an enrollment of nearly 800 patients, is taking place at 20 centers with a high level of surgical expertise in ovarian cancer.

“This trial is going to be really important from a practice-changing standpoint because if it validates that there is no difference between those 2 modalities, then neoadjuvant chemotherapy will become an even bigger standard. If it refutes it, then it is going to change the way people look at surgical candidacy in ovarian cancer, and that will be practice changing,” Coleman said. 

Coleman also is anticipating the results of the phase 3 ATHENA trial (NCT03522246), which is testing the combination of the PD-1 inhibitor nivolumab (Opdivo) plus the PARP inhibitor rucaparib (Rubraca) as maintenance therapy for patients who have responded to frontline platinum-based chemotherapy and have completed cytoreductive surgery. The study, which aims to enroll 1000 patients, has 4 arms: intravenous (IV) nivolumab plus oral rucaparib or placebo, rucaparib plus IV placebo, and an oral placebo plus an IV placebo. The primary end point is progression-free survival, and secondary end points include overall survival, ORR, and DOR.

“There are a lot of drug combinations that are working their way through [the pipeline], as well as novel treatments, including tumor treatment fields to novel biologics to gene therapy. PARP inhibitors will continue to roll out. We’ll have OS data starting to emerge on some of the mature trials. The exciting story for PARP inhibitors in 2021 is combinations,” Coleman said.

In endometrial cancer, Coleman hopes to see data this year from the phase 3 LEAP-001 trial (NCT03884101), which is studying the combination of pembrolizumab plus lenvatinib (Lenvima) versus the chemotherapy regimen of paclitaxel plus carboplatin. 

“This will be important to see if we can replace chemotherapy in the metastatic, recurrent space,” he said.

Bevacizumab solution. FDA. Updated September 1, 2015. Accessed January 14, 2021. https://bit.ly/3srYmJS 

FDA approves pembrolizumab for advanced cervical cancer with disease progression during or after chemotherapy. FDA. Updated June 13, 2018. Accessed January 15, 2021. https:// bit.ly/3qnCXQf 

Iovance Biotherapeutics reports third quarter and year-to-date 2020 financial results and corporate updates. News release. Iovance Biotherapeutics Inc. November 5, 2020. Accessed December 8, 2020. https://bit.ly/2JF681I 

Jazaeri AA, Zsiros E, Amaria RN, et al. Safety and efficacy of adoptive cell transfer using autologous tumor infiltrating lymphocytes (LN-145) for treatment of recurrent, metastatic, or persistent cervical carcinoma. J Clin Oncol. 2019;37(suppl 15):2538. doi:10.1200/JCO.2019.37.15_suppl.2538 

Jazaeri AA, Gontcharova V, Blaskovich M, et al. In vivo persistence of Iovance tumor-infiltrating lymphocytes LN-145 in cervical cancer patients. Ann Oncol. 2020;31(suppl 4):S642. doi:10.1016/j. annonc.2020.08.1012 

Agenus initiates rolling BLA submission of balstilimab for recurrent/ metastatic cervical cancer. News release. Agenus Inc. September 18, 2020. Accessed December 8, 2020. https://bit.ly/39NQuM2 

O’Malley DM, Oaknin A, Monk BJ, et al. Single-agent anti-PD-1 balstilimab or in combination with anti-CTLA-4 zalifrelimab for recurrent/metastatic (R/M) cervical cancer (CC): preliminary results of two independent phase II trials. Ann Oncol. 2020;31(suppl 4):S1142-S1215. https://www.annalsofoncology.org/article/ S0923-7534(20)42346-4/pdf 

Agenus receives fast track designation for balstilimab & zalifrelimab in advanced cervical cancer. News release. Agenus, Inc. March 12, 2020. Accessed December 8, 2020. https://bit.ly/3lZnUtm 

Coleman RL, Lorusso D, Gennigens C, et al. Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer: results from the phase II innovaTV 204/GOG-3023/ENGOT-cx6 study. Ann Oncol. 2020;31(suppl 4):S1142-S1215. doi:10.1016/j. annonc.2020.08.2262 

Rischin D, Gil-Martin M, González-Martin A, et al. PD-1 blockage in recurrent or metastatic cervical cancer: data from cemiplimab phase I expansion cohorts and characterization of PD-L1 expression in cervical cancer. Gynecol Oncol. 2020;159(2):322-328. doi:10.1016/j.ygyno.2020.08.026

Articles

Robert L. Coleman, MD, discusses key data for these therapies and touched on emerging developments concerning new therapies in ovarian and endometrial cancers. 

Coleman Looks Forward to a Big Year for New Cervical Cancer Therapies

That is the estimated number of cases of cervical cancer that were expected to be diagnosed in the United States in 2020.

