Panitumumab triplet therapy in colorectal cancer

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Published: 9 Sep 2017
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Prof Michael Geißler - Klinikum Esslingen, Esslingen am Neckar, Germany

Prof Geißler speaks with ecancer at ESMO 2017 about the VOLFI trial of FOLFOXIRI chemotherapy combined with panitumumab, an EGFR binding antibody, to treat RAS wildtype metastatic colorectal cancer.

He introduces the rationale of the trial, to investigate the impact of any monoclonal antibody with a FOLFOX based chemotherapy backbone, and notes the significant increase to response rates in both left and right-sided colorectal tumours.

Prof Geißler also notes the number of patients eligible for resection of secondary disease, and that the lack of improvement in PFS among trial patients is typical for metastatic colorectal cancer.

An essential consideration for panitumumab suitability will be patient fitness, as Prof Geißler notes the significant toxicity profile associated with the triplet combination.

ecancer's filming has been kindly supported by Amgen through the ECMS Foundation. ecancer is editorially independent and there is no influence over content.

The VOLFI trial is sponsored by the AIO, it’s the first randomised trial comparing the very active FOLFOXIRI backbone, consisting of 5FU, irinotecan and oxaliplatin, with a modified FOLFOXIRI with some dose modifications plus any monoclonal antibody and in this case with the EGFR antibody panitumumab. The scientific rationale is that we know the higher response rates are the more likely is the deftness of response and the early tumour shrinkage. Both of these parameters translate into prolonged overall survival as demonstrated, for example, in the FIRE-3 trial. So far no trial has demonstrated that any monoclonal antibody against VEGF or EGFR has the possibility to improve outcomes against FOLFOXIRI alone. That means all trials so far are just one arm with cetuximab or panitumumab or bevacizumab or the TRIBE trial in both arms, FOLFIRI and FOLFOXIRI, bev was included. Therefore the VOLFI trial is now the first proof of concept study showing that a monoclonal antibody adds something on top of a very active triple chemotherapy backbone.

Could we start looking into some of the response rates from the trial?

Yes, the primary endpoint of this trial, the objective response rate, was clearly positive. There was a 25% increase in response rate by adding panitumumab to the FOLFOXIRI backbone with a dose reduction in irinotecan and 5FU. In my view this is a very interesting result because I never would have expected that the increase is as high as 25%.

This varied in terms of the outcomes for the left or right sided origin of the tumour?

Yes, of course. RAS wildtype, BRAF wildtype, left-sided are the best ones. We know that the left-sided colon cancers are very good, disease is treated with EGFR antibodies, this is the preferred treatment option in Europe on left-sided colorectal cancer. Here the response rates were above 90%. On the other side the response rates on the right side were lower but still 60%. So a 60% response rate on right-sided colon cancer is very, very high because these right-sided colon cancers are very aggressive. The most important finding of this trial, although the numbers of patients are small, are the 71% response rate in BRAF mutated disease. I think this is a striking result and demonstrates that EGFR monoclonal antibodies, in this case panitumumab, has effectivity not only left but also on the right side and also on BRAF mutated disease. Only in the response rates, we know not in PFS and not in OS, here the EGFR antibodies on the right side are not very active.

I was just about to ask how much that translates to progression free survival.

The progression free survival is not such a problem. We know from all trials, from the US trial, from the FIRE-3 trial, from PRIME, from PEAK, from CRYSTAL, that PFS sticks around 10.5-11.5 months. There is no significant improvement in PFS during the past ten years but we have the improvement in objective response rates and in overall survival. So with the new drug combinations, with the new biological agents against VEGF and EGFR we were not able to definitely prolong the PFS in a really clinically meaningful matter, statistically in some occurrences but not in a relevant clinical matter. But overall survival and objective response rates, they could be improved. Therefore, for me, it was not surprising that PFS was not different between the two arms.

I noted that some of the patients went on for a resection after treatment.

Yes, this was besides the objective response rate the major finding of this trial. It was astonishing that 70% of patients classified as potentially secondary resectable that they could be resected and the majority of them are 0. This is extremely clinically relevant, demonstrating to us if we use a very active protocol inducing remission then the surgeons have better options to resect metastatic lesions. In our trial just 10% were liver only patients, that means we had a lot of patients with lung metastases, with peritoneal carcinomatosis and all of them were also resected.

Finally, just a note on the toxicity of having the triplet combination?

Toxicity is a major issue. FOLFOXIRI is already a pretty toxic regimen and adding panitumumab to FOLFOXIRI, even with lