FDA Grants Pembrolizumab Priority Review for TMB-High Tumors
April 07, 2020 04:24pm
By Lisa Astor
In an interview with Targeted Oncology, Robert L. Coleman, MD, FACOG, FACS, discussed the importance of molecular testing in ovarian cancer and how the treatment landscape will continue to evolve in tailoring treatment to patients based on the biology of their tumors, which was the topic of his lecture at the 2020 Society for Gynecologic Oncology (SGO) Annual Meeting.
While statistics indicate that new cases of ovarian cancer and death rates in this disease continue to decline, researchers note that the prevalence of ovarian cancer continues to rise. This suggests that women are living longer than before with this disease, and this could be attributed to the major advances in the field over the last few years.
A major topic in the treatment landscape now is personalized medicine by selecting the right agent for the right patient. This often requires some form of molecular testing to understand the biology of the patient’s tumor. With better knowledge of an individual patient’s biology of their disease, physicians can select targeted therapies or other treatments that are more likely to improve their outcomes.
Most recently, the FDA granted approval in April 2020 to niraparib (Zejula), a PARP inhibitor, for the frontline treatment of patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum chemotherapy. The approval was based on data from the phase III PRIMA study (NCT02655016), which demonstrated an improvement in outcomes for patients treated with the study drug and consistent benefit for select mutational groups.
This underscores the expanding need to test patients with ovarian cancer. As targeted therapies, immunotherapies, and potential combinations come to the forefront of the treatment landscape in clinical trials, treatment can be individualized based on findings from the molecular profiling of patients with ovarian cancer.
“With the recent approval of niraparib in patients with frontline ovarian cancer who had responded to induction treatment for maintenance therapy, we are now expanding our reach of using targeted therapies in a much broader audience of patients,” Robert L. Coleman, MD, FACOG, FACS stated.
In an interview with Targeted Oncology, Coleman, chief scientific officer, The US Oncology Network, discussed the importance of molecular testing in ovarian cancer and how the treatment landscape will continue to evolve in tailoring treatment to patients based on the biology of their tumors, which was the topic of his lecture at the 2020 Society for Gynecologic Oncology (SGO) Annual Meeting.
TARGETED ONCOLOGY: Can you speak to the improvements that have been made to technologies for testing that have allowed for more personalized approaches?
Coleman: The primary advance we are seeing with oncology right now is in the identification of the elements that are considered critical to the cancer biology. We have known for years that there are several markers of disease, and we are learning now that we are able to interrogate a vast domain of different types of alterations in a way that we can isolate whether or not they are relevant to the biology of the specific tumor. For instance, we can find estrogen receptors on ovarian cancer cells, but that doesn’t mean anything to ovarian cancer development, progression, metastases, and response to the anti-estrogen therapies.
Now we are gathering a much deeper knowledge of the mutations and signaling so that the entire mutanome and secretome of these specific alterations and how they interact and relate to not just the cancer cell but all the cells in the microenvironment. Taking that 1 step further, which I spoke about in my lecture at the SGO meeting, is how the soil may be altered in a way that is more inducive for cancer growth in the metastatic environment and what kind of changes happen along the way that could potentially be altered. The science of understanding the biology is now being translated into the introduction and efficacy of new compounds. That is what we are learning now, and that is what has been so revolutionary over the last couple of years.
TARGETED ONCOLOGY: Do you believe physicians are testing as often as they should in this space?
Coleman: That is a really important question. Not all the elements I mentioned of the tumor biology are predictive, so I mean that while they may be associated with prognosis, using a drug that targets the prognostic factor may not actually lead to an advance or benefit in their treatment. We have very few of those, although they are starting to emerge. The ones that have been most successful is the use of PARP inhibitors, and those are tied to our ability to measure homologous recombination deficiency (HRD) first by understanding the germline, secondly by understanding the somatic alterations, and thirdly by identifying this reflection of having global HRD in the tumor that is not necessarily associated with a specific tumor. That is an easy way to look at the predictive biomarkers.
Are we under or over testing? That is hard to answer because we don’t have a lot of drugs linked to a specific alteration. There are some notable examples, such as in endometrial cancers we have the microsatellite instability (MSI)-high status as a marker for the use of pembrolizumab (Keytruda), which is now applied across the board and is seen in some patients with ovarian cancer. We have also seen some interesting activity with the expression or overamplification of the HER2 neu mutation where some of these agents are starting to show efficacy. We are beginning to expand out of the PARP world, but the idea is that the testing frequency right now is that most people are routinely getting a minimum of germline testing but because of the new indications, they are also getting somatic evaluations for all newly diagnosed ovarian cancer cases.
