: Dr. Tewari, let’s move on to biomarkers. This first section is about biology, screening, and prevention. You’ve been an advocate of biomarkers, and you have an NIH [National Institutes of Health] grant for biomarkers in cervical cancer. For the practicing clinician, what are the biomarkers that are relevant in treating cervical cancer today?

For treatment, it’s a matter of looking at patients that need to be treated with immune checkpoint inhibitors. Patients with recurrent or metastatic cervical cancer, we calculate a CPS [combined positive score] for looking at their PD-L1 expression of not just the cancer cells, but also the lymphocytes, and the macrophages. We get a score and that can help guide selection of therapy, especially in the second line. As far as other panel testing, if you want to sequence the entire genome, you could get the tumor mutational burden and immunotherapy. PD-L1 expression is the predominant biomarker that’s used in practice today.

: We’re going to talk about a phase 3 trial that’s called KEYNOTE-826, where 89% of the patients were combined PD-L1 score greater than 1+. Of those 11% that are negative, many of those are adenocarcinomas, and at least some of them, are TMB high, tumor mutational burden-high, or MSI [microsatellite instability]-high. By the time you take the 89% that are PD-L1 positive, and then add 2-3% of TMB and MSI, Dr. Pothuri, is it worth testing at all? Or do you say there’s so few patients that are biomarker negative, give a checkpoint to everybody?

 I test because I’ve had some insurance difficulties without having the PD-L1 status to utilize pembrolizumab [Keytruda]. Going forward, given the data from KEYNOTE-826 and the cemiplimab [Libtayo] data, it appears to be efficacious regardless of PD-L1 status. In the future, we’re not going to need to test.

: Yes, that’s likely. Where we are today, it’s the labeled indication, it’s companion diagnostic, and maybe it will evolve. Dr. Huh or Dr. Thaker, looking at the TCGA [The Cancer Genome Atlas], there were EGF [epidermal growth factor] activating mutations and now there’s data saying that in the small proportion that have EGF-activating mutations, you can use a tyrosine kinase inhibitor and would require next-gen [next generation] sequencing. Do you do that or is it hard to get the medication paid for and it’s just a PD-L1-TMB-MSI world?

 In our recurrent patients for cervical cancer, we are doing commercially acceptable testing. We have next-gen sequencing, and a lot of immunohistochemistry, because to your point, there’s that rare patient that could use neratinib [Nerlynx]. It’s even smaller portions of the pie, but for that 1 patient that you’re seeing in front of you, you can make a huge difference.

Yes, we do the exact same thing. It’s become the standard of care, at least at our institutions, to do next-gen sequencing on essentially every cervical cancer patient, particularly in the recurrent setting. We’re looking for mutations that would put them on a clinical trial whether to taper or match. But I agree with Dr. Thaker, we take a similar approach to that. Is it hard? Yes. But is it worth fighting for? Absolutely. And we’ve seen successes that are notable.

Videos

The panel reflects on the current, optimal use of biomarker testing to guide the management of cervical cancer.

What is the Current Role of Biomarker Testing in Cervical Cancer?

: Dr. Thaker, you’ve been a passioned advocate for all levels of special populations. This is a preventable disease. We live now in the pandemic and vaccination is important. What’s the role of vaccination in preventing what Dr. Pothuri said, a virally-induced cancer? Tell us about that.

 It’s critical to know that we’ve had an HPV [human papillomavirus] vaccine that’s been approved since 2006. I wish the United States was as great as other countries have been in vaccination, but we’re catching up slowly. There’s critical work done by the CDC [Centers for Disease Control and Prevention] and ASCO [American Society of Clinical Oncology], looking at our SEER [Surveillance, Epidemiology, and End Results] databases and our cancer databases trying to see the impact of vaccination, and we are seeing a decline especially in our women who have been vaccinated at the ages of 10 to 11. I do think we’re making progress. We’re making progress in the cancers that we can screen for, like cervical cancer, but we’re also seeing a rise of anal and rectal cancers. We need to get the word out about vaccination, but also being proactive with screening for other cancers, too.

