Matulonis Highlights Novel Strategies, Emerging Agents in Ovarian Cancer

Ursula A. Matulonis, MD

Physicians are beginning to think about recurrent ovarian cancer differently, in terms of emerging therapeutic approaches, a refined focus on disease histology, and reevaluating the definition of platinum resistance, according to Ursula A. Matulonis, MD.

One such novel strategy was presented at the 2018 ESMO Congress. In a prospective phase III trial, the combination regimen of pegylated liposomal doxorubicin and carboplatin with bevacizumab (Avastin; CD-BEV) was found to significantly improve progression-free survival (PFS) versus carboplatin/gemcitabine and bevacizumab (CG-BEV) in patients with recurrent ovarian cancer whose first recurrence was ≥6 months following frontline platinum-based chemotherapy.

Results showed that the median PFS was 13.3 months (95% CI, 11.7-14.3) in patients randomized to CD-BEV versus 11.7 months (95% CI, 11.1-12.8) in patients treated with CG-BEV (HR, 0.807; 95% CI, 0.681-0.956; P = .0128).

OncLive^®: How would you define the recurrent ovarian cancer setting?

Could you highlight the available data on adding bevacizumab to standard chemotherapy?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Ovarian Cancer, Matulonis, chief, Division of Gynecologic Oncology at Dana-Farber Cancer Institute, professor of medicine at Harvard Medical School, highlighted available and emerging treatment options and strategies for patients with recurrent ovarian cancer.Matulonis: There are a lot of exciting things going on in this realm, so that is pretty exciting. There are new options for patients—options that are FDA approved. I focused mostly on those [in my presentation], and I gave some updates on new trials that may have been presented recently with exciting new drugs and new strategies to treat [patients with] recurrent ovarian cancer. I presented data on adding bevacizumab to standard chemotherapy—so either carboplatin/gemcitabine or carboplatin/pegylated liposomal doxorubicin for recurrent platinum-sensitive ovarian cancer. There was a trial presented at the 2018 ESMO Congress of carboplatin/pegylated liposomal doxorubicin/bevacizumab versus carboplatin/gemcitabine/bevacizumab. And, I reiterated older results of the AURELIA trial, which looked at the addition of bevacizumab to nonplatinum-based chemotherapy for patients with platinum-resistant cancer. These are not new data; we are thinking about recurrent ovarian cancer a little differently.

Could you expand on the study that was presented at the 2018 ESMO Congress?

How would you describe the potential of immunotherapy in this setting?

What are your thoughts on the JAVELIN Ovarian 200 trial of avelumab (Bavencio), in which the PD-L1 inhibitor missed the PFS endpoint?

We have typically thought about platinum resistance as having a platinum-free interval for less than 6 months and platinum sensitivity for more than 6 months, but our paradigm is changing. We are thinking about patients who are appropriate and not appropriate for platinum-based therapy. Those definitions are probably definitely going to be seeping into our clinical trial eligibility, but they haven’t quite been defined that way yet. However, it’s a good way of thinking about it because there are patients who may be defined as platinum resistant in the true sense of how the definition was previously, who are really going to have platinum-sensitive disease.This was predominantly a European study that showed benefit to the carboplatin/pegylated liposomal doxorubicin/bevacizumab arm compared with carboplatin/gemcitabine/bevacizumab. The primary endpoint was PFS. The result was a little more striking for patients who had not received prior bevacizumab. For those who had received prior bevacizumab, there was a statistically significant difference but it wasn’t overwhelming. We do have 1 FDA approval of immunotherapy for women who have recurrent gynecologic cancers, and that is pembrolizumab (Keytruda). It’s a broad approval for patients who have microsatellite instability-high (MSI-H) cancers; we see that more in recurrent endometrial cancer and occasionally, we will find it in recurrent ovarian cancer. Most pathologists are not doing MSI testing, but a lot of the next-generation sequencing tests will look at MSI to sort of define a cancer as microsatellite proficient versus instable. Somatic tumor profiling might give you the sense that this patient may have an MSI-H tumor. This was a phase III study with a primary endpoint of PFS and overall survival looking at avelumab alone, pegylated liposomal doxorubicin by itself, or the combination. It did not meet its primary endpoints to show benefit of the combination over the single agents. We await final discussion of that data at [an upcoming medical] meeting, and then also final publication of the results.

What factors do you consider when making therapeutic decisions for patients with recurrent disease?

What updates can you share about some other recently presented trials?

What other messages would you like to relay to physicians treating these patients?

The results [were broadly discussed] in a press release in November 2018, but the question is, “Is that disappointing or not?” It is what it is, and we know that single-agent immune checkpoint blockade, either PD-1 or PD-L1 inhibitors, have pretty low response rates overall at 8%, 9%, or 10%. Again, I don’t think that was surprising just because of the inability of single-agent checkpoint blockade to have a major impact in this cancer—it was kind of an overall standpoint.It depends on the individual patient’s cancer status: where her cancer is, what symptoms she has, what her prior treatment was, the reaction to prior treatments, prior toxicities, and her underlying medical problems. All of those clinical items have to factor into how you make the decision. I tend to use bevacizumab in the more platinum-resistant patients as opposed to using in the platinum-sensitive patients, because of the use of PARP inhibitors. Unfortunately, there lacks a biomarker for the use of bevacizumab.I spoke on mirvetuximab soravtansine, which is an antibody-drug conjugate against the folate receptor alpha. There is a phase III study called FORWARD-I, which is expected to report out in the first half of 2019. We certainly await those results. We have tested that drug in addition to bevacizumab, and also in addition to pembrolizumab with carboplatin, so we and several other groups around the United States have been able to employ this drug with our patients. There are also PARP inhibitor combinations with antivascular drugs that my colleague Joyce Liu, MD, has done a lot of work with—a drug called cediranib—and Panagiotis A. Konstantinopoulos, MD, has done work on PARP inhibitors plus immuno-oncology agents, such as PD-1 inhibitors. [There is also research with] PARP inhibitors plus avelumab, so PD-L1 inhibition, as well. It is important for both oncologists, as well as women who have ovarian cancer, to just be aware of the various clinical trials that are ongoing. There is a great magnitude of trials right now that are testing very exciting agents. We are thinking about patients’ ovarian cancer histology—whether it’s high-grade serous, low-grade serous, mucinous, or clear cell.

It is really important because it will give you a sense of how to treat that patient. For example, low-grade serous carcinoma can be quite sensitive to hormonal therapies. Therefore, it’s important for physicians to look at the pathology report. And, [if the report] just reads “adenocarcinoma” for ovarian cancer, it needs a pathologist's call on exactly what this is because that kind of pathology report has become obsolete. It’s going to be specific to the histology because those histologies will then translate to the genomic underpinnings of the cancer, which can then translate to personalized therapy for women with recurrence.

Pfisterer J, Dean AP, Baumann K, et al. Carboplatin/pegylated liposomal doxorubicin/bevacizumab (CD-BEV) vs. carboplatin/gemcitabine/bevacizumab (CG-BEV) in patients with recurrent ovarian cancer. A prospective randomized phase III ENGOT/GCIG-Intergroup study (AGO Study Group, AGO-Austria, ANZGOG, GINECO, SGCTG). In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract 933O.