Shannon N. Westin, MD, MPH, on Endometrial and Ovarian Cancers: New Data on Selumetinib and Olaparib From the SOLAR Trial

This was a phase 1b trial that was combining the MEK inhibitor selumetinib with the PARP inhibitor olaparib. And we had some really interesting preclinical data to indicate that targeting these two pathways really made sense and would be synergistic in a number of RAS mutant, as well as potentially PARP resistant, models. And so we moved forward with this phase 1b trial, first, to determine the recommended phase two dose, and then to expand into four relevant areas including ovarian cancers with RAS aberrations, endometrial cancers with RAS aberrations, solid tumors in general with a RAS aberration, as well as PARP resistant ovarian tumors. And the way we define RAS aberrations included KRAS mutations, NRAS mutations, HRAS, BRAF, NF-1 loss of function, as well as RAS amplification. The bottom line, we were able to achieve the recommended phase two dose at the maximum tolerated dose for both drugs, which was very exciting. And overall, the adverse events were as expected for each agent. The drugs were well tolerated. We only had 8% discontinuation rate. We did have about 50% required dose interruptions and 13% required dose reductions. But overall, patients were able to stay on a very long time with quite a bit of activity. Now, we did have the opportunity to look at anti-tumor activity for the combination, both across all cohorts, as well as specifically in different cancer subsets. And the bottom line is it was active. There was a 21% response rate in the entire group, and up to 50% had some type of clinical benefit. But when we teased that out by cancer type, that's really where things got interesting. What we found were the highest response rates were actually in RAS aberrant ovarian cancer, and this was as expected because we knew there was going to be a lot of patients with low grade serous ovarian cancer in this subgroup, and we know MEK can be active. So we saw a 32% response rate in the group as a whole, with 70% achieving clinical benefit. Interestingly, when we teased out the patients with low grade specifically, there was a 44% response rate and 77% clinical benefit. But what's important here is there was a benefit in other histologies aside from low grade, so that's very exciting. In RAS aberrant endometrial cancer, we also saw really exciting data, with 35% response rate and a 60% clinical benefit rate. And again, this was beyond endometrioid type. This was in patients with serous type, mesonephric type, and really rare tumors that are quite aggressive. So we were very excited about those data. In solid tumors, it wasn't as exciting. There was only an 8% response rate. When you look at lung cancer, specifically that group seemed to have about 50% clinical benefits, so maybe something of interest there. But the RAS aberrant group as a whole not as exciting. And similarly PARP resistance, we just didn't see the activity we were expecting, about a 17% response rate. And so this combination is moving forward. We're exciting to say that the combination of selumetinib and olaparib will be explored in the ongoing combo match trial. We are the EAY191-N4 arm, and we are enrolling patients with RAS mutant ovarian and RAS mutant endometrial cancer to determine if this is a drug regimen that should move forward with our patients.