At the 2023 ASCO Annual Meeting, Kathleen Moore, Stephenson Cancer Center at The University of Oklahoma, Oklahoma City, Oklahoma, presented results from the phase 3 MIRASOL trial, evaluating mirvetuximab soravtansine for patients with platinum-resistant ovarian cancer, with high folate receptor-alpha expression.

Dr Moore stated, “Mirvetuximab is the first novel treatment to demonstrate a benefit in overall survival in platinum resistant ovarian cancer in a phase 3 trial.” She went on, “These data are truly practice changing for our patients, and position mirvetuximab as a new standard of care for patients with folate receptor alpha-high platinum-resistant ovarian cancer.”

Transcript:

My name's Dr. Kathleen Moore, and I'm the Associate Director of Clinical Research at the Stevenson Cancer Center in Oklahoma City. At the 2023 ASCO Annual Meeting, I had the great honor of presenting, on behalf of my co-authors and ImmunoGen, the top-line results of the phase 3 study known as MIRASOL. This is a phase 3 study of mirvetuximab soravtansine versus investigators choice chemotherapy in platinum resistant folate receptor alpha-high expressing ovarian cancer.

What I presented at the ASCO 2023 meeting was really transformational data. No clinical trial in the history of ovarian cancer in the platinum resistant space has ever demonstrated an overall survival benefit, and we did so in this study. This is also the first positive trial in the platinum-resistant space for a novel targeted therapy. Mirvetuximab soravtansine is an antibody drug conjugate. It's comprised of a folate receptor alpha-binding antibody, a cleavable linker, and it's conjugated to a maytansinoid DM4 cytotoxin which is a potent tubulin-targeting agent.

Folate receptor-alpha is an important target in ovarian cancer. You can find it expressed in almost all high-grade serous ovarian cancers, but about 35% to 40% of platinum-resistant ovarian cancer tumors will express what we call folate receptor alpha-high expression, which we define as greater than 75% of tumor cells being positive with at least 2-plus intensity.

Now, we know the activity of mirvetuximab already from the phase 3 single-arm study, the SORAYA trial, which demonstrated an overall response rate of 32% at a median duration of response of 7 months in platinum-resistant ovarian cancer. Importantly, that was all bevacizumab pretreated. MIRASOL is the confirmatory trial to that single-arm study which garnered accelerated approval and will ideally lead to global approvals from mirvetuximab across the world.

The study designed for MIRASOL as was stated, was an open-label phase 3 trial and enrolled women with platinum resistant ovarian cancer. They could have 1 to 3 prior lines of chemotherapy. They were folate receptor alpha-high as previously defined, and they could have been pretreated with prior bevacizumab or prior PARP inhibitors, but these were not required. It used 1-to-1 randomization to mirvetuximab soravtansine versus investigator's choice chemotherapy, and the primary end point was progression-free survival as assessed by the investigator, and analytic secondary end points were overall response rate and overall survival, as well as patient-reported outcomes as an end point as well.

The demographics were very well balanced between the 2 arms as controlled by stratification and randomization; but notably, about 60% of patients who participated on the MIRASOL study had prior treatment with bevacizumab, while about 55% had prior treatment with a PARP inhibitor, which is very consistent with current labels. And when we look at the stratification factors, which were number of lines of prior therapy and the investigator choice chemotherapy, about 50%, just a little less than 50% of the participants came on with 3 prior lines of chemotherapy. So, a relatively heavily pretreated population. Only 14% came on with 1 line of chemotherapy. And the most commonly-selected investigator's choice chemotherapy was weekly paclitaxel at 41%, followed closely by pegylated liposomal doxorubicin at 36%, and last by topotecan at 23%.

The primary end point was progression-free survival by investigator. The median progression-free survival for the control arm was very consistent with the estimate set forth in statistical plan and was found to be 3.98 months. The median progression-free survival for the mirvetuximab arm was 5.62 months. But more importantly, the hazard ratio for the reduction in risk of progression was 0.65. In other words, there was a 35% reduction in the hazard of progression or death with the use of mirvetuximab as compared to investigator's choice chemotherapy, and this was statistically positive with a P-value less than 0.0001. Because this was positive, we could roll alpha to a secondary analytic endpoint of overall response rate, which was also clinically and statistically superior.

