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Bradley J. Monk, MD, FACS, FACOG, discusses key updates in cervical cancer treatment, exciting ongoing research efforts, and emerging approaches that are shaking up the treatment paradigm.
Strategies pairing checkpoint inhibitors with anti-VEGF or anti–CTLA-4 agents or with chemotherapy and radiation are improving outcomes in patients with cervical cancer, according to Bradley J. Monk, MD, FACS, FACOG, who added that the emergence of antibody-drug conjugates (ADCs) and tumor-infiltrating lymphocytes (TILs) has generated excitement in the expanding paradigm.
“The pace of discovery, for the first time ever, is fast,” said Monk. “We had anti-VEGF, bevacizumab, checkpoint inhibitors with chemotherapy and radiation, as well as chemotherapy and bevacizumab with CTLA-4. We also have new therapies, ADCs and TILs. The reason that this landscape so rich is because of the investigators [who are working so hard to improve outcomes].”
In an interview with OncLive, Monk, the medical director of Gynecologic Oncology Research at US Oncology and a professor at the University of Arizona College of Medicine, discussed key updates in cervical cancer treatment, exciting ongoing research efforts, and emerging approaches that are shaking up the treatment paradigm.
OncLive: Could you speak to what the surgical paradigm looks like in cervical cancer?
Monk: Surgery is still an important modality. When caught early, cervical cancer is almost always curable. Early diagnosis is a result of Pap testing. We don't say “Pap smear” anymore because we don't smear it, we test. As a part of that, we can actually test for the human papillomavirus. The best way to prevent this is with a vaccination; however, we're not vaccinating enough, so we’re seeing very little reduction in the incidence of cervical cancer since vaccines were rolled out in 2006. We really need to do better.
However, when caught early, surgery is an option. We can even do surgery now in a fertility-sparing way. When it's a serious lesion, an open hysterectomy may be necessary. It's one of the few cancers where minimally invasive surgeries, whether it be laparoscopic or robotic, may not work, allowing the cancer to continue to spread. We also look at surgery in every setting. Generally, the lymph nodes are biopsied. We can use dye to get a few sentinel lymph nodes or take all the lymph nodes out. If it’s a serious cancer, after surgery if the lymph nodes are negative, [we use] radiation. If it’s not a serious cancer, then [we do] nothing. However, if [the cancer is still] in the lymph nodes, then [we use] chemotherapy and radiation. After radical surgery, you [can do] nothing, observation, radiation alone, or radiation and chemotherapy.
Beyond surgery, what approaches are being used?
Some cases are too advanced to resect; these are locally advanced cancers and they are primarily treated with chemotherapy and radiation. Cervical cancer was the first solid malignancy ever to be cured with radiation. In fact, Marie Curie, who championed the use of radiation in medicine, received 2 Nobel Prizes. This is a historic cancer, but we're not doing enough in the metastatic setting where chemotherapy or systemic therapy is the norm.
Are there any emerging therapies on the horizon?
The best time to impact any illness is in the beginning. In locally advanced stage II and III disease, where chemotherapy and radiation are used primarily in cancers that are too big for surgery, you can also add immunotherapy to [the mix]; this strategy has been used in several other solid tumors.
Two global trials are being done in that setting. One is called CALLA, which is adding durvalumab (Imfinzi) to chemotherapy and radiation, and then another is [KEYNOTE-]A18, which is adding pembrolizumab (Keytruda) to chemotherapy and radiation. As the cells die from chemotherapy and radiation, the immune system it can be sensitized, and then [by adding] the checkpoint inhibitor, [you may see] a higher response rate and a potentially even higher cure rate; that’s what I’m most excited about.
Pending positive results with these approaches, do you anticipate any sequencing challenges?
In the setting of metastatic disease, when the cancer has spread to the lungs, the liver or the lymph nodes, the standard treatment is a regimen called GOG 240. Data published in The New England Journal of Medicine by my colleagues and I, led to the first FDA approval of any targeted therapy in cervical cancer in 2014. This approach added the antiangiogenic bevacizumab (Avastin), a humanized monoclonal antibody against VEGF, to platinum- and taxane-based chemotherapy. Essentially, we took a doublet, let's say cisplatin and paclitaxel, and turned it into a triplet [by adding] bevacizumab. That triplet is now the global standard; it has been approved for use around the world. Ultimately, it improved survival by about 4 months; this is not enough. As such, my friends and I had an idea that, if immune checkpoint inhibitors are so great, why don't we just add immunotherapy to [that triplet]?
