Mirvetuximab Plus Bevacizumab Combo Appears Durable in Platinum-Agnostic Ovarian Cancer

Lucy Gilbert, MD, MSc

The addition of mirvetuximab soravtansine to bevacizumab (Avastin) induced promising objective response rates (ORRs) in patients with platinum-agnostic ovarian cancer regardless of the platinum status, according to interim findings of a study presented during the American Society of Clinical Oncology Virtual Scientific Program.

The ORR for the entire cohort of patients was 47%, but in a subset of patients with high folate receptor alpha (FRα)-expressing tumors, the ORR was 64%. For patients with platinum-resistant disease, the ORR was 59%, and for those who were platinum-sensitive, the ORR was 69%.

After a medium follow-up of 5.5 months, the progression-free survival and duration of response data were still immature. The primary objective of the study is to determine the safety and tolerability of the combination, as well as the efficacy in this patient population. A total of 60 patients have been treated in the study, of which 92% demonstrated tumor burden reduction, although a deeper tumor reduction was observed in patients with high expression of FRα.

The regimen also appeared tolerable in the interim data, in which the most common grade 3 or 4 adverse events were hypertension and myelosuppression, which occurred in 12% and 10% of patients, respectively. Only 22% of patients discontinued treatment due to treatment-related toxicities.

In an interview with Targeted Oncology, Lucy Gilbert, MD, MSc, professor, Department of Obstetrics & Gynecology and the Department of Oncology, McGill University and director of Gynecologic Oncology and Women’s Health Research Unite, McGill University Health Centre, discussed the interim findings for mirvetuximab in combination with bevacizumab as treatment of patients with platinum-agnostic ovarian cancer.

TARGETED ONCOLOGY: Could you discuss what makes FRα an attractive target in this space?

Gilbert: FRα is not expressed in adult normal cells. However, it is significantly upregulated in ovarian cancer cells. Because of this, an ADC targeting FRα works very well in ovarian cancer.

TARGETED ONCOLOGY: Could you shed light on the mechanism of action for mirvetuximab?

Gilbert: Mirvetuximab is an ADC that targets FRα cells, and the payload is a … which is a potent tubular targeting cytotoxic agent. The combination of anti- FRα with this bevacizumab, proves to be highly effective.

TARGETED ONCOLOGY: Why are you looking at the platinum-agnostic ovarian cancer in this trial?

Gilbert: Once ovarian cancer recurs, it is divided into platinum-sensitive and platinum-resistant. In platinum-resistant, mirvetuximab as a single-agent was found to be effective, and mirvetuximab in combination with bevacizumab was shown to be effective. Now in platinum-sensitive patients, we could use platinum, but the efficacy of single-agent platinum has been shown to have a very low response rate. It seems interesting to try and see whether in platinum-sensitive patients, the combination of mirvetuximab with bevacizumab would be effective. That is why we chose to use a platinum-agnostic group. Regardless of their platinum sensitivity, we chose patients in which a non-platinum-based doublet would be appropriate.

TARGETED ONCOLOGY: Could you elaborate more on the patient population in this study?

Gilbert: This was a phase 1b trial in which mirvetuximab was combined with bevacizumab in recurrent, high-grade epithelial ovarian cancer regardless of platinum sensitivity. We chose to use both platinum-resistant and -sensitive patients, and the primary objective was to evaluate the response rates as well as the toxicity. We had 60 patients, and the median age was 60 with a range of 44 to 83 years. Two-thirds of the patients had 2 or more prior lines of therapy. About 30% of patients had 3 or more prior lines. Because we had both platinum-sensitive and platinum-resistant patients, about 53% of the patients were platinum-resistant and the remainder were platinum-sensitive. It’s important to note that of the platinum-sensitive patients, only 13% had a platinum-free interval of more than 1 year. This is an important thing because it means the response rates were not driven by platinum-sensitive disease.

TARGETED ONCOLOGY: What were the findings?

Gilbert: The results were quite encouraging because the response rates were very good overall. Overall, the ORR was 47%, but in the high FRα -expressing patients, the ORR was 64%. These are confirmed ORRs, so 64% overall in patients who are high FRα -expressors is very encouraging. If you look at the subgroup of high FRα -expressers in greater detail, in the platinum-resistant subset, the confirmed ORR was 59%, which is almost double what we would see with other agents used in platinum-resistant disease. If we take the platinum-sensitive subset, we observed a confirmed ORR of 69%, which again is quite an encouraging finding.

Overall, these results are encouraging. The other important point to make is these are interim results. The trial is still ongoing, and with a median follow-up period of 5.5 months, almost half the high FRα -expressors are still on trial. Some patients have been continuing the study for 9 months, and some have been on study for over 1 year.

The progression-free survival and duration of response data are immature, but it’s encouraging that with a median follow-up of 5.5 months, almost half the patients are still continuing treatment. I would also like to emphasize that how we classified medium expressors and high expressors of FRα. Medium expressors are those in whom between 50% and 74% of the cells exhibit FRα and if more than 75% of the tumor cells express FRα, they are high expressors. The best response is seen in the high FRα -expressors.

TARGETED ONCOLOGY: Could you discuss the tolerability of the regimen?

Gilbert: That is an extremely important part. This is what is encouraging about this, because once ovarian cancer recurs, despite our best efforts, you need treatments that prolong life with minimal toxicity as possible. What is encouraging about this combo is there were no new side effects or AEs that were not previously known for mirvetuximab alone or bevacizumab alone. There was no added toxicity for the combination. The vast majority of patients had grade 1 or 2 toxicities. The most common were gastrointestinal and ocular toxicity, which is a known class effect of ADCs. However, the ocular toxicity is quite manageable with low proactive local strategies, which include liberal use of lubricating eye drops and steroid eye drops. Grade 3 or more toxicities were thankfully quite low. There was a 12% hypertension because of bevacizumab and neutropenia, but this combination was not myelosuppressive. Only 10% grade 3 neutropenia was [observed] and this is lower than what is seen with single-agent chemotherapy in the recurrent setting.

TARGETED ONCOLOGY: What are the next steps for this research?

Gilbert: We would like the data to be more mature. The most important thing is to let people know that there is a combination that can be used regardless of platinum-sensitivity with minimal toxicity. We would like the data to become mature, then given mirvetuximab has good single-agent activity, there are some ongoing trials, [such as] a phase 3 trial in which mirvetuximab is compared with standard of chemotherapy in recurrent platinum-resistant patients. That is an important trial, and we are hoping to start this very soon.

TARGETED ONCOLOGY: What do you hope oncologists take away from these findings?

Gilbert: What is exciting is in the high FRα -expressing patients, responses were seen as early as 6 weeks. This is quite unusual in the recurrent setting. The reduction in tumor burden, as I said, started as early as 6 weeks, and the depth and duration of response was much higher in the FRα -high expressors. What is exciting is with a median duration of follow-up of 5.5 months, half the patients are still on trial. This is very encouraging. As an investigator with almost 30 years of experience, this is very unusual and exciting.