: It’s a new indication for head and neck cancer, too. If we’ve learned anything from the pandemic, if you don’t get vaccinated, you might die.

: And if you don’t get vaccinated against HPV, you might die.

 We need to get the word out to vaccinate not only our females, but our males. When we first came out, the stigma was only females, and now it’s all-encompassing and we’ve extended the age of vaccination, not that we’re advising people in their 40s, but we have the indication. We’re trying to get people vaccinated before they’ve been exposed to HPV, which is the key. We need to get the word out.

 Dr. Monk on that topic, countries like Australia that have some of the highest vaccination rates in the world, are making statements that cervical cancer will largely be eradicated in 15 to 20 years. They’ll accomplish it. It’s not a pipe dream. It’s an attainable goal.

 How many cases were in Australia to begin with, 5?

: Enough to be prevented, Dr. Tewari to your point. What’s the problem, Dr. Pothuri? Why aren’t we doing better with vaccination?

 There’s a stigma associated with the HPV vaccine, and it’s unfortunate. People think that it’s sexual in nature and you’re promoting that by saying you can get the vaccine and be safe. It begs to better education of parents because it’s the children that need to be vaccinated. We have to pivot away from that. This is a vaccine that can prevent cancer, probably the most important discovery that we’ve had in GYN oncology, and we need to push that home. We can prevent cancer with this.

: Dr. Warner, you’ve done remarkable things in creating guidelines. Screening is still here, because as they said we’re not vaccinating enough. What are the screening recommendations, whatever you prefer, the U.S. Preventive Services Task Force, the American Cancer Society? What are the guidelines for screening?

 As you know, Dr. Monk, there are slight differences between the Task Force and the American Cancer Society and now even ACOG [American College of Obstetricians and Gynecologists]. There are 3 things for the listeners that are important. One is when do we start screening, and it’s clear that we are raising the age of screening. Not long ago, we started screening at 18 or within 3 years of sexual activity. We increased it to 21, and now the American Cancer Society is espousing starting at the age of 25. Cervical cancer is exceedingly rare and uncommon and arguably unscreenable under the age of 25.

At 25, we have the Pap, but most experts in the U.S. and worldwide want people to use HPV testing, either by itself or in conjunction with Pap. There’s not a single negative phase 3 randomized trial that has demonstrated that HPV is worse or performs equal or less to Pap. If you screen women with HPV, that constitutes about a 70% lifetime risk reduction of getting cervical cancer. At 20 to 30, either getting an HPV test by itself or with a Pap, also known as co-testing, and you screen every 5 years. If you get a Pap, it’s every 3 years. The third thing is to have an end screening, and this is where I profoundly disagree with the recommendations. We recommend cessation of screening at 65, but we’ve published data that demonstrates about 20% of all cervical cancer cases, at least in the U.S., occur in women after 65 years of age. The problem is the majority of those people are on Medicare, and Medicare won’t cover screenings. It’s a major gap in how we screen people. The bottom line, use HPV screening, that’s the best. HPV screening is a better paradigm for screening the general population.

: Yes, test for the virus from the cervix, and women need to keep themselves safe.

A comprehensive review of the current paradigm for HPV vaccination and screening to prevent cervical cancer.

Role of HPV Vaccination and Screening to Prevent Cervical Cancer

 Peer Exchange entitled “Recent Advances in Cervical Cancer Treatment.” We’re sharing a negative phase 3 trial, 2 positive practice-changing phase 3 trials, and a recent approval of the first antibody-drug conjugate in a gynecologic malignancy; this will be a robust discussion. My name is Brad Monk, I’m a gynecologic oncologist from Phoenix, Arizona, and a professor at the University of Arizona and Creighton University, both in Phoenix. I am joined by 4 experts from across the country, and I want to introduce to you Warner Huh.

 Thanks, Dr. Monk. Warner Huh, I’m the chair of ob-gyn at the University of Alabama at Birmingham, practicing gynecologic oncologist, and I am excited to be here.