In fact, there are 3 ways to make immunotherapy better. First, there is chemotherapy and radiation, which we talked about this a frontline opportunity. Next, we could add an anti-VEGF therapy and, as you know, anti-VEGF [plus] anti–PD-1/PD-L1 is an approved regimen in tumors such as renal cell and lung cancer. Now [we are examining] platinum/taxane/bevacizumab with a checkpoint inhibitor; those studies are ongoing. One study adds pembrolizumab (Keytruda) to that and the other adds atezolizumab (Tecentriq).
The pembrolizumab study is called KEYNOTE-826 and the atezolizumab/bevacizumab study is called BEATcc and both of the trials are enrolling around the world. After chemotherapy and radiation with or without a checkpoint inhibitor, and platinum/taxane/bevacizumab with or without a checkpoint inhibitor, now you get to second-line metastatic disease. This is where the whole field becomes unstable; although, there has been a lot of discovery. There is no standard therapy for the second line but 4 strategies are used in this setting. Single-agent pembrolizumab got approved in the second-line metastatic space in June 2018. The response rate with this agent was only 14%, which is not very exciting, but it proved to be durable.
Now, people are trying to add medications to single-agent pembrolizumab or a PD-1 inhibitor.
They're also trying to get pembrolizumab or a similar checkpoint inhibitor approved around the world. The accelerated approval with pembrolizumab was only granted in the United States; the rest of the world wants checkpoint inhibitors in the second-line setting. There's a study called EMPOWER Cervical-1, which randomizes patients to receive either the checkpoint inhibitor cemiplimab (Libtayo) or physician's choice of chemotherapy. With regard to the chemotherapy, there are no standards, so there are many opportunities here; topotecan or vinorelbine could be used, but none of those medications work [well]. That study is still ongoing.
The other option is to add an anti–CTLA-4 inhibitor to a PD-1 inhibitor. Remember, there are 3 ways to make checkpoint inhibitors work better: chemotherapy and radiation, anti-VEGF, or anti–CTLA-4. In March 2020, nivolumab and ipilimumab received FDA approval for use in hepatocellular cancer. We believe this could also work in cervical cancer; we know it works in melanoma, lung cancer, and so on. We have an attempt to make checkpoint inhibitors work better in the second-line setting. Data [with this combination] that were presented at the 2019 ESMO Congress [showed activity with this approach].
What challenges should be addressed going forward?
Cervical cancer clinical trials, at their core, are difficult. These women are younger than the traditional patient with gynecologic cancer; they are typically in their forties or fifties and frequently, they still have kids at home. They are matriarchs; this is very different from the 60- or 70-year-old patients with endometrial cancer. They're also under resourced. The screening and vaccination paradigm did not provide an acceptable opportunity for them. At the core, cervical cancer research is very complicated.
Where is future research focused?
We need new agents. We need to get checkpoint inhibitors around the world, add them to chemotherapy and radiation, to GOG 240, and maybe even to CTLA-4 and anti–PD-1. We’re trying to think outside of the box.
If you look at anticancer therapies as a class, ADCs are becoming very common. You see what they're doing in liquid tumors; another breast cancer approval was recently announced. Genmab and Seattle Genetics are working in collaboration on an ADC, which we're excited about. That study is in clinical trials, and the target is tissue factor; it’s part of the coagulation cascade. The agent is called tisotumab vedotin. The vedotin payload has been very effective in other solid tumors. Emerging data may even lead to an accelerated approval in the second-line setting for patients with metastatic disease.
Finally, there is the idea of engineering T cells. Although, we don't know how to engineer T cells against a cervical cancer lesion yet. We've taken a different approach where we cut a 1.5 cm piece of the tumor out and there are T cells in there that are already engineered by the patient to fight that particular metastatic focus. We isolate the cells that are fighting it, which are called TILs and we expand them and make billions of them. We then do marrow conditioning chemotherapy, killing the other T cells in the patient, and reinfuse these isolated and expanded TILs and give high-dose interleukin-2 to help them grow. I'm going to use the phrase: The idea is not crazy, it’s just innovative.
A report from the National Institutes of Health showed that the approach may have cured some patients. Moreover, a study by Iovance Biotherapeutics is being run around the world. We got breakthrough designation, for the first time ever, for a response rate of more than 40% in the first cohort. As such, this is a very exciting therapy. It’s a study that we open at St. Joseph’s; I just saw a patient who was treated and is responding.
The pace of discovery, for the first time ever, is fast. We had anti-VEGF, bevacizumab, checkpoint inhibitors with chemotherapy and radiation as well as chemotherapy and bevacizumab with CTLA-4. We also have new therapies, ADCs and TILs. The reason that it's so rich is because of the investigators.