Binimetinib May Be Beneficial for Patients With KRAS+ Low-Grade Serous Ovarian Cancer

The MILO/ENGOT-ov11 study (NCT01849874) aims to determine the efficacy of binimetinib (Mektovi) versus physician's choice of chemotherapy (PCC). The study enrolled 341 patients between June 2013 to April 2016. Patients were randomized 2:1 to binimetinib or PCC. Progression-free survival (PFS) data is available for 144 patients and response rate data is available for 135 patients. Forty-seven mutations were found in 5% or more of participants. 

According to the analysis, patients harboring a KRAS mutation had 3.4 times the odds of responding to treatment with binimetinib compared to patients who did not (95% CI, 1.57-7.67; P =.002). No difference in effects on PFS were observed between patients with KRAS G12C mutations and those with other KRAS mutations. However, PFS was found to be better in patients harboring a MAP kinase mutation versus those without (HR, 0.5; 95% CI 0.31-0.79; P = 0.003). The same was not observed for this population who received PCC.

In an interview with Targeted Oncology, Rachel N. Grisham, MD, the section head of ovarian cancer and director of Gynecologic Medical Oncology at Memorial Sloan Kettering Cancer Center, discussed binimetinib's effect on patients with ovarian cancer harboring a KRAS mutation. 

Targeted Oncology: Can you give a recap of what was observed with binimetinib versus chemotherapy of physician's choice in the primary analysis of this trial?

GRISHAM: The MILO/ENGOT-ov11 study was initiated back in 2012, and enrolled patients up until 2016. At that time, an interim analysis was performed that included a pre-planned futility analysis. It was found at that time that the hazard ratio had crossed the predefined futility boundary. And so, the decision was made at that time to halt enrollment to the study. However, patients that had already enrolled to this study were allowed to continue on treatment until progression of disease or coming off for other reasons, such as toxicity or withdrawal of consent. Overall, more than 300 patients were treated on this study. An updated analysis based on a 2019 data cut off, as well as the primary analysis were published in 2020, in the Journal of Clinical Oncology. There we found that based on the updated analysis, the response rate to binimetinib in patients with recurrent low grade serous ovarian cancer was 24%. The results was similar to the response rate in those patients treated with chemotherapy, which was higher than we had expected, based on historical data. It likely reflects the fact that this study was limited to patients with 1, 2, or 3 prior lines of chemotherapy. It hasn't been a very heavily pretreated population. Those initial results were based on an unselected population, and the study enrolled patients without any knowledge of what their molecular status was.

What was the rationale for the post hoc analysis that you presented during ASCO 2021?

The rationale for the post hoc analysis was that the investigational agent being used here, binimetinib, is a MEK inhibitor, which is a targeted drug that is trying to target alterations in the MAP kinase pathway. Now a low-grade serous ovarian cancer is molecularly distinct from the most common type of ovarian cancer, high-grade serous ovarian cancer. In high-grade serous ovarian cancer, we ubiquitously see p53 mutations, and also commonly see homologous recombination deficiency (HRD), and BRCA mutations. These are all very rare in low-grade serious ovarian cancer. The most common alterations that we see are those affecting the MAP kinase pathway, the most common being KRAS, which is found in about 33% of patients, then less commonly other alterations, such as BRAFv600e, which is found in about 9% of our recurrent patients, and NF1, other RAS alterations.

Putting this all together, significantly, more than half of our patients with recurrent low-grade serous ovarian cancer will have the alterations affecting the MAP kinase pathway. So, we wanted to look at that group of patients to see if they were more likely to respond to treatment with the MEK inhibitor.

What did you find during this analysis?

This analysis was based on foundation medicine data. So, we had planned from the beginning to later look at molecular subtypes, and how they responded to treatment with binimetinib. At the time of enrollment to the study, all patients were required to submit archival tissue for molecular analysis performed by a foundation medicine. Based on these results, we were now looking at these foundation medicine results and how they correlated with response to therapy. Overall, about a third of the patients treated on the study had a KRAS mutation, as we would expect, based on historical data. And those patients that had a KRAS mutation that were treated with binimetinib had 3.4 times the odds of responding to treatment versus those patients without a KRAS mutation. This tells us that presence of a KRAS mutation does predict for better response to binimetinib in patients with recurrent low-grade serous ovarian cancer.

We also wanted to see if we lumped together the other less common alterations affecting this pathway, would we see similar results. So, we put together those patients with a KRAS mutation, a BRAF mutation, NF1 mutation, and RASmutation, and looked at them as a group. Similarly, we saw a higher response rate to binimetinib in these patients versus those without a MAP kinase alteration. For those patients harboring a MAP kinase alteration, the response rate to binimetinib was 41% versus 13% for those patients without a MAP kinase alteration. Now, of course, this analysis was limited by multiple testing. However, I think this is very interesting, and may help us to better predict those patients most likely to respond to these important treatments.

In your opinion, what is the current role of biomarker testing today? What do these findings imply about biomarkers for the future?

That's such an important question because increasingly, we are trying to use biomarkers in a knowledgeable way and direct our therapies so that we can give patients the treatments that are most likely to be effective. We are also trying to save them from the toxicity of treatments that are less likely to be effective. So, in ovarian cancer, it is currently recommended based on multiple guidelines, including the NCCN guidelines, that all patients with ovarian cancer in general, undergo molecular testing to look for presence of BRAC mutations in particular. That includes both germline and somatic testing. Now, while these platform tests look for BRCA mutation, they also commonly look for other alterations, including KRAS and BRAF. I think by using this platform testing to look not only for BRCA mutations, but also for these other alterations, such as KRAS and BRAF, at the time of diagnosis, or most certainly at the time of recurrence, we can make better, more informed decisions for treatment of our patients. Therefore, I think we should consider it to be a standard of care to do somatic tumor testing in all of our patients with recurrent low-grade serous ovarian cancer, so that we can best determine which treatments to use for them.

What do you think is next for this agent in the ovarian cancer space?

Based on the primary results of the study, I do think that binimetinib has shown similar response rates to other viable MEK-inhibitors for treatment of this disease. Trametinib (Mekinist) showed a very similar response rate in a phase 3 study of trametinib versus PCC for recurrent low-grade serous ovarian cancer. However, in that study, the control arm had a much lower response rate, as it did not limit the number of prior therapies, patients were allowed to have unlimited priors, were heavily pretreated, and therefore had lower response rates to chemotherapy or endocrine therapy in the control arm. Given that we see that in the primary results presented in the Journal of Clinical Oncology's 2020 paper that the response rate to binimetinib is similar to that to trametinib in the overall population of patients. Now we'll have this additional information about which patients are most likely to respond to binimetinib. I think it would be very reasonable for binimetinib to similarly become National Comprehensive Cancer Network compendium listed as trametinib is so that we just have more options for treatment of our patients with recurrent low-grade serious ovarian cancer. It is important that we have access to more than 1 drug. Sometimes patients cannot tolerate 1 drug or other issues that can prevent them from receiving 1 drug over another. 

In terms of future studies, I think the next question is how can we further enhance these response rates that we're seeing? This is particularly the case for the patients that are molecularly most likely to respond. The next generation of studies are building on novel combinations to try to enhance the activity of MEK inhibitors in patients with recurrent low-grade serous ovarian cancer, such as the ongoing RAMP201 study (NCT04625270), which combines a dual MEK/RAF inhibitor with a FAK inhibitor to try to further improve the response rate in our patients with recurrent low-grade serious ovarian cancer. Similarly, that study is looking at patients' molecular profile, however, in a prospective fashion to see how the activity differs in those patients with a KRAS mutation versus those without.