Expert Highlights Latest Advances, Ongoing Trials During Cervical Cancer Awareness Month

Noelle G. Cloven, MD

Cervical Cancer Awareness Month, which is recognized every January, shines a light on an important area of unmet need in gynecologic oncology. Although great strides have been made in terms of reducing the number of patients diagnosed with cervical cancer as well as the incidence through screening and vaccinations, the challenge of access to care remains, and a major area of unmet need includes patients with recurrent or metastatic disease.

Pembrolizumab (Keytruda), the immune checkpoint inhibitor, received FDA approval in June 2018 for the treatment of patients with advanced PD-L1-positive cervical cancer, generating excitement for a new treatment option in this patient population, following the prior approval in 2014 for bevacizumab (Avastin); this agent was approved in combination with paclitaxel and cisplatin or paclitaxel and topotecan as treatment of patients with persistent, recurrent, or metastatic disease.

In order to continue improving the outcomes for patients with cervical cancer, particularly those with advanced disease, many clinical trials remain ongoing or will begin recruitment soon for a number of new therapeutic approaches that appear promising. Some of these treatments have demonstrated positive results in other cancer types, suggesting there may be hope for these new agents, including targeted therapies and immunotherapies, in the cervical cancer space.

In an interview with Targeted Oncology, Noelle G. Cloven, MD, gynecologic oncologist, Texas Oncology-Fort Worth Cancer Center, and associate chair, Gynecologic Research Program, The US Oncology Network, discussed the current cervical cancer treatment paradigm, the unmet needs that still remain to be addressed, and encouraging new directions of research in clinical trials in honor of Cervical Cancer Awareness Month.

TARGETED ONCOLOGY: What is the prognosis like for patients with cervical cancer, and what are the current treatment options?

Cloven: I think it's important that you start with saying that this is a huge problem worldwide, and here in industrialized countries, we've made great strides for decreasing both the numbers of patients who get cervical cancer and also the incidence. Through screening and vaccination, the numbers have decreased, but we still have a big problem with patients who don't have access to care. That's 1 of the biggest risk factors for getting cervical cancer, [such as] not having had a pap smear.

The prognosis depends a lot on what stage you are at in diagnosis. If you have an early-stage cervical cancer, a lot of times we're able to do a hysterectomy. Sometimes we can do the hysterectomy using minimally invasive surgery if the cancer is small enough. If the cancer is large, there were recently 2 trials that showed inferior outcomes of minimally invasive surgery. We're back to doing open surgery which just means a laparotomy for cervical cancer. There is a difference based on the size of the tumor. If you have anything greater than a 1a/2 cervical cancer, we'll do a radical hysterectomy.

There are some studies that show that you can do fertility-sparing surgery in younger patients, and that's something that's usually done at some of the bigger centers, like MD Anderson and UT Southwestern. If you get beyond a stage 1b/3, which is just a very bulky cervical cancer, you're going to be treating with a combination of chemotherapy and radiation. There were 5 randomized trials back in the 1990s that showed that if we added a low dose of cisplatin weekly to the radiation, patients had better outcomes. The standard of care currently for locally advanced cervical cancer is chemotherapy and radiation followed by a breakthrough therapy.

We just opened a [new] study because there's so many recurrences, even with aggressive treatment for these patients. It's hard to give numbers as far as prognosis because it depends on so many different factors, such as size of tumor, patient factors, faster space involvement, whether there's nodes. We just opened this study here in Fort Worth that's looking at adding immunotherapy, pembrolizumab, to the chemotherapy and radiation upfront for cervical cancer and then continuing it after you're finished with treatment as maintenance to see if we can improve survival.

Finally, the last group would be patients that have either advanced or distant metastasis and cervical cancer, so this is probably the most difficult group. It's a very high unmet need. We're making progress. It's been years ago, but we were finally able to find a chemotherapy regimen that did improve survival. However, it wasn't that long ago that we didn't have many options for patients with either recurrent or advanced cervical cancer, so we found chemotherapy that seemed to help. Then I think it's been close to 10 years ago for the GOG 240 study, so we're looking more at targeted therapy for this sort of situation, and the trial was published in the New England Journal of Medicine. This was a trial of anti-angiogenesis therapy, so using bevacizumab, which is a monoclonal antibody that blocks blood vessel formation, and combining that with chemotherapy. That showed a statistically significant improvement in survival without any impact on quality of life, and so that's become the standard of care, using chemotherapy combined with targeted therapy bevacizumab for either advanced or recurrent cancer.

