Dr Lori Friedman, director of cancer signalling and translational oncology at Genentech, speaks about a session at the 2011 AACR congress where a number of previously undisclosed drugs in Stage I clinical trials were presented. The first drug discussed was a molecule which targets FGFR1, FGFR2 and FGFR3 in order to combat gastric and haematological malignancies. The second is a highly specific small molecule to target HER2. This drug is particularly exciting as it is able to cross from the blood into the brain. Due to this property it may be useful in treatment of HER2 positive breast cancer that has metastasised into the brain. Finally Dr Friedman talks about a drug which targets the ALK gene responsible for a subset of non-small lung cancer. Pfizer have previously developed a first generation drug to target both c-MET and ALK but this second generation drug is more specific and targets only ALK.
AACR 102nd Annual Meeting, 2—6 April 2011, Orlando, Florida
AACR 102nd Annual Meeting, 2—6 April 2011, Orlando, Florida
AACR 2011: New Phase I targeted cancer drugs
Dr Lori Friedman – Genentech, California, USA
The whole idea of finding out what molecules are available to be drugged or treated is very exciting; there was a whole session on this. Lori Friedman, you’ve been looking at new drugs on the horizon here at the AACR meeting, could you sum up, there were a few criteria; first of all, what were the criteria for qualifying for your session?
We choose from among the people who apply to get into this session, we choose based on criteria that are: the drug must be entering into early stage clinical trials, so phase I, and then a second criteria is that this must be the first disclosure of what the actual compound is that’s entering into the clinic.
So this is breaking news?
This is very much breaking news and it’s a very well attended session because people are very excited to see how some of the preclinical research have solved some of the harder issues in drug discovery.
Now let me ask you about some of this breaking news then, because you’ve been looking at FGFR1, 2 and 3. Now Nigel Brooks gave a presentation, what was that all about and which cancers and what came out of it?
There had been a first generation of FGFR inhibitors several years ago and those turned out to be not very well tolerated in the clinic and the culprit was thought to be FGFR4. So this new generation of drugs now has eliminated FGFR4 activity, focussed on the actual drivers in cancer, FGFR1, 2 and 3, and then the hope with these new molecules is when they enter phase I they will be tolerated and yet also be able to be targeted to the patients who have driver mutations.
And the data you heard was on gastric and hematologic malignancies, what came up?
The preclinical models, for instance the evaluated gastric cancer patient models with FGFR2 amplifications , and those indeed showed cell death when treated with these inhibitors. So we think these are very promising and look forward to new data as the phase I trials progress.
That’s phase I, you haven’t got the efficacy yet, but another one was a HER2, we’ve heard a lot about HER2 of course but you’ve got a small molecule that was talked about.
Yes, Kevin Koch from Array discussed a new small molecule that’s specific for HER2 and here their goal was to remove or diminish the EGFR activity. So there are some dual inhibitors in the clinic like lapatinib which has approval in breast cancer and the goal of this project was to say, OK, can we reduce any of the side effects and increase the tolerability and how will we progress that in the clinic? If we can get more drug on will we be more effective?
So a more specific drug for HER2?
It’s a more specific drug for HER2 compared to lapatinib, so a small molecule way to attack the HER2 positive breast cancers. The other thing unique about this molecule is that preclinically it can cross into the brain so that there’s a hope that there would be the ability to treat metastatic breast cancer that has been metastasised into the brain.
So you’ve got tolerability information so far, any hint of efficacy?
There are some hints of efficacy, so there was a bit of phase I data presented in some HER2 positive patients and there were indeed some PRs.
And lung cancer is a disease where you really do need some markers and there was some news here, wasn’t there, in your session?
Yes, that’s correct. There has been molecular characterisation of lung cancer has been coming out over the last several years and one driver mutation that was recently identified is called ALK. This ALK protein product is activated in lung cancer and so there was a first generation molecule by Pfizer that hit both c-MET and ALK and this has shown activity in early clinical trials. Now this, what we presented at the New Drugs on the Horizon session, by Dr Sakamoto from Chugai, the molecule now is a new generation which very precisely inhibits the ALK protein only. So the hope is that it will turn out in the clinic to be a very specific and pure molecule to interrogate this disease.
Now as a druggable molecule, how good is it looking at the moment?
The first data from Pfizer look very good; the response rate is quite high. It’s very interesting because it’s only a subset of non-small cell lung cancer but it seems to be a very wonderful way to attack this disease. So we’re looking forward to both the data in the clinic from the first generation and the second generation molecules to see if we can really effect cures.
And this selective ALK inhibitor could be useful in both squamous and non-squamous carcinoma.
Yes, it’s very much more defined by the DNA mutation, the driver being ALK, and agnostic to which subtype of the disease it is.
Judging from your session on new drugs on the horizon, what are your feelings? There’s a big desire now to generate specific targets and to be more refined in the approach to treating cancer, how encouraged are you?
I’m very encouraged. I think with personalised healthcare really coming to the forefront it will take us time and iterative methods to really design the most precise and best drugs and one of the challenges, of course, in cancer research and cancer drug discovery is to really understand what the targets are doing. So the better inhibitors we have, the more precise these inhibitors are and the more selective, the more we’ll be able to understand the biology about what that protein target does.
Of course these are all very encouraging things but they can seem rather distant, what would you say to doctors who have patients to treat about some of these new targets? Are they too far ahead or are there lessons that can be learned for your own individualising of therapy right now?
I think it’s a very exciting time because things are moving so quickly, both on new ways to stratify patients, their diseases can be molecularly characterised now, and now that there are all these new therapeutics coming through in clinical trials and many will start to be approved, many more targeted therapies will be approved very soon, so it’s a chance to really redefine the disease and move beyond what’s seen in a histology method and really understand the molecular underpinnings and then match the right drug to the right patient. So basically these are wonderful molecules for doing the precise human experiment which is the ultimate goal so that we know how to match the right drug to the right patient.
And do you think there’s enough in it for the busy cancer doctor though, at the moment?
I think there will need to be because of the… certainly, I’m from the US and so the state of how healthcare is being managed is in a state of flux right now and the more we really think about how to do precision medicine, how to personalise the treatments that will get the most benefit for the patient, this is what all the healthcare providers and reimbursers and so on will be looking for. So as the day to day physician treats their patients, they will start saying, ‘OK perhaps we need to send a sample to this other lab where it will be analysed on a molecular basis.’
Dr Friedman, it’s great to have you with us here on ecancer.tv.
Thank you very much, it’s a pleasure to be here.