Rebastinib/Paclitaxel Shows Efficacy in Platinum-Resistant Ovarian Cancer

Erika Hamilton, MD

An ongoing study of rebastinib (DCC-2036) in combination with paclitaxel demonstrated positive preliminary outcomes in patients with platinum-resistant ovarian cancer according to data presented at the 2021 European Society for Medical Oncology Congress.

Rebastinib is a switch control inhibitor that targets the TIE2 pathway. In this 2-part, open-label phase 1b/2 study (NCT03601897), rebastinib was administered orally along with weekly paclitaxel doses. The trial is meant to evaluate the safety and tolerability of using rebastinib in treatment of patients with advanced and metastatic tumors.

Twenty-nine patients were included in the safety population, all of whom had previously been given chemotherapy, while 90% (n = 26) had received bevacizumab (Avastin), 62% (n = 18) received PARP inhibitors, and 31% (n = 9) received immunotherapy. The median duration of treatment was 2.8 months.

Investigators observed antitumor activity in multiple tumor types in part 2 of the trial, including patients with platinum-resistant ovarian cancer. There was an objective response rate of 38% and a clinical benefit rate of 88% at 8 weeks in the modified intent-to-treat population (n = 24). Of those evaluated for a cancer antigen-125 (CA-125) response, it occurred in 10 out of 17 patients (59%).

In an interview with Targeted Oncology^TM, Erika Hamilton, MD, director of the Breast Cancer and Gynecologic Cancer Research Program and principal investigator at Sarah Cannon Research Institute, discussed the findings from the study and unmet needs in this setting.

TARGETED ONCOLOGY: Can you explain the mechanism of action of rebastinib and what rationalizes its use in combination with paclitaxel for this patient population in your study?

HAMILTON: This was a study of weekly paclitaxel in combination with rebastinib. Rebastinib is an oral drug that inhibits TIE2. This is in the angiogenesis pathway, so you can think of it like a VEGF [pathway], except it hits a few additional targets as well. So [it is] a proven strategy for ovarian cancer targeting with both chemotherapy and an antiangiogenesis drug.

Can you discuss the study design and go into the methods used for this study?

The study was a phase 1/2 study and 38 patients with platinum-resistant ovarian cancer were treated. Patients received either 50 mg or 100 mg of rebastinib by mouth twice daily along with weekly paclitaxel. These patients were quite heavily pretreated. Over 60% of patients had seen at least 4 lines of therapy. All of these patients had received paclitaxel, 87% had seen bevacizumab, and 68% had seen a PARP inhibitor.

What were the results presented during ESMO?

What we saw was a [median] progression-free survival [PFS] of over 9 months and a duration of response of about 5.5 months. Most importantly, maybe, is [that] the clinical benefit rate at 16 weeks was 76%. So again, these patients had ovarian cancer, 73% of them had a decrease in CA-125 to treatment. This is pretty competitive when we think about what we would have expected to see with single-agent paclitaxel and patients with platinum-resistant ovarian cancer. We would expect maybe 3 to 4 months PFS for patients with platinum-resistant ovarian cancer. So seeing over 9 months was quite encouraging for this early data.

What conclusions can be drawn from this research?

I think the takeaway message is the encouraging early activity we saw with the PFS of 9.1 months and a clinical benefit rate at 16 weeks in over three-quarters of patients. It was pretty well tolerated. We saw fatigue, alopecia, nausea, neuropathy, all of the adverse events we would anticipate to see with paclitaxel, and then some extra that are specific to rebastinib: edema and muscle weakness. However, all of these adverse events that I've mentioned, none of them were present in over 10%, grade 3 or higher. So [it was] well tolerated and looks very active for these patients. So we look forward to exploring more about this drug combination.

Outside of this study, what are the key unmet needs for this patient population right now?

Ovarian cancer is a difficult disease for a number of reasons. First, there's no good screening test for ovarian cancer. So oftentimes, when people get diagnosed with ovarian cancer, they present later lines: stage III, stage IV. Most patients respond quite well initially to carboplatin-type agents; paclitaxel and carboplatin combined is most often what we give up front. But unfortunately, a lot of patients—well over 50% of our patients—end up relapsing. Once patients relapse within 6 months of their most recent platinum-containing compound is when we deem them platinum-resistant.

Probably the greatest unmet medical need is [having] more drugs in this space. There are a lot of drugs out there that we're looking at, certainly combinations like this with chemotherapy and antiangiogenesis drugs. We now have PARP inhibitors for ovarian cancer. We've looked at immunotherapy, although the results on that have been a bit mixed, and then another new class of drugs coming to ovarian cancer that we're probably going to see some successes in are the antibody drug conjugates, where we have chemotherapy that's bound to an antibody to help target the cancer cell and leave some of the rest of the body alone.

_Reference:

_{Hamilton EP, Goel S, Arend RC, et al. A phase 1b/2 study of rebastinib and paclitaxel in advanced or metastatic platinum-resistant ovarian cancer. Poster presented at: 2021 European Society for Medical Oncology Congress; September 16-21, 2021; virtual; Abstract 3335.}