The question that comes up frequently is, how much more testing do we need to do? Should we do it at every line of therapy? I sense that we do not have enough attributable targeted therapies yet to be able to want to expand it like we are doing in lung cancer, for instance, where there are multiple drugs linked to a specific alteration in the tumor microenvironment. The world changes, though, and as we keep moving our discoveries forward, there is an opportunity for maybe more testing or different types of testing that should be done as time goes on.
TARGETED ONCOLOGY: What are some of the latest updates that have been made with targeted therapies and combinations in ovarian cancer?
Coleman: There are a lot of combinations that are of interest, and I think that we are starting to see, as we have explored the value and role of single-agent PARP inhibitors beginning in the recurrent setting and moving to the frontline setting, the next wave of these trials will look at combinations that might make sense. However, there is also a fair amount of work being done in looking at other new therapies, such as antibody-drug conjugates, that are working their way through with slightly different tumor targeting.
We also have trials trying to take advantage of what we know about the tumor biology when resistance develops. At SGO, there were a couple of small trials looking at alternative mechanisms targeting the anti-angiogenesis pathway, 1 with bevacizumab and another with a bispecific antibody that combines CTLA4 targeting with an anti-VGEF targeted therapy. We are also exploring the role of how different elements in the cell cycle can be altered to actually potentially take a homologous recombination proficient tumor and make it vulnerable to a PARP inhibitor where we wouldn’t expect them to work. Those are some interesting combinations that are up and coming, and we will see some of these as they develop.
At SGO, we also saw some information regarding bevacizumab with niraparib. This is an opportunity to see how this combination will work, similar to what happened with bevacizumab and olaparib in the frontline setting. That trial was presented. We are also trying to evaluate exactly where immunotherapy fits. We know it probably has a role, but we are not exactly sure how. At SGO, we saw the results of the JAVELIN 100 trial, which is a 1,000 patient trial looking at different chemotherapy strategies using avelumab, not only in combination with chemotherapy but also combined with chemotherapy plus maintenance.
We are still trying to figure out exactly where all those assets fit, but this is exciting because we have even more options. With the recent approval of niraparib in patients with frontline ovarian cancer who had responded to induction treatment for maintenance therapy, we are now expanding our reach of using targeted therapies in a much broader audience of patients.
TARGETED ONCOLOGY: Where do you see personalized medicine heading in this space?
Coleman: I think of personalized medicine in a broader sense, and that is the individualization of treatment, so the right drug at the right time in the right patient. That premise still holds today, so where we are going with this is both on the discovery side, so identifying which factors are relevant, and the effector side, so which ones change the biology and provide an outcome that is positive for patients. That is where we are going, and because both of those are actively being done, the story is continuing to be written.
Where we are going is taking known assets and determining how to best leverage them while we are doing discovery of the types of patients who would best benefit from them. We are also doing work on identifying new assets to bring into the equation. We are very hopeful that as we understand more about the biology, this will lead to more individualized therapies that are targeting processes that are relevant to the biology.
TARGETED ONCOLOGY: What is your key takeaway on the treatment landscape of ovarian cancer now?
Coleman: The thing to remember in all of this is that there are raw statistics that people quote all the time, such as new cases, deaths, most malignant, and highest mortality, but those things don’t tell the whole story. They are important to understand, but if anything, we have seen over the last several years a decrease in both the incidence and death rates of this disease. They have gone down, not a lot but they have trended down over time. However, what has changed remarkably is prevalence. Prevalence is the statistic of how many women in the United States right now have ovarian cancer.
With declining rates of incidence and parallel rates of mortality, why are we having more patients with disease? It doesn’t make sense. The only way that can happen is if patients are living longer with their disease, so the fruit of our efforts in discovery, individualized therapy, participation in clinical trials, and having access to expert care is bringing the opportunity for an individual patient to survive. That is what our ultimate [goal] is. Prevalence has increased by almost 40% in the last 10 years, so it means we have more patients to manage, but it also provides an important resource that we can continue to try to advance the field and move the needle so we can cure more women with this.