 Of those, 4290 deaths would have likely occurred.

However, some numbers have turned a corner. Cervical cancer incidence and mortality rates have dropped significantly, in part due to screening via the Pap test, which has allowed for early cancer detection. 

Nearly all cervical cancers are driven by the human papillomavirus (HPV), and HPV vaccination is recommended in all boys and girls by the age of 13 years, according to the Centers for Disease Control and Prevention.

 According to the American Cancer Society, HPV vaccines do not protect against all HPV types—emphasizing the importance of adherence to cervical cancer screening guidelines.

The 5-year relative overall survival (OS) rate in the United States for cervical cancer is 66%; however, these rates differ for African American women who are aged 50 years and older (46%) and white women younger who are than 50 years (78%).

 For patients who have localized disease (44%), the 5-year OS rate is 92%.

Conversely, another area of cervical cancer that is less discussed but has been documented, is HPV-negative disease. 

In a study of Belgium women with cervical cancer prior to 2000, 13% were found to have HPV-negative disease,

 while an additional trial reported 7.1% of women with HPV-negative cervical cancer between 2001 and 2008.3 Globally, the percentage of HPV-negative cervical cancer cases ranges from 7% to 11%.

Potential explanations for HPV-negative results include cervical cancers that are independent of high-risk HPV, cervical cancers that lose HPV expression, cervical cancers due to low-risk and intermediate-risk HPV, misclassified cancers, and HPV testing methods, including false-negative results.

 One explanation for why the global rates of HPV-negative disease are so low is because of an increase in HPV testing overall, and improved testing methods over time.

For example, in an observational study out of Spain, investigators reanalyzed a cohort of 136 women with cervical cancer who previously underwent HPV testing, 14 (10.2%) of which were found to be HPV negative through Hybrid Capture 2 testing. However, when investigators retested these samples with highly sensitive polymerase chain reaction techniques, 8 of the total cancers (5.8%) were actually found to be HPV negative.

 The confirmed HPV-negative cases were observed in 5 patients with adenocarcinoma and 3 with squamous cell carcinoma (

 = .017). Additionally, HPV negativity showed a significantly worse disease-free survival than those with HPV‐positive tumors at 51.9 months versus 109.9 months, respectively (

Furthermore, results of another study showed that next-generation sequencing, which was used to characterize primary cervical cancers, demonstrated 5% of 178 analyzed cervical cancers were HPV-negative and harbored relatively high frequencies of 

However, the idea that HPV-negative cervical cancer is possible, especially in a disease that is mainly driven by HPV positivity, is not a unanimous opinion. Maurie Markman, MD, editor-in-chief, 

, and physician and president of Medicine and Science at Cancer Treatment Centers of America, said that 

 is that the HPV may simply not be found through testing, but is present.

“If you're talking about the cervical cancer that we speak about, you can have the HPV found after very carefully searching, [even] if it's 1% [of HPV positivity] or less,” Markman said. “Some of this is definitional. The fact that you don't find it doesn't mean it isn't there.”

Furthermore, the possibility of not having HPV detected in a disease should not deter individuals from undergoing HPV vaccination nor regular cervical cancer screening, he emphasized.

“We can certainly show that 70% to 80% of HPV-positive cervical cancers are due to the 2 major types: HPV 16 and 18. There are another 20% to 30% of cervical cancers that are due to other [HPV] types, and there are dozens of HPV types. Therefore, it's not at all clear that the issue with lack of preventing cervical cancer has anything to do with being HPV negative. It's just there are types of HPV that we may not be including in the vaccine.” 

HPV status is not a factor of a treatment considerations for a patient with cervical cancer, Markman said. Overall, cervical cancer continues to be an active area of exploration beyond chemoradiation and surgery. Bevacizumab (Avastin) is also available in combination with paclitaxel plus cisplatin or topotecan as a treatment for patients with persistent, recurrent, or metastatic cervical cancer.

Immunotherapy has been an area of research in the space in recent years, following the FDAs’s 2018 accelerated approval of pembrolizumab (Keytruda) in patients with advanced, PD-L1–positive cervical cancer with disease progression on or after chemotherapy.

Clinical trials focusing on immunotherapeutic strategies, including combinations and targeting the up-front setting, continue to enroll patients with cervical cancer. For example, a single-arm, phase 2 trial is evaluating pembrolizumab, bevacizumab, and chemotherapy in patients with recurrent, persistent, or metastatic disease (NCT03367871), while the phase 1/2 SKYSCRAPER-04 trial (NCT04300647) is looking at atezolizumab (Tecentriq) with or without tiragolumab in patients with recurrent/metastatic PD-L1–positive cervical cancer. 

