Novel Combination Shows Early Efficacy in Ovarian Cancer

David O'Malley, MD

Recent data suggested that the antibody-drug conjugate mirvetuximab soravtansine is efficacious and well tolerated in patients with folate receptor alpha (FRα)-positive ovarian cancer. Now, maturing safety and activity profiles from the FORWARD II trial presented at the 2018 ASCO Annual Meeting indicate the agent pairs well with bevacizumab (Avastin).

Patients (n = 51) with platinum-resistant FRα-positive disease who received a median of 3 prior lines of systemic therapy were administered mirvetuximab at 6 mg/kg combined with bevacizumab at 15 mg/kg on day 1 of a 21-day cycle. In the total population, the overall response rate (ORR) with the combination was 43% with a median progression-free survival (PFS) of 7.8 months. In a subset of patients (n = 39) who received <3 prior lines of therapy and had medium to high FRα expression, the ORR was 49% and the median PFS was 9.5 months.

“As we've been able to garner greater experience with this agent, we are clearly showing that patients with medium and high expression tend to do better both in the overall and progression-free response rates,” said David O’Malley, MD, who is the lead investigator of FORWARD II.

OncLive: Please provide an overview of this abstract.

What activity did you see in terms of efficacy?

Could FRα potentially be a solid biomarker?

What is it about mirvetuximab soravtansine that makes it such an intriguing agent in the field of ovarian cancer?

Can you discuss some of the safety data from the trial?

What are some next steps to this study?

What other tumor types could mirvetuximab soravtansine be used in?

In an interview with OncLive, O’Malley, a professor in the Department of Obstetrics and Gynecology, The Ohio State University Comprehensive Cancer Center, discussed the emerging combination of mirvetuximab soravtansine plus bevacizumab and the evolving treatment landscape in ovarian cancer.O’Malley: This is a combination of mirvetuximab soravtansine and bevacizumab. This is part of a larger phase Ia/Ib trial looking at 3 separate combinations [with] mirvetuximab soravtansine.We reported on patients with mature data on efficacy. Of those we saw—depending on how we break down the populations—out of the overall population, we saw about a 40% ORR with PFS of about 9 months. Now, because we have both the escalation and the expansion cohorts, we broke those down into subsets [of patients who received] 1 to 3 prior therapies and medium to high FRα expression. Also, we took another subgroup that would be consistent with 1 to 2 prior therapies and medium to high FRα expression.FRα has started to pan out and clearly show that it is a biomarker for mirvetuximab. When we originally looked at this, we included both low expression at 25% to 50%, medium expression at 50% to 75%, and high expression at >75%. As we've been able to garner greater experience with this agent, we are clearly showing that patients with medium and high expression tend to do better both in the overall and progression-free response rates. That is why we're concentrating on patients with medium and high expression as we move forward. Interestingly, we still see some marked responses in those with low expression.With FRα being so highly expressed in the majority of ovarian cancer cells, we are able to target those cells and get that drug directly into the cancer cells, limiting our toxicity. With its microtubule mechanism, we see this as a taxane-like agent without alopecia and neuropathy.Interestingly, with the combination, we didn't see any safety signals beyond what you would expect to see with bevacizumab or mirvetuximab [alone]. We were able to combine these 2 drugs without any added toxicity. We saw some hypertension like you would in a patient who takes bevacizumab alone and we saw similar levels of gastrointestinal toxicity that you'd see with single-agent mirvetuximab soravtansine. Those did not seem to increase when we combined those agents. Is there synergy between bevacizumab and mirvetuximab soravtansine? I'm not sure we can say there's synergy between the 2 agents quite yet. This is one of the things we're trying to figure out. We're definitely seeing that we can increase our PFS, and it also appears we can increase ORR, similar with what we've seen with standard cytotoxic chemotherapies. Mirvetuximab soravtansine, on its own, is such an active drug in the FRα expressers that we really see the impact on PFS. We're seeing this now approach 10 months in patients with platinum-resistant, heavily pretreated ovarian cancer. These are some pretty exciting results here.Currently, FORWARD I has completed enrollment in a randomized phase III trial of single-agent mirvetuximab soravtansine in platinum-resistant patients. We are looking forward to seeing those results in the next year or so. However, what we're looking at is utilizing mirvetuximab soravtansine—anywhere that we've used it has also included paclitaxel. We're hoping to see the opportunities potentially go into the platinum-sensitive setting and maybe one day go into upfront treatment. We're not quite there yet.Right now, we're looking at other tissues that express folate receptors. For example, we're looking at non—small cell lung cancer (NSCLC) and certain uterine cancers. As we gather some more information on those diseases and we can get more into clinical trials, this is a good opportunity to use this agent well beyond ovarian cancer, uterine cancer, and NSCLC.

As we've seen with PARP inhibitors, HRD mutations are seen well beyond triple-negative breast cancer and ovarian cancer. As we garner more and more of these rare molecular abnormalities in other tissues, we're going to see an opportunity where this drug can be utilized well beyond the current solid tumors.

O’Malley D, Martin L, Gilbert L. Mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients (pts) with platinum-resistant ovarian cancer: maturing safety and activity profile from the FORWARD II phase 1b study. J Clin Oncol. 2018;36 (suppl; abstr 5549).

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The phase III FORWARD I trial is investigating mirvetuximab soravtansine as a single agent against chemotherapy in patients age ≥18 years old with platinum-resistant, FRα-positive ovarian cancer (NCT02631876). It has met its enrollment goal of more than 333 patients, O’Malley said, and results are expected in approximately 1 year.