Although immunotherapy’s use in ovarian cancer lags other cancer types, Matthew Powell, M.D., believes there is still promise for checkpoint blockades in this field, likely in combination with other agents.
Although immunotherapy’s use in ovarian cancer lags other cancer types, Matthew Powell, M.D., believes there is still hope for checkpoint blockades in this field, likely in combination with other agents.
Powell is a professor of obstetrics and gynecology and chief of the Division of Gynecologic Oncology, Washington University School of Medicine, at Siteman Cancer Center in St. Louis. He sat down with OncLive, a sister publication of CURE, to discuss the potential of immunotherapy for the treatment of this disease now and in years to come.
Can you give an overview of immunotherapy in ovarian cancer?
Immunotherapy is an emerging area within gynecologic malignancies. We now have approval for therapy for our microsatellite instability (MSI)-positive cancers, mostly that being endometrial cancer, but a small cohort of ovarian cancers will be MSI-positive.
There's a lot of interesting enthusiasm for developing this further. The initial phase 2 studies looking at efficacy in our recurrent ovarian cancer patient population has been a little bit disappointing, with our response rates in the single digits or teens. It prompted a lot of interest in investigating combinations. Whether those combinations are combined with chemotherapy, which we know induces neo-antigens. We used to think that maybe chemotherapy would damage the immune system and make immunotherapy not work. But it seems to be the opposite, and we have some data from lung cancer that makes that look to be a compelling combination.
We're also looking at combinations of anti-VEGF strategies in combination with immunotherapy, PARP inhibitors combined with immunotherapy and moving therapy not from recurrent, resistant disease, but moving it to frontline therapy. That's really the trend within gynecologic malignancies at this point. So, I think it's a very exciting time for us.
Can you discuss some of those disappointing studies for immunotherapy in gynecologic cancer?
There has been several phase 1 and 2 studies in platinum recurrent ovarian cancer. Obviously when I say ovarian cancer, I mean fallopian tube cancer, primary peritoneal carcinoma. Some of these studies have been as small as 12 patients, some as large as over 300 patients.
With our four key PD-1, PD-L1 inhibitors, if we look at Tecentriq (atezolizumab), that was a relatively small study that evaluated about two out of every eight patients showed response in that stage 1b study, which is a 25 percent response rate, but based on very small numbers. But it's compelling and it is showing that there are some patients that do seem to respond. And when they do respond, they do so for quite some time. So there are some signals there.
Our largest study, which is the Keytruda (pembrolizumab) study, had over 300 patients. The response rate ended up being about 8 percent for that population. I don't know if there's a big difference when we look at cross-trial comparisons and such. But as far as Opdivo (nivolumab), Bavencio (avelumab) falling in between those, with 15 and 11 percent response rates, respectively. Again, (that’s) based on 20 and 75 patients in those studies.
How far along are any of the immunotherapy plus chemotherapy or PARP inhibitor studies?
There's a lot of them. When we look at these combination studies, we have several that are in development, so they're starting to enroll patients. The one study that has been reported. The TOPACIO, or KEYNOTE-162 trial, was a combination of a PARP inhibitor, Zejula (niraparib) combined with a PD-1 inhibitor, Keytruda. This trial involved 36 patients and was quite exciting because certainly we started to see a signal. Over half the patients seemed to have some level of at least stable disease or response of some disease control. And that was both in wildtype patients, as far as their BRCA status, and in the mutated BRCA1 and BRCA2 patients.
Recently, tumor mutational burden has been looked at in lung cancer as another potential biomarker for immunotherapy. Do you foresee that something similar could be done in ovarian cancer?
Tumor mutational burden is very much being looked at. We look at mutations per megabase, and that's typically how we'll report that. There was a series that came out of a compilation of several trials, putting that biomarker together. It really looked like that maybe that could be a pretty good predictor of who is going to respond, at least in a wide variety of tumors.
Specifically, in ovarian cancer, is that ready for primetime yet? Probably not. It doesn't meet the criteria of some of the trials that are ongoing, but that's certainly something we're looking at.
What impact do checkpoint inhibitors have on the MSI-high population?
About a third of our patients with newly diagnosed endometrial cancer will have microsatellite instability or mismatch repair deficiency. We can find that by testing either with immunohistochemistry, so for the four “big players” in mismatch repair, testing those genes versus doing microsatellite instability with sequencing. That can be done with next-generation sequencing now.
We do find upwards of 40 to 60 percent response rate in that population. The really exciting thing is that they are very durable responses. Yes, it’s a little rarer in our ovarian cancer population, it does tend to be the endometrioid and the endometriosis-associated cancers that are leading to that type of defect. So, it's worth looking. We need to find these patients. We see responses. Anecdotally, I have one patient who has done very well, and we would not have guessed that she had that deficiency and now I test everybody.
Where do you see the role of immunotherapy going in five years from now?
The future of immunotherapy is quite exciting. Four or five trials are putting it early on in the care of these patients. And I hope that we're going to see more cures. We don't use that word very often in ovarian cancer, but by giving more of these things upfront, we may be able to find all the weaknesses of these cancers and hopefully lead to more patient cures.
In five years, we'll have a lot of data out. Many of these upfront trials will be reporting and it should be some exciting times.