Moreover, the phase 3 FERMATA trial (NCT03912415) is looking at the PD-1 inhibitor BCD-100 combined with platinum-based chemotherapy with and without bevacizumab in the frontline setting of advanced cervical cancer. 

The investigational PD-L1 inhibitor balstilimab, alone and in combination with the CTLA-4 inhibitor zalifrelimab, is actively being explored in metastatic disease. The rolling submission was from an ongoing phase 2 trial (NCT03894215), which demonstrated that the monotherapy elicited encouraging responses in patients with advanced cervical cancer. However, the completion of a biologics license application for the drug in this setting has been delayed to the first half of 2021, in order to have data reviewed on 2 patients who went from having durable disease stabilization to confirmed responses on long-term treatment.

 The agent was also granted fast track status by the FDA in April 2020. 

An additional agent, tisotumab vedotin, has also shown antitumor activity. In data that were virtually presented during the 2020 ESMO Congress, the antibody-drug conjugate showed a 24% objective response rate (ORR) in patients with recurrent and/or metastatic cervical cancer who were previously treated with doublet chemotherapy and bevacizumab, if eligible, in the single-arm, phase 2 innovaTV 204 trial.

Robert L. Coleman, MD, chief scientific officer of The US Oncology Research, explained that the year 2021 is expected to be a banner year for cervical cancer treatment. 

“Other really important things that are happening in cervical cancer this year would be the continuous move of immunotherapies into earlier lines of treatment, all the way up to not only in the adjuvant setting, but also with chemoradiation or radiation plus [immunotherapy], followed by maintenance therapy. [There is] the concept of moving maintenance therapy into cervical cancer, and into earlier lines of therapy, which is going to be an important addition. We'll hear data starting to emerge from those kinds of strategies. That's going to be really exciting for cervical cancer; we just haven't had anything for quite a while for that space.”

The issue lies in patient selection for some of these therapies, Markman explained, especially as ORRs with checkpoint inhibitors in cervical cancer range from 10% to 15%.

“As exciting as these drugs are, it is a minority of patients who benefit from them. It is actually even a smaller minority of patients, but a very relevant minority, in whom those benefits not only occur, but they're long lasting,” said Markman.

The overall arena of biomarker development is one that experts are still trying to grapple with in cervical cancer, Markman said.

“The future of cancer medicine is precision cancer medicine, which means trying to be more precise in determining the relevant targets and direct our therapy towards those targets to both improve effectiveness and decrease toxicity,” he concluded. “That is the future: to try to figure this out so that we direct our therapies where they're more likely to work. And, where they're not likely to work doesn't mean we give up. It means we look for other therapeutic strategies.”

Editor’s Note: This article on HPV-negative cervical cancer is part of OncLive®’s recently launched Rare Cancer Series.

Cancer Facts & Figures 2020. American Cancer Society. 2020. Accessed January 14, 2021. https://bit.ly/3qAmDvw 

Tjalma WA, Weyler JJ, Bogers JJ, et al. The importance of biological factors (bcl-2, bax, p53, PCNA, MI, HPV and angiogenesis) in invasive cervical cancer. 

. 2001;97(2):223-230. doi:10.1016/s0301-2115(00)00541-8

Tjalma WA, Trinh XB, Rosenlund M. A cross-sectional, multicentre, epidemiological study on human papillomavirus (HPV) type distribution in adult women diagnosed with invasive cervical cancer in Belgium. 

. 2015; 7(2):101-8. https://pubmed.ncbi.nlm.nih.gov/26175888

Clifford GM, Smith JS, Plummer M, Muñoz N, Franceschi S. Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. 

. 2003;88(1):63-73. doi: 10.1038/sj.bjc.6600688

Guan P, Howell-Jones R, Li N, et al. Human papillomavirus types in 115,789 HPV-positive women: a meta-analysis from cervical infection to cancer. 

Hopenhayn C, Christian A, Christian WJ, et al. Prevalence of human papillomavirus types in invasive cervical cancers from 7 US cancer registries before vaccine introduction. 

. 2014;18(2):182-189. doi: 10.1097/LGT.0b013e3182a577c7

Insinga RP, Liaw KL, Johnson LG, Madeleine MM. A systematic review of the prevalence and attribution of human papillomavirus types among cervical, vaginal, and vulvar precancers and cancers in the United States. 

. 2008; 17(7):1611-1622. doi:10.1158/1055-9965.EPI-07-2922

Li N, Franceschi S, Howell-Jones R, Snijders PJ, Clifford GM. Human papillomavirus type distribution in 30,848 invasive cervical cancers worldwide: variation by geographical region, histological type and year of publication. 

