World Congress on Gastrointestinal Cancer 14, Barcelona, Spain
Exploring new targets in GI cancer
Professor Josep Tabernero – Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
What are some of the new drugs and topics that have been discussed here at the ESMO 14th WCGC?
Basically here we have presented new data, actually some of the abstracts that were presented here have not been presented before anywhere, more focussing on the targets that are considered important so far for gastrointestinal malignancies, I mean the HER family, especially the epidermal growth factor receptor, as well as angiogenesis and the different properties of angiogenesis. But perhaps the most important thing here is that we have been discussing a lot on other new targets that are being drugged at this time point, also, being considered important for particular tumour types or even more for subpopulations of tumours because we are addressing more and more the differences of the different tumours in different patients for each tumour type. So we are micro-dissecting the tumours in different subtypes. This is going to give us more opportunities to treat patients with either new targets but also with new drugs and also considering which are the targets and the drugs that are relevant for each tumour type.
Can you comment on some of the data presented, such as the TML study?
We had updates on new data, especially for some of the studies that were initially presented at ASCO but in here, for example, in the bevacizumab TML data we had analysis of different subsets of patients according to the biomarkers. So we had the data on whether this approach of continuing bevacizumab after progression of the first line treatment could also work in the KRAS wild-type as well as in the KRAS mutant population and this was the case. This was data that was presented here so definitely making the point that for inhibiting angiogenesis the KRAS status in the tumour is not really important. Also we have some new data on the progression free survival in this trial, especially in looking at the different patient characteristics and also we didn’t see any differences in the advantage of treating patients with bevacizumab in the second line setting according to the clinical characteristics. This was presented in two different presentations, two different abstracts, preferred papers.
We also heard about the CORRECT study?
The CORRECT study has evaluated the role of regorafenib in late stage metastatic disease, so this means patients that have failed all available treatments. This particular trial has shown that regorafenib is active in this setting so patients that receive regorafenib benefit in terms of progression free survival and overall survival and we had here data presented according to the different subtypes. This was probably the most important data that was presented on angiogenesis.
The first findings of the PETACC8 study were presented here, what are your thoughts?
In the field of colorectal cancer we had the first presentation on the data for the PETACC8 study. The PETACC8 study was an adjuvant study in patients with stage 3 colon cancer and they were randomised to be treated with FOLFOX or with FOLFOX and cetuximab initially for all comers but when all the data of the KRAS mutation status became apparent this trial was amended and only patients with KRAS wild-type tumours were included from that time point. So globally, in looking at the data, the trial has to be considered negative. We in part expected the results because the American trial that had been presented one year ago was also negative with the same concept of adding cetuximab to standard chemotherapy in the adjuvant setting. But here we had, as mentioned, the first data on the PETACC8 study, negative but not detrimental, the American study had a little bit of a detrimental effect in patients that were receiving cetuximab. In the European study cetuximab does not offer any additional benefit but it’s not detrimental for overall survival and for disease free survival. I think that these were the main aspects on colorectal cancer.
What about other tumour types, such as pancreatic cancer?
It was interesting data in other less frequent tumours like pancreatic cancer. We had an update of the data that was presented at the EACR meeting, also this year, on a very interesting compound, a new generation compound, from a company called Threshold and this is an angiogenesis disruptor compound. Basically these are the results of a randomised phase II study that suggested that the addition of this disruptive compound to conventional gemcitabine chemotherapy increased efficacy in progression free survival and overall survival. Obviously this data has to be confirmed in the context of a phase III study but due to the mechanism of action of this compound, this data is really very interesting and definitely merits further evaluation in phase III studies.
Overall, which of these data could be the most clinically important?
The most interesting data that was presented this year at the World GI probably in looking at the population of patients that may benefit from the treatment, is the CORRECT study data of the addition of regorafenib. The reason for that is that in this setting, in this late refractory setting, these patients do not have further options. So definitely if regorafenib at the end gets approved by… the full recommendation has been reviewed by the regulatory authorities, both in the United States, in Europe and in other countries, this is going to be a new treatment option for patients in the late stage where, as mentioned, they don’t have further options. All the other trials that I have discussed before and I have mentioned, like the TML data, also the VELOUR study with aflibercept, actually what they’d like to figure out is whether in the second line setting one option is better than the other. But we do have options in second line and even in the third line for the KRAS wild-type tumours. But in the later stages, this means third line for KRAS mutant tumours or fourth line for KRAS wild-type tumours, actually we don’t have further options. And here regorafenib is definitely a new option for these patients.
What were some of the treatments that patients would have been on before regorafenib?
One of the inclusion criteria, actually, is that all patients should have exhausted all available treatment options. This means that all patients should have received oxaliplatin-based chemotherapy, irinotecan-based chemotherapy, bevacizumab at any time of the treatment, and for those patients that had KRAS wild-type tumours, they had to have either received cetuximab or panitumumab. So, all available approved options had to be considered in this trial in the previous treatment for patients.
The FDA has just given priority review status to these regorafenib data, what effect will that have in Europe?
The fact that the FDA has considered the approval of regorafenib in the later stage advanced colorectal cancer, my first drug, actually makes things a little bit easier in the United States where probably this drug is going to be available very rapidly. Unfortunately, this does not translate immediately to the same type of approval by the European authorities, they are much more conservative so they are going to evaluate the full datasets. This means that probably it’s going to take one year more in Europe to get the drug approved by the European authorities. Nevertheless, in the meantime there is a planned extended access programme for regorafenib in these later stage metastatic colorectal cancers, so this means that patients may be able to receive this drug even if it’s not approved because of this extended access programme.
What are your thoughts on where the treatment of mCRC is headed?
One of the things that has been discussed during today is the way that we should develop new drugs in patients with gastrointestinal malignancies, focussing especially on colorectal cancer. So colorectal cancer is no longer a unique disease, it’s very clear that there are different subtypes and this is the same in the other tumour types so we are investing and generating more and more platforms just to micro-dissect the different tumour subtypes that patients have in order to do more rational based trials, trials based on the biology of the disease and the mechanism of action of these drugs in the disease, but also the mechanisms of resistance, either primary or secondary. So we have been discussing also during these days the way that we should move forward with this rational based drug development and one of the things that we discussed two days ago was to establish a platform in the context of the European Union, sponsored by the EORTC, and this is what we call the Spectacle Platform. This is a platform that is going to be established in all countries in which you will be able to molecularly profile any tumour from any patient with colorectal cancer in the countries of the European Union. Then, with this information, the physician that is treating the patient is going to be able to treat him or her with the regular options or even to include this patient in a clinical trial more focussed on a particular target or a particular pathway that is de-regulated in the tumour that the patient has.
