Clinical Trials and Prospective Agents in Ovarian Cancer

Robert L. Coleman, MD:The key piece that I think probably should be addressed at every decision point for therapy is whether or not the patient’s eligible for a clinical trial. We cannot understate this, and we cannot underestimate the benefit. So, a patient like this who’s young, who has good performance status, and has a disease that has already demonstrated that it’s not responding like we would anticipate—and she has already gone through a couple different lines of chemotherapy—she’s a very good candidate for a consideration of clinical trial. Fortunately, we have a number of clinical trials that she would be eligible for. But I want to highlight that it’s absolutely critical at every treatment decision point that a clinical trial option be at least addressed. There are many places around the country where patients can now participate in clinical trials, and it’s ultimately the only thing that’s going to move the needle on expectations for outcomes not only for the patient herself, but also future patients.

I mentioned that clinical trials were a good option and a consideration for this patient, and I think that there are a number of very interesting compounds under development. Fortunately, we have a number of clinical trials that a patient could participate in. And I would say that those trials have centered around 3 specific areas that we’ve already mentioned—PARP, angiogenesis, and immunotherapy.

So, the immuno-oncology agents that we’ve seen in this setting have had kind of limited outcomes as single agents. And so, there’s a lot of work being done to try to figure out ways to make this particular disease more immunoreactive, and that’s involving a number of different combinations. There’s a number of combinations that are under investigation trying to amplify or accentuate the relatively modest response rates we’re seeing in single-agent immune checkpoint inhibitors.

Another thing I would mention in the immune oncology angle part of this is that these combinations of these 3 drugs, as I mentioned—PARP, angiogenesis, immuno-oncology—is that they’re being used together. So, they’re being used together as doublets and they’re being used together in triplets trying to figure out whether or not that’s a way to actually accentuate the response rates of each of those individual components.

Now there’s another class of drug out there that’s under pretty mature development, which we call the antibody-drug or antigen-drug conjugates. And there’s one that’s being evaluated in the FORWARD 1 trial, which is an antibody-drug conjugate that targets folate receptor alpha, mirvetuximab. This particular drug actually works kind of like a stealth bomb. It’s attached to the antibody. It has a chemical or chemotherapy warhead. So, the idea is that with expression of folate on the cancer cell as opposed to the non-cancer cell, this would attach the taking into the cell, the cleave, the linker to the chemotherapy, and release the chemotherapy. So, it’s kind of a nice model for delivering chemotherapy agents. And this trial is ongoing and it’s randomizing this novel compound to physician-choice chemotherapy. Kind of similar, as I mentioned, in some of the other clinical trial designs.

Ovarian cancer, we’re learning, is a very complicated disease, and is probably not one disease. Today, we focused on a patient who presented in a typical way but had an atypical recurrence pattern. And there’s a number of obviously different ways that a patient could present and have her natural history. And they’re good fodder for future kind of discussions. But I think the case illustrates some very important factors that should be common no matter what happens.

So, I mentioned family history and the disconnect between that and germline. A young patient should automatically alert that there’s something potentially going on and how to take that kind of family history. The second is that she has epithelial ovarian cancer, and that should be an automatic for germline testing. You know we didn’t have that information, and if we didn’t have that information at the time the patient was seen, we would have been able to get that information.

And we talked about the complexity of choosing surgery, when to do it, and in the context of what’s the optimal chemotherapy. And all of that is still kind of being worked out, but I think we’re starting to center on a standard approach that’s incorporating novel therapy and chemotherapy together, or biological therapy with chemotherapy together. And there’s a number of clinical trials in that space that are being done to investigate what’s the optimal frontline treatment.

And an area we didn’t really talk about but is also becoming more of interest is the term maintenance. So, in our case history, we didn’t get a chance to really delve into the maintenance issue. But there’s a lot of investigative work being done there as an effort to kind of prolong or ultimately reach that goal, as I mentioned, of cure.

Fortunately, in the recurrent setting, we have a lot of options, and that work needs to be continued because, as we know, unfortunately most patients who develop recurrent disease ultimately die from that disease or the complications from that. So, it’s very important for us to continue relentlessly to expand what our options are in that space so that we can ultimately achieve that elusive goal of cure for those patients.

Transcript edited for clarity.

December 2016

• A 38-year old female presented with bloating and pain
• PMH: unremarkable
• FH: no malignancy
• Abdominal/pelvic CT scan: pelvic mass (9-cm) arising from the right ovary, omental cake (15-cm), and extensive peritoneal carcinomatosis
• CA-125: 1027 U/mL
• The patient was diagnosed with stage IIIC epithelial ovarian cancer
• She underwent hysterectomy, bilateral salpingo-oophorectomy, and omentectomy
  • Scattered residual peritoneal nodules (<1 cm) remained following surgery
• Following surgery, treated with 6 cycles of IP/IV carboplatin/paclitaxel
  • After 6 cycles of therapy, CA-125 level declined to 2.5 U/mL
  • Symptoms were ameliorated

March 2017

• Patient reported bloating and abdominal pain
• Lab results showed elevated CA 125 (985 U/mL)
• CT scan confirmed recurrence with ascites and visible disease (2-cm peritoneal mass)
• She was treated with bevacizumab and topotecan for 4 cycles
  • Patient had good response therapy
  • After 4 cycles, she was switched to bevacizumab maintenance

October 2017

• Patient returned with complaint of abdominal pain
• CT scan revealed ascites and several 1- to 2-cm peritoneal masses in the pelvis and upper abdomen