 2011;128(4):927-935. doi: 10.1002/ijc.25396

Petry KU, Liebrich C, Luyten A, Zander M, Iftner T. Surgical staging identified false HPV-negative cases in a large series of invasive cervical cancers. 

. 2017; 4:85-89. doi: 10.1016/j.pvr.2017.10.003

Tjalma WAA. HPV negative cervical cancers and primary HPV screening. 

. 2018;10(2):107-113. PMCID: PMC6516188

Rodríguez-Carunchio L, Soveral I, Steenbergen RDM. HPV‐negative carcinoma of the uterine cervix: a distinct type of cervical cancer with poor prognosis. 

. 2015;122:119-127. doi:10.1111/1471-0528.13071

Cancer Genome Atlas Research Network, Albert Einstein College of Medicine, Analytical Biological Services, et al. Integrated genomic and molecular characterization of cervical cancer.

. 2017;543:378-384. doi:10.1038/nature21386

Completion of balstilimab BLA filing extended to 1H2021. News release. Agenus Inc. December 3, 2020. Accessed December 4, 2020. 

Coleman RL, Lorusso D, Gennigens C, et al. Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer: results from the phase 2 innovaTV 204/GOG-3023/ENGOT-cx6 study. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract LBA32.

The idea that HPV-negative cervical cancer is possible, especially in a disease that is mainly driven by HPV positivity, is not a unanimous opinion. 

HPV-Negative Cervical Cancer: Myth or An Area to Therapeutically Tackle? 

HPV-Negative Cervical Cancer

, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, 

 covers every angle of oncology practice, from  new technology to treatment advances to important regulatory decisions. 

Today, we had the pleasure of sitting down with Maurie Markman, MD, physician and president of Medicine and Science at Cancer Treatment Centers of America, and the editor-in-chief of our flagship publication, 

, to discuss the current scope and global burden of cervical cancer. 

In 2020, there was an estimated 13,800 cases of cervical cancer that were expected to be diagnosed in the United States. Of those, 4,290 deaths would have likely occurred. 

However, some numbers have turned a corner. Cervical cancer incidence and mortality rates have dropped significantly, in part due to screening via the Pap test, which has allowed for early cancer detection. 

Nearly all cervical cancers are driven by HPV and HPV vaccination is recommended in all boys and girls by the age of 13 years. According to the American Cancer Society, HPV vaccines do not protect against all HPV types, emphasizing the importance of adherence to cervical cancer screening guidelines. 

The 5-year relative overall survival rate for cervical cancer in the United States is 66%, but these rate differ for African American women who are aged 50 years old and white women who are younger than 50 years. For those who have localized disease, the 5-year overall survival rate is 92%. 

Another area of cervical cancer that is less discussed, but has been documented, is HPV-negative disease. However, Dr. Markman said that the issue surrounding HPV-negative cancer is that HPV is likely always present, but may simply not be found through testing. 

In our exclusive interview, Dr. Markman discusses the clinical milestone of the HPV vaccine as a means to prevent cervical cancer, the debate on HPV-negative disease, and what efforts can be done on a global scale to reduce the incidence and mortality of cervical cancer.

Podcasts

Dr. Markman discusses the clinical milestone of the HPV vaccine as a means to prevent cervical cancer, the debate on HPV-negative disease, and what efforts can be done on a global scale to reduce the incidence and mortality of cervical cancer.

Markman Talks Vilified Vaccines, Taboos, and Treatment for Cervical Cancer

Maurie Markman, MD, physician and president of Medicine and Science at Cancer Treatment Centers of America, and the editor-in-chief of our flagship publication, 

, discusses remaining questions regarding human papillomavirus (HPV)–negative cervical cancer.

Patients with cervical cancer that is considered HPV negative could actually be HPV positive, Markman explains. Although other cancers, such as lymphomas and sarcomas may affect the gynecologic region, cervical cancer is frequently caused by the presence of HPV. Notably, patients with HPV-negative disease may have low HPV expression of 1% or less that traditional screening methods may miss, Markman says. Additionally, HPV that is in mitochondrial DNA can be just as detrimental as HPV that is within the genome, says Markman. 

The relationship between cervical cancer and HPV expression is different from that of lung cancer and smoking, Markman says. Patients who smoke tobacco have a significantly increased risk of developing lung cancer; however, many never smokers can develop the disease as well. Conversely, HPV is not as easily documented because a patient who tests negative for HPV may in fact be positive, concludes Markman.

Videos

Maurie Markman, MD, discusses remaining questions regarding human papillomavirus–negative cervical cancer.  

