AP26113 is a second-generation ALK and ROS1 inhibitor that seems in vitro to also have some activity against the activating epidermal growth factor receptor (EGFR) mutations and T790M. However, it needs to achieve an order of magnitude higher concentration to be active against the EGFR targets than it does against the ALK/ROS1 targets. We are showing the results from the phase 1 dose-escalation studyacross a broad dose range.
In the ALK patients, most of whom have not responded to crizotinib, we are seeing fantastic activity: a 75% response rate in patients who had progressed on crizotinib. That is occurring at doses from 60 mg all the way up to 240 mg. They are now taking 180 mg forward as the recommended phase 2 dose. It seems to be very well tolerated. One case of pneumonitis occurred at one of the lower doses, and some other patients with low performance status at entry did relatively badly. But after pausing, tightening up on the inclusion criteria, and adding extra patients to those cohorts, we were able to move through that.
EGFR story is a work in progress. Because the drug is less active against the EGFR targets than the ALK and ROS1 targets, to get activity in the clinic we need to achieve blood drug levels that are significantly above those that will work on ALK and ROS1 to have a chance of activity against EGFR-driven cancers. At 180 mg, we are predicted to be achieving those exposures, but many of the patients with EGFR mutations treated to date went on at lower doses. In terms of the dataset, there were relatively few known T790M-positive patients who came straight from erlotinib to this drug at those higher doses. There will be a dedicated T790M-specific cohort at the recommended phase 2 dose, so we will know fairly soon whether this is just an ALK and ROS1 inhibitor or whether it is truly an ALK, ROS1, and EGFR inhibitor.
The second mutations in ALK and the copy number gain in ALK (what we call ALK-dominant mechanism) are the ones we expect to respond to second-generation inhibitors. The highest estimate is about 50% and the lowest is about 30%, yet we are seeing responses of 50%-80% for many of these second-generation inhibitors. That tells me that our frequency of ALK-dominated mechanisms is an underestimate. We don't know whether that is because we are missing mutations, we haven't figured out what the level of ALK copy number gain is that is required to lead to resistance, or because there are other ALK-dominant mechanisms that exist that we haven't quite found a way of capturing yet, or because crizotinib is an okay but not great inhibitor and is, for example, only inhibiting 50% of the sensitive clones instead of 100%, and this is just a better ALK inhibitor even when the biology is the same.