Ongoing Research to Move Needle Forward in Gynecologic Cancer Treatment

Robert Coleman, MD

Over the past few years, major clinical advances have been made in gynecologic oncology. The field of ovarian cancer has transformed with several combinations being explored in the phase III setting, and the introduction of immunotherapy into the cervical cancer space has provided a springboard for future development, said Robert Coleman, MD.

But in order to continue to move the needle forward, he said, strategy is key.

In ovarian cancer, the initial approval of olaparib (Lynparza) by the FDA was a gamechanger. Since its initial approval, the PARP inhibitor has been approved for indications as a maintenance treatment, and most recently, for use as frontline maintenance therapy in adult patients with BRCA-mutated advanced ovarian cancer. FDA approvals for additional PARP inhibitors in the maintenance setting, rucaparib (Rubraca) and niraparib (Zejula), followed suit.

“That kind of launched a whole cascade of development strategies that have launched these new drugs and new drug combinations as a way of expanding the portfolio of patients with recurrent ovarian cancer,” said Coleman, who is a gynecologic oncologist at The University of Texas MD Anderson Cancer Center.

However, advances have been made beyond PARP inhibitors, with other areas of research including novel chemotherapy agents, angiogenesis inhibitors, and immunotherapy. The future of this research lies in combining checkpoint inhibitors, antiangiogenic agents, and PARP inhibitors in an effort to improve outcomes.

Beyond ovarian cancer, checkpoint inhibitors are making headway in the cervical cancer space.

“We’ve known for a long time that diseases that are caused by an infection are generally immunogenic, and so, cervix cancer is no exception,” said Coleman. “We know that this is a disease caused by HPV, and we would expect that immunotherapies should have some type of role there if we could figure out exactly how to do it.”

The June 2018 FDA approval of pembrolizumab (Keytruda) as a treatment for patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy, and whose tumors express PD-L1 (combined positive score ≥1) as determined by an FDA-approved test, was a first step in this direction. The next phase, according to Coleman, is to move the agent into an earlier treatment setting. Trials are already ongoing in this area.

OncLive: Could you highlight some of the recent progress made in ovarian cancer?

In an interview with OncLive during the 2019 SGO Annual Winter Meeting, Coleman sat down with us to highlight recent advances made in gynecologic cancers and provide insight into ongoing research to move the needle forward.Coleman: The field of ovarian cancer has undergone a rebirth, in a way, because of the ability for pharmaceutical companies and for investigators to see a path forward for development of new drugs. This has occurred by working with the FDA to identify endpoints that are relevant for patients, as well as endpoints that are relevant for clinical trials. It allowed us to develop these trials in a way that we would have endpoints that would be reachable and meaningful for patients in a timeframe that was acceptable to industry and our industry partners.

With that came, initially, the accelerated approval of olaparib in ovarian cancer. The PARP inhibitors was a big win for us; that has been expanded into multiple different settings. Initially [these agents were being used] just as treatment for a highly selected group of patients, namely those with germline BRCA mutations, now [their use] has expanded to both somatic and BRCA and homologous recombination deficiency. Then, [it moved into] in the settings of our recurrent platinum-sensitive space. We have 3 drugs approved for all comers if they respond to a platinum drug; that has been very nice. It is a good development in a relatively short period of time, coming about in just the last 5 years or so.

From there, because of that precedent, there has been a lot of drugs that have entered into the market; some of these are falling along the lines of other biologicals. Obviously, we have drugs like bevacizumab (Avastin) that have continued to develop. Those combinations are starting to enter the domain. We’re seeing several trials now being done with at least a PARP inhibitor and angiogenesis [in the] space. There have been a couple of those angiogenesis inhibitors, which are in active investigation right now.

Then, we also have drug development down the path of chemotherapy, so there are some new chemotherapy agents. The most exciting of those are drugs that are using a more targeted or directed approach; we call those antibody-drug conjugates (ADCs). Certainly, rituximab (Rituxan) is one [that is furthest along] in development, using the folate receptor alpha expression on tumor cells to direct chemotherapy into the cancer cell. It is kind of a “smart bomb” approach.

Could you elaborate the ongoing trials investigating immunotherapy combinations?

Then, we have immunotherapy, where there is obviously very high interest for a lot of people and a lot of different solid tumor types. Our hope is that we could figure out a way to make these therapies work in ovarian cancer. We know that the single agents are struggling, so now our strategy is to figure out what kind of partners or what kind of patients these drugs might work best in. Right now, there are multiple trials in the frontline, recurrent, and maintenance settings where these immunotherapeutics are being combined with these other exciting elements. Therefore, it’s very exciting to have all this going on at one time.Immunotherapy, antiangiogenics, and PARP inhibitors have all shown promise in this disease and there’s good rationale to think that the drugs might work together as doublets. If you think about the pairs of those 3 drugs, the immunotherapy/angiogenesis inhibitors, immunotherapy/PARP inhibitors, PARP inhibitors/angiogenesis inhibitors—all 3 of those doublets are essentially under development now. There is good rationale for it, because we know that the immune microenvironment for ovarian cancer is one that needs some type of boost to make it more visible to the immune system. Whether it be through an angiogenesis pathway, which is altering the tumor microenvironment for the constitution of the type of immune cells that are present, or through the PARP pathway where we think there is a greater development of neoantigens—due to cytosolic DNA or activation of different pathways, like the cGAS-STING cytosolic DNA sensing pathway—these might actually be a way to improve that potential efficacy in a way that we hope is actually synergistic.

Of course, there are limitations we have with giving chemotherapy with these drugs, which are important for where these drugs are being developed. In the frontline setting, chemotherapy is still the backbone of everything we do. When we’ve proven that angiogenesis inhibitors added to chemotherapy can extend PFS—that led to the ultimate approval of bevacizumab in that setting—when we gave it with an immunotherapy, we haven’t had quite the same robust [response].

Moving onto cervical cancer, what advances have been made with immunotherapy in this space?

However, we know that we can’t give it with many of the PARP inhibitors at full dose. There is 1 PARP inhibitor veliparib, for which there is an ongoing phase III trial that has completed its enrollment. We’re waiting for data to emerge relatively soon; that can be combined with reduced doses of chemotherapy. We can’t just give them all to everybody; we have to strategize where we give them. With the thought being that both primary and maintenance are important in ovarian cancer, we’re now looking at ways of giving induction chemotherapy followed by a maintenance regimen that involves these drugs. We’re looking at ways of incorporating the immunotherapy or the angiogenesis therapy either alone or in combination with chemotherapy, and then doing some form of the doublet or triplet as a maintenance strategy. That’s the kind of strategy for what we can get away with and it’s happening in the recurrent setting as well.It has been reported that these single-agent PD-1/PD-L1 inhibitors have been tested in cervix cancer and one of them—pembrolizumab (Keytruda)—is now approved for PD-L1—positive tumors; that’s a good first step. I wouldn’t say it was a “home run,” because the response rates were relatively low and fall into the same place that we saw with bevacizumab—for instance, when it was being studied in patients with recurrent disease.

However, it is a biomarker-directed therapy and a good starting point for the next step, which is to move it earlier. What we would like to do is to take advantage of that strategy and then move it into that primary adjuvant [setting]. Or, [we could] incorporate it into the frontline setting, where curative therapy is being administered—whether it be with radiation therapy or radiation and chemotherapy. Our strategy at moving immunotherapy into cervix cancer, based on the results that we’ve seen in the patients whose tumors are expressers, is to see if we can improve the efficacy in both the frontline and recurrent spaces. Those trials are ongoing.

Also, immune checkpoint inhibitors are not the full extent [of what’s being done in immunotherapy]. Obviously, there are other compounds that we think are going to be potentially relevant. Data that emerged from the National Cancer Institute (NCI) looking at these therapeutic vaccines for cervix cancer are quite interesting.

We also know that if we can expand the tumor-infiltrating lymphocytes (TILs) that we find in these tumors, we might be able to achieve some responses. Even in our own pilot work with that at The University of Texas MD Anderson Cancer Center, we’ve seen some amazing responses to TIL-based therapy. We’re still kind of working on the details of how to do it best and in a way that’s not associated with excessive toxicity, but we’re showing the proof of principle. Therefore, figuring out—whether vaccines, adoptive cell therapy, immune checkpoint inhibitors, or some combination of them—how those particular modalities fit into the ultimate treatment for this disease is quite exciting and represents a nice area for future development.

In addition to that whole point, we’ve done a lot of exploration for other drugs and therapeutic targets in cervix cancer. We have started to look into the tumor and the microenvironment in more detail, and so, there are some exciting, potential new options as we learn more about individual patient’s cervical tumors and try to do more tailored approaches.

Thus far, there has been at least 1 strategy looking at targeted ADCs—one targeting tissue factor. This is a drug that has actively shown some impressive data in the phase II setting and is now being poised to be looked at in the recurrent setting—either alone against standard of care or in combination with other drugs. Those studies are ongoing in the Gynecologic Oncology Group Foundation. We are very excited about that potential aspect.

What key clinical trials in this space have the potential to move the needle forward?

Then, we have had bevacizumab around; it’s FDA-approved now in combination with chemotherapy for advanced stage or recurrent cervix cancer. We are trying to figure out ways to expand that. Again, since immunotherapy is important in this disease, it makes sense to try to at least move the immune checkpoint inhibitors in combination with that strategy. It wouldn’t be a far stretch to look at chemotherapy plus bevacizumab plus an immune checkpoint inhibitor as a potential development strategy; we are actively pursuing this.In ovarian cancer, the phase III development environment is pretty crowded obviously because there is lots of excitement with many drugs being made by different pharmaceutical partners. The GOG-3005 trial, in which we are looking at the combination of olaparib with chemotherapy, is imminent to report. We’re excited about seeing that potential program.

We launched a trial called ATHENA, which is looking at the combination of an immune checkpoint inhibitor with a PARP inhibitor, and that is a 4-arm trial. It may undergo some modification—we’ll see now with the recent data—but that’s another primary maintenance strategy that is being developed.

I mentioned that the combination of immune checkpoint inhibitors and angiogenesis and PARP inhibitors were being looked at in frontline ovarian cancer. There are several trials out there trying to look at specific combinations. We have the FIRST trial, which is looking at the PARP inhibitor niraparib and the checkpoint inhibitor TSR-042. We have the ENGOT-ov46 and the ENGOT-ov43 trials, which are looking at doublets and triplets of these particular compounds of the PARP inhibitors, checkpoint inhibitors, and angiogenesis inhibitors.

We have the IMagyn050 and GOG-3015 trials, which are looking at that combination of a checkpoint inhibitor plus bevacizumab. We have this great strategy of all these drugs in the frontline space, which will vastly change the environment. Hopefully, this will improve the cure rates, which is something we haven’t talked about in a long time in ovarian cancer.

What is your take-home message?

In cervix cancer, obviously we have trials that are ongoing—some are sponsored by the National Cancer Institute and some are sponsored by industry. We’re looking at chemotherapy in combination with checkpoint inhibitors; that trial is close to launching and have a similar type of strategy, which is looking at this in combination with bevacizumab. As I mentioned, that chemotherapy plus bevacizumab regimen is already proven, so adding atezolizumab (Tecentriq) to it is another ongoing trial to hopefully move that needle as well. There is a lot of phase III work, which is super exciting.Having an inquisitive mind and an investigative spirit is really important. Our patients are an incredible, precious resource. They need to be thanked for their participation on these trials; they’re the only way we move the needle. Investigators in the space have the passion to want to move the needle, but knowing that we don’t have unlimited resources, we need to be smart about how we do the trials and we need to try to accrue them. We’re having more opportunities and we’re getting better at writing our trials, but we want to have a broader participation and to develop the future investigator, and to keep the clinical questions coming.

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