ECC 2015

Add panitumumab or bevacizumab to improve first-line metastatic colorectal cancer therapy?

Dr Fernardo Rivera - Hospital Universitario Marques de Valdecilla, Santander, Spain

You’ve been conducting the PEAK trial, you were looking particularly at metastatic colorectal cancer and ways of improving therapy. What were you trying to do in this study?

In patients with RAS wildtype metastatic colorectal cancer we have today two possible new drug treatments. One is anti-EGFR monoclonal antibodies, we have panitumumab and cetuximab, and the other possible treatment is bevacizumab. So it’s not possible to combine them because we have negative results when we have tried to combine these two different drugs and we have to use one first and then the other. We don’t know which is the best sequence, which targeted agent should be used in first line. So in this trial we are comparing both treatments, bevacizumab versus panitumumab, combined with chemotherapy in first line treatment of RAS wildtype patients with metastatic colorectal cancer. It’s not the only trial to have done this, there’s another two trials.

And all the patients had FOLFOX of course?

Yes, yes, the backbone was FOLFOX and FOLFOX was combined with bevacizumab or with panitumumab.

OK, so you’ve gone head to head with an EGFR based therapy against a VEGF therapy, what happened?

In the PEAK trial, the PEAK trial is not a very big trial, it’s only a randomised phase II trial that originally included 283 patients with KRAS wildtype. But after the trial had been conducted we know now that only patients with K and NRAS wildtype tumours benefit from these drugs. So we have to repeat the analysis focussing on the patients with K and NRAS wildtype, that was really only 170 patients. So it’s not a very big number of patients.

But what happened?

What happened in this subgroup of patients, the primary endpoint of the trial was progression free survival. We have now analysed, we have the final results of the trial with a longer follow-up with mature data and progression free survival is better in the panitumumab arm, that was the primary endpoint of the trial. The response rate was the secondary endpoint, according to this criteria it was not different between the two arms but overall survival, which was a secondary endpoint, in the first analysis that was published one year ago in the JCO, numerically median overall survival was quite more important in the panitumumab arm. The difference was more than twelve months but in this first analysis the follow-up was short and the survival data was not mature. We are presenting now mature data for overall survival; it’s a very important thing of this presentation. With longer follow-up and with mature data in this final analysis overall survival is still numerically better in the panitumumab arm but the difference is not really statistically significant.

Right, now it is important to get that statistical significance. What should doctors be taking home from these findings?

There are important messages. It’s not clear which new targeted drugs, VEGFR inhibitor versus anti-EGFR inhibitor is better in first line. The PEAK trial is not the only trial, we have another two trials, the FIRE-3 trial that obtained better overall survival with cetuximab, that is another anti-EGFR monoclonal antibody, versus bevacizumab. So two trials with better results with anti-EGFR but you have a third trial, that is the CALGB trial. We have not all the data from the CALGB trial yet but with the data we have no differences in overall survival. So it’s not clear. But taking all the results together there’s a bit more data in favour today of anti-EGFR monoclonal antibodies.

However, toxicity would come into it also. Are there different toxicities between these two different approaches?

Yes, the toxicity is really very different between these two approaches. The main toxicity in the EGFR monoclonal antibodies is the skin toxicity, it’s not a life-threatening toxicity, not toxicity but it’s very bad for the quality of life of the patients. The main toxicity of anti-VEGFR are mainly vascular toxicity, hypertension, arterial thrombosis, that is a very important toxicity but it’s infrequent. So really they are different toxicities, probably for the quality of life of the patient skin toxicity is a bit more problematic but if you really have improvement in important results like overall survival it’s… Yes, I think if you balance the toxicity and the improvement there is really probably today in some groups of patients, probably it would depend on the monoclonal antibodies.

Could you then sum up very briefly the interim recommendations to doctors?

I have another data that we have presented at this. Also the response is similar between the two arms. If we consider the quality of the response its better with the panitumumab response, it lasts longer, it’s obtained earlier and it’s deeper with panitumumab. Other trials have also said this. So for some kinds of patients, probably patients with potentially susceptible disease that you need a response, a very good response, because you can’t perform a surgery and currently cure it.

Are you leaning in the direction of EGFR based therapies rather than VEGF based therapies or not?

I think that probably we would need a better selection of the patients, an even better selection, because we have first KRAS positions then we have other RAS mutations, K and NRAS, and better selection, more improvement with anti-EGFR. Probably the next step will be BRAF mutations, other possibilities. But with each step we are focussing more and more the benefit in a very select group of patients and I think that today with RAS wildtype tumours probably we have better results, especially if you need a response, patients with potentially susceptible disease, patients with very aggressive disease with antibodies. But to use as well is another option, it’s not permanent, it’s open the question.