Based on that trial, bevacizumab was FDA-approved for cervical cancer. Now we're looking at immunotherapy, and pembrolizumab was FDA-approved for patients with recurrent cervical cancer who have failed chemotherapy and have PD-L1-positivity, so that's something that's made a big difference. It's been nice to have something like that to offer patients, [it being] a non-chemotherapy option. We're seeing some results, some positive outcomes, and some success stories for that drug.

We have 2 trials in Fort Worth that are open for patients with recurrent metastatic cervical cancer. One of the theories, based on data from other cancers such as melanoma, is that if you use combined immunotherapy, so not just blocking the PD-L1 receptor, like we do with pembrolizumab, but if you also block the CTLA-4 receptor, you can get a better response rate. We're setting that in cervical cancer, and we're very excited about it. We're hopeful, and so we have another trial right now called the RaPiDS trial (NCT03894215). It's a randomized phase 2, and it's comparing AGEN2034, which doesn't have a name yet but is an anti-PD-1 as monotherapy, versus the combination therapy, which includes the anti-CTLA-4 therapy or placebo.

That study just opened, and it's worldwide. We've started to accrue here in the United States, and we're excited about that clinical trial that the second one that we have is actually, there is a new drug that is on FDA Fast Track right now called AK104, and what's nice about this 1 is that it is a bispecific antibody, so it's a monotherapy, but it blocks both receptors, the PD-L1 and also the CTLA-4. We're currently enrolling patients on this trial (NCT04380805). We're hoping that we get the same results that they've had in other cancers and doing the combined immunotherapy.

The other thing we're getting ready to open is a phase 3 trial using a drug called tisotumab vedotin. This is an antibody-drug conjugate, and so there was a European trial that was presented at ESMO last year that showed very good results, so we're trying to see if we can use this drug and can get better or similar results to investigator's choice of chemotherapy. There are also some other ongoing trials, but we don't have them open here in Fort Worth. However, people are looking at blocking HER2-neu receptors, and there are other areas of targeted therapy.

TARGETED ONCOLOGY: What challenges must we still overcome in cervical cancer?

Cloven: One is the access to care problem. I would also like to see higher rates of vaccination in younger and younger folks, both boys and girls, so working on it from a preventative standpoint, for the early cervical cancer, I think we're in pretty good shape. Of course, we can always look at ways to decrease long term effects of surgery. Fertility sparing, I think, is very important. One thing about cervical cancer is it does tend to affect younger patients than some of the other cancers we see in the got gynecologic oncology community, so we do have people that come in, late 20s and 30s, or 40s, and there are people who are still interested in childbearing. That's something that we could also improve on.

For the locally advanced patients, I'm interested to see what happens with combining the immunotherapy upfront with the chemoradiation. Also, the maintenance therapy is very interesting because we've seen good results with maintenance therapy in other cancers. If we can find a drug that is tolerable, doesn't cause a lot of side effects, and we can cut down on the risk of recurrence, I think that'd be great.

Like I said, the biggest unmet need is the patients with recurrent or metastatic disease, and we're making progress with those trials and the immunotherapy. It seems to be progressing more rapidly than it had in the past.

TARGETED ONCOLOGY: What advice would you like to share with the community oncologist seeing patients with cervical cancer?

Cloven: I would say that referral to a gynecologic oncologist is very important. If they're a surgical candidate, they would need to have specialized surgery, or they could need radical surgery if they have metastatic disease. Consider a clinical trial, as that would be an opportunity for patients to get access to some of these targeted therapies before they're even potentially FDA-approved, and they're showing a lot of promise right now.

TARGETED ONCOLOGY: What message would you like to share with your fellow colleagues in the field in honor of Cervical Cancer Awareness Month?

Cloven: I'm very excited about the trials that we have, and you can go on ClinicalTrials.Gov and search clinical trials to look and see what's available. It's always good for patients to have a good understanding of what their options are, and even if they choose standard treatment, there are ways with targeted therapy that we can improve patient outcomes across the board. We may find that even for the earlier stage patients, that helps, but right now, we do know, for the advanced patients, that if you do targeted therapy, you can get better outcomes.