The response rate was 16% for investigator's choice chemotherapy, again, very consistent with the statistical analysis plan estimates versus 42% for mirvetuximab. This difference is 26.4% and gives us an odds ratio of 3.8 and a P-value less than 0.0001. Notably, if you look at the waterfall plots for mirvetuximab versus investigator's choice chemotherapy, there are some differences. The first being that we see complete responses from mirvetuximab in 5% as compared to none in investigator's choice chemotherapy. Then when you consider responses that don't meet RECIST criteria, we would call it stable disease or minor responses, you see 80% of the participants who received mirvetuximab had some tumor reduction as compared to only 55% with some tumor reduction, and this includes RECIST responses in the investigator's choice chemotherapy. This really reflects what our patients are looking for.

Because overall response rate was positive, we were able to roll alpha to the interim overall survival analysis. Now, this overall survival analysis was an interim and would be considered statistically significant if the P-value were less than 0.01313. In the control arm, the median overall survival was 12.75 months. Again, very consistent with statistical assumptions at the outset of the study. The median overall survival with mirvetuximab was 16.5 months. This gave us a hazard ratio of 0.67, so 33% reduction in the hazard of death with use of mirvetuximab as compared to investigator's choice chemotherapy with a P-value of 0.0046, and so less than the preset P-value, and this is a statistically significant improvement in overall survival.

When we look at the safety summary from mirvetuximab versus investigators choice chemotherapy, this has been demonstrated in prior studies and really there's no new safety signals. We saw numerically fewer grade three treatment emergent adverse events at 42% versus 54%, fewer serious adverse events at 24% versus 33%, and significantly fewer discontinuations due to treatment emergent adverse events at only 9% for mirvetuximab as compared to 16% for investigator's choice chemotherapy.

When we look granularly at the treatment emergent adverse event profile, again, it's very consistent with prior studies with negligible hematologic toxicity for mirvetuximab as compared to investigator's choice chemotherapy. We do see less peripheral neuropathy as compared to the most appropriate comparator, which is weekly paclitaxel at 22% versus 29%. Notably, no alopecia is noted with mirvetuximab. There are gastrointestinal side effects that are similar to investigator's choice chemotherapy with common but low grade diarrhea at 29%, and common but low grade nausea at 27%. The class effect or the common effect associated with mirvetuximab is ocular disturbances, which as in prior studies were common but low grade. Approximately 41% of patients experienced some ocular side effect. Again, the majority of these were low grade with only 8% being grade 3 or higher, and these consisted of blurred vision and/or ketatopathy, and/or dry eye, and mitigation strategies exist.

In conclusion, mirvetuximab is the first novel treatment to demonstrate a benefit in overall survival in platinum-resistant ovarian cancer in a phase 3 trial. It demonstrated statistically significant and clinically meaningful improvement in progression-free survival, overall response rate, and overall survival compared to investigator's choice chemotherapy, and has a differentiated safety profile consisting predominantly of low grade ocular and gastrointestinal events. Mirvetuximab is the first antibody drug conjugate for ovarian cancer with proven efficacy and is the only FDA-approved biomarker directed therapy for platinum-resistant ovarian cancer. These data are truly practice changing for our patients and position mirvetuximab as a new standard of care for patients with folate receptor alpha-high platinum-resistant ovarian cancer.

We are very grateful to all of our participating sites worldwide for helping us move this important medication closer to approval. And most importantly, we are very grateful and forever indebted to the patients who so selflessly volunteered to participate in the MIRASOL study, and I hope they're very proud of the accomplishment that we have achieved.

Thank you very much.

Source:

Moore KN, Angelergues A, Konecny GE, et al. Phase III MIRASOL (GOG 3045/ENGOT-ov55) study: Initial report of mirvetuximab soravtansine vs. investigator's choice of chemotherapy in platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate receptor-alpha expression. Presented at 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract LBA5507