MyPathway guidance of targeted therapy based on molecular profiles
Dr John Hainsworth - Sarah Cannon Research Institute, Nashville, USA
I’m presenting the preliminary results of the MyPathway trial which is a phase II multiple basket study looking at the effects of molecular targeted drugs in solid tumours.
When it comes to targets there are some very famous ones out there. Could you tell us how MyPathway has set them apart and what the research entails?
As you just stated, there are lots of targeted drugs now that are picked for patients based on the finding of specific molecular abnormalities in the cancers. Most of those drugs are approved for specific cancers like HER2 treatment for HER2 positive breast cancer, BRAF inhibition for BRAF mutated melanoma. The thing is about all of those mutations is that there are other cancers that have that exact same mutation at a lower incidence in those cancers that haven’t really been studied. You’d think that some of those would respond to those same drugs that work well in certain cancers. With the recent increase in molecular profiling from patients, more and more of these odd mutations in unusual cancers have been identified. So that’s what this trial is addressing, the treatment of patients with well-recognised molecular abnormalities but with non-indicated cancers.
So in this trial we have 4 targets – HER2, BRAF, EGFR and the Hedgehog pathway and we pair those with the drugs that target those pathways. All of the 4 drugs and treatments that we’re using in this trial are approved already for use in at least one cancer type but these patients have non-indicated cancer types, they also had to have previous treatment and be refractory to standard treatment before they’re eligible for this trial.
So that’s the trial design. This is an interim report, we have 129 patients treated now and of the 129 we’ve had 29 that have had responses, so these are all refractory patients, they responded to this single agent treatment that we’re using in this trial. 12 different tumour types totally responded, all out of indication. The most common group that we have so far are the patients with HER2 abnormalities and that’s about two-thirds of the patients in the trial actually. 61 of the patients had HER2 amplifications, the others had mutations so the amplifications are the biggest group and of that group we had a response rate of 28%.
Interestingly, the three biggest subgroups within that were colorectal cancer, bladder cancer and biliary cancer. Colorectal, of 20 patients 7 had major responses and that’s going to be a response duration of at least 7 months. More than half of the responses are still ongoing so we don’t know that for certain yet but in refractory patients those patients had a median of four previous treatment regimens before coming on this study. So it’s a pretty remarkable activity, we think. The other, I mentioned bladder and biliary, are smaller groups but the bladder is three for eight, the biliary is three for six as far as response. So we’re interested to see how that develops as well.
The BRAF target has been a good one too, we’ve had 33 patients with BRAF abnormalities, 8 responses within that group. Again, 6 different tumour types have responded; the only one, really, with a sizable number right now is non-small cell lung cancer and there we had 3 responses in the first 15 patients, another couple of patients had stable disease for more than 4 months. It’s interesting, in that group we accepted all BRAF mutations. The V600E mutation is the specific one that has been very predictable in melanoma for a response, and that’s where the drug is approved, and also in this group it turned out that that was the one that mostly responded. So 7 of our 8 responses were in V600E mutations and the response rate there in that group was actually 37%. So that also looks like a strong signal for those patients.
So so far the study is still ongoing but we’ve proved at least that this design is feasible where we can find these patients and accrue patients to a trial based on molecular abnormality rather than tumour type or primary site, which has been the traditional way to look at patients. 12 different tumour types have responded, the 4 biggest groups that we’re really most interested in now, just because they’ve already showed a signal, are the HER2 amplified colorectal, bladder, biliary cancers and then the BRAF mutated non-small cell lung cancer. Those all met the protocol criteria for efficacy and the cohorts have been expanded. The trial is continuing, we have over 200 patients on the trial now.
We’re all very excited by these results. First of all, we weren’t sure that this trial could accrue, this is the first kind of trial like this and we are at the right place at the right time as this volume of patients getting comprehensive molecular profiling increased we were there to get the patients that were resulting from it. We’re about to escalate or expand 2 additional cohorts in the study and it’s very interesting to see what develops. Certainly the colorectal cancer, if it keeps up at that rate or anything like it that’s going to be a strong indication to move forward with that actually for an indication for colon cancer. This is just giving signals of activity; if it’s that active in patients that have had 4 previous regimens for advanced colorectal cancer probably it’s going to be active in first line treatment along with other treatment for colorectal cancer. So this has a lot of implications for where this can go for patients and this is the minimum impact we’re making now, treating these patients after they’ve already had everything else.