: My pleasure. I’m glad you could join us. Warner was a former president of the Society of Gynecologic Oncology. He has held every meaningful position, and now he’s chair of ob-gyn and likely leading gynecologic oncologist in cervical cancer screening and a thought leader in treatment. Bhavana Pothuri, greetings, please introduce yourself.

 Hi, I am Bhavana Pothuri. I am a GYN [gynecologic] oncologist at NYU Langone Health and Perlmutter Cancer Center [New York, New York]. I’m a professor there and I’m also the director of GYN oncology clinical trials. I am active with GOG [Gynecologic Oncology Group] Partners and serve as an associate clinical trial advisor for ovarian and endometrial cancers, and have an interest in cervical cancer. Thank you.

: We appreciate your leadership in the GOG Partners program. You’re changing the world, and many of these trials that we’re going to discuss are GOG Partners trials. Krish Tewari, greetings, how are you?

 Great, thank you. My name is Krish Tewari. I’m a practicing GYN oncologist at the University of California Irvine [Orange, California].

: We’re going to discuss more than one New England Journal paper that Dr. Tewari has coauthored, so we’re interested to hear your perspectives. Last, but not least, Premal Thaker.

 Hi, thank you for this opportunity. I’m Premal Thaker. I’m a professor of GYN oncology at Washington University School of Medicine and Siteman Cancer Center in St. Louis, and I am the director of our gynecologic oncology clinical research.

: Washington University St. Louis is one of our top enrolling sites. It’s one thing to talk, and we’re going to talk today, but when it comes to getting things done, Dr. Thaker and her colleagues in St. Louis always do. I’d like to discuss biology and screening. Most people acknowledge that this is a preventable disease. Bhavana, can you talk about the histology’s and the staging for cervical cancer.

 Yes, cervical cancer is important to discuss. It’s the fourth leading cause of cancer death in women worldwide, and over 99% are caused by HPV [human papillomavirus]. It is the causative agent. This is a cancer that affects younger women, most are diagnosed between the ages of 35 and 44. It’s important that we’re having this discussion and focusing on these patients. The majority are classified as squamous cell cancers, about 80%, and the remainder are largely adenocarcinomas.

: There’s a staging system. Dr. Tewari, tell us about the FIGO [International Federation of Gynecology and Obstetrics] staging system. It’s different than what people are used to, the TNM [tumor nodes metastases] staging system.

 We’ve been using FIGO for years to stage cervical cancer, and for a long time it was a clinically assigned staging. If the cancer is involving the cervix, it’s a stage I; if it spreads into the upper vagina or the perimetrial tissues surrounding the cervix, it’s a stage II; if it goes up the pelvic side wall, it’s a stage III; if it’s involving the bladder or rectum, it’s a IVA; and if it’s metastasized, it’s a IVB. Recently, in 2018, FIGO updated their staging to allow for radiographic and/or pathologic evaluation specifically of lymph nodes. We have guidance and can designate a patient with stage III disease by virtue of their lymph nodes, whether they’re positive on pathologic examination or by radiographic imaging. You should denote that with a subscript.

: I like it because it’s the same as endometrial or uterine cancer, right? IIIC1 means it’s in the pelvic lymph nodes, and IIIC2 means it’s in the aortic lymph nodes. There’s not much to remember there.

Experts provide a brief overview of cervical cancer, focusing on the driving biology and FIGO staging system.

Understanding the Biology and Staging of Cervical Cancer

Bradley J. Monk, MD, FACS, FACOG, professor, Division of Gynecologic Oncology, Arizona Oncology (US Oncology Network), University of Arizona College of Medicine, Creighton University School of Medicine at St. Joseph’s Hospital, medical director, Gynecologic Program, US Oncology Research Network, and co-director, GOG Partners, discusses outcomes with pembrolizumab (Keytruda) plus chemotherapy in patients with recurrent or metastatic cervical cancer, as reported in the phase 3 KEYNOTE-826 trial (NCT03635567).

KEYNOTE-826 has evolved the treatment paradigm for front-line cervical cancer by adding pembrolizumab to standard-of-care bevacizumab (Avastin) chemotherapy, according to Monk. The study enrolled 617 patients and met all of its therapeutic end points at the time of the first interim analysis, Monk continues.

Patients in the control arm in this study, bevacizumab alone, experienced similar response rates as have been observed in previous studies, at approximately 48% to 50%, Monk explains. The addition of pembrolizumab improved response rates, increasing them to 66%. Although these data are generating excitement, the goal is tumor control, Monk says. The hazard ratio for progression-free survival was 0.65. 

What is most important in this research is survival and tolerability, and no new safety signals were observed, according to Monk. The results showed more tumor shrinkage, longer tumor control, longer survival, and better patient-reported outcomes, which transforms the standard of care in a meaningful way, Monk says. The median overall survival in the investigative arm has not been met, and at 2 years, 33% more patients were alive. This treatment regimen will likely acquire global regulatory approval and broad reimbursement, Monk concludes.

Bradley J. Monk, MD, FACS, FACOG, discusses outcomes with pembrolizumab plus chemotherapy in patients with recurrent or metastatic cervical cancer, as reported in the phase 3 KEYNOTE-826 trial.

Dr. Monk on Transformative KEYNOTE-826 Data in Frontline Cervical Cancer 

Bradley J. Monk, MD, FACS, FACOG, professor, Division of Gynecologic Oncology, Arizona Oncology (US Oncology Network), University of Arizona College of Medicine, Creighton University School of Medicine at St. Joseph’s Hospital, medical director, Gynecologic Program, US Oncology Research Network, and co-director, GOG Partners, discusses the utility of PARP inhibitors as maintenance therapy in ovarian cancer. 

Of the 9 FDA approvals for PARP inhibitors for use in ovarian cancer, 3 are indicated for use as maintenance therapy in the recurrent setting for patients with platinum-sensitive disease, Monk explains. These patients have to have a response to platinum-based therapy to qualify for maintenance PARP inhibition per the inclusion criteria from the phase 2 Study 19 (NCT00753545) trial, and the phase 3 SOLO-2 (NCT01874353), NOVA (NCT01847274), and ARIEL3 (NCT01968213) trials. Moreover, patients with platinum-sensitive disease are likely to respond to maintenance PARP inhibition irrespective of homologous recombination deficiency or 

Treatment decisions are needed to select between olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca) because the FDA indications are identical, Monk explains. The decision requires a shared and personalized approach between the patient and provider, Monk concludes. 

Bradley J. Monk, MD, FACS, FACOG, discusses the utility of PARP inhibitors as maintenance therapy in ovarian cancer.  



Dr. Monk on the Utility of PARP Inhibitors as Maintenance Therapy in Ovarian Cancer 

Bradley Monk, MD, FACOG, FACS, a gynecologic oncologist at Arizona Oncology, discusses the mechanism of action of VB-111 in patients with ovarian cancer.

VB-111 is a targeted anticancer viral gene therapy that is based on a non-replicating, non-integrating adenovirus 5 vector that contains a transgene expressed solely in angiogenic blood vessels, according to Monk.

The agent has a dual mechanism of action, Monk says. The agent targets endothelial cells, which causes vascular disruption and results in tumor starvation, and induces immune response through local inflammation, Monk concludes.

Bradley Monk, MD, FACOG, FACS, discusses the mechanism of action of VB-111 in patients with ovarian cancer.

Bradley J. Monk, MD, FACOG, FACS

Articles

What is the Current Role of Biomarker Testing in Cervical Cancer?

Role of HPV Vaccination and Screening to Prevent Cervical Cancer

Understanding the Biology and Staging of Cervical Cancer

Dr. Monk on Transformative KEYNOTE-826 Data in Frontline Cervical Cancer

Dr. Monk on the Utility of PARP Inhibitors as Maintenance Therapy in Ovarian Cancer

Dr. Monk on the Mechanism of Action of VB-111 in Ovarian Cancer