Anti-angiogenic trials; key highlights of the 14th WCGC
Professor Eric Van Cutsem – University Hospital Leuven, Gasthuisberg, Belgium
How has the treatment landscape for mCRC changed since the first WCGC was held?
We see we have clearly made progress over the past fourteen years in the treatment of metastatic colorectal cancer with a couple of, let’s say, general ideas. One, we have introduced different agents, today we have a cytotoxics fluorouracil, irinotecan, oxaliplatin; we have introduced over the past years bevacizumab and then also the anti-EGFR targeted antibodies cetuximab and panitumumab. Then this year we have now positive data for aflibercept and regorafenib and we expect that these drugs will also be approved in the future. So the panel of different drugs is increasing, on top of that we have a validated biomarker, at least a predictive biomarker for KRAS mutant patients, saying that, KRAS mutant patients do not benefit, with a few exceptions always, from cetuximab or panitumumab. So we have learnt a lot on the molecular biology, on the targets, and we are starting to learn aspects on the markers. Second, what is important also is the multi-modal approach; fifteen years ago we rarely did resection of liver metastases, today it is a way to cure some patients. Resecting liver metastases or lung metastases, if we can obtain a complete resection we can cure some patients. On top of that, we have learned more the strategy that if you have patients with initially non-resectable metastases, liver metastases for instance, if we can give them one of the better chemotherapy cocktails in combination with the biological targeted agents, we can downsize some of the metastases from initially not resectable to resectable. So that we can cure some patients, we can convert these metastases from non-resectable disease to resectable. So the revolution in strategic thinking and multidisciplinary approach, multi-modal approach, has changed completely over the last fifteen years.
What were some of the important themes talked about at WCGC?
We see several important developments in GI cancer. A general theme is the multidisciplinary approach, that it’s clear that if you can go for expert centres and expertise and then link that to multidisciplinarity that that’s better for the patient outcome in general. There are several of the sessions where there is a focus on the aspects of chemotherapy, surgery, radiotherapy, sequential treatment strategies, combining the different treatment options, so that’s a first important theme. A second important theme is the development of micro-markers where we see more and more data coming through that micro-markers are crucial and are important and may be more and more important. Many of them still need further validation but our knowledge is clearly increasing. The example of KRAS is well known in colorectal cancer as a predictive marker for lack of activity for anti-EGFR targeted antibodies, but also in gastric cancer we see an increasing knowledge. For instance, what was known already was the HER2 story, that HER2 is an important target for antibodies, for trastuzumab in gastric cancer, but also, for instance, at this meeting there was a lot of discussion on c-Met as an important target as well for gastric cancer as hepatocellular carcinoma. We know that 40-50% of gastric cancers express Met on the immunohistochemistry and we have at least phase II data that inhibition of this, or targeting the Met receptor with antibodies may lead to activity in patients with gastric cancer, and the same with c-Met with hepatocellular carcinoma.
What recent developments in pancreatic cancer were discussed?
We’ve seen several new studies, most of them were phase II studies and then there was a discussion on the emerging phase III data that will come through in the near future in pancreatic cancer. Because metastatic pancreatic cancer is a very bad disease, most patients will die very fast unfortunately. But there are now expectations that maybe some changes, we have seen already the data on FOLFIRINOX, and what we see is that FOLFIRINOX, at least in patients in very good condition, in a selected group of patients, is becoming a reference treatment in these patients. But it means also that the bar is becoming higher and that we will see some other data, for instance the Abraxane data may be reported soon. There was some discussion on the potential role of Sparcure or the potential role of hENT as a predictive marker for gemcitabine in pancreatic cancer.
Are there any studies in particular you’d like to highlight?
2012 was a year where there were important data on angiogenesis. We have seen three sets of data this year that are important and we’ve seen some new updates also at this meeting on these agents. First of all, the concept of continuation with bevacizumab in second line after progression on bevacizumab plus a chemotherapy backbone, what we see is that the TML trial, as it is called, is a pivotal proof of concept study that shows that in second line patients continuing bevacizumab after progression on first line, that in this situation, after continuing bevacizumab and just switching the chemotherapy, that these patients have a better outcome. I will present data at this meeting for the first time that this is regardless of KRAS status, that this was true as well in KRAS mutant as in KRAS wild-type patients. The progression free survival was prolonged with this progression continuation concept and strategy in KRAS wild-type and mutant patients.
Can you comment on the AFFIRM study?
The second drug is aflibercept, the first data for aflibercept were presented last year at the same ESMO GI meeting here in Barcelona. We now have more robust data of aflibercept in second line, also showing that one third of the patients were pre-treated with bevacizumab and then also in this group of patients pre-treated in first line with bevacizumab, in second line the continuation of or the change to aflibercept improves the outcome. So that’s an important dataset also regarding angiogenesis.
CORRECT study data were also presented, could you tell us about that trial?
The CORRECT study is a study that evaluates the activity of regorafenib. Regorafenib is an oral multi-tyrosine kinase inhibitor targeting different targets. We did a randomised study in patients failing all different treatment options, failing the classic cytotoxics fluorouracil, irinotecan, oxaliplatin as well as bevacizumab and the anti-EGFR targeted antibodies in KRAS wild-type patients. We did a study in last line, regorafenib versus placebo, 2:1 randomisation, and we have shown that the survival, as well as the progression free survival, was clearly prolonged with regorafenib compared to placebo. This is an important study because this is a patient population where there is an unmet need, we don’t have other treatment options in these patients and with this drug we can improve the survival as well as the progression free survival.
What have been some of the reactions to the CORRECT trial data since they were first presented at ASCO 2012?
The reactions were that it is very interesting that there is an unmet need for patients in this situation, that’s an important reaction. Of course we don’t cure patients and the difference, although a statistically significant difference and although also clinically relevant, remains modest but you have to realise that this is a very difficult situation, these patients failing all different treatment options. That’s why many of my colleagues are happy in that this drug will be taken forward. Of course we have to learn and it’s clear that not all patients do benefit from regorafenib but if you look at the progression free survival curves, the initial six weeks, the first six weeks in the placebo and the regorafenib arm they are together and then they start separating. If you see a curve like that, that means that there is probably a marker so that we can select which patients do benefit and which patients do not benefit. That’s going to be important that we do enormous efforts and that’s also what my colleagues want, that we do efforts to try to find out which patients do not benefit or positively which patients do benefit in this setting. We have started with a biomarker programme also for regorafenib to find that out.
Would regorafenib work in other tumour types?
Regorafenib is an interesting drug because also at the last ASCO meeting there was some interesting data presented of the third line trial. Patients with GIST, gastrointestinal stromal tumours, failing imatinib and sunitinib, and in third line it was randomisation regorafenib versus placebo, and they’ve shown also the trial met the primary endpoint which was a progression free survival. It was an important difference of the progression free survival in patients with GIST so this year, 2012, we have seen two interesting and important phase III trials showing the activity and confirming the activity of regorafenib in chemo-refractory metastatic colorectal cancer and in third line GIST tumours.
PETACC8 trial results were presented for the first time at the WCGC, could you comment on the trial?
Another important study that was presented for the first time at this meeting is a randomised phase III study from the PETACC group which is a pan-European group trial in adjuvant colon cancer. We did this study, a large study, in more than 2,000 patients, stage 3 colon cancer. We randomised the patients with FOLFOX or FOLFOX cetuximab and we enriched the population for KRAS wild-type patients. The results were presented here at this meeting for the first time and they’ve shown that there was no benefit of adding cetuximab to FOLFOX in stage 3 colon cancer patients. We don’t have an explanation why this is but the data are quite robust and are consistent data that are presented here. The interesting discussion point is why is the effect of cetuximab in KRAS wild-type patients when combined with FOLFOX different in stage 3, such as the adjuvant PETACC8 study that is being presented here, compared to stage 4, to patients with metastatic disease. Nobody has a good explanation, several hypotheses are brought forward and are being discussed also here at the meeting but the data are quite robust and consistent as they are being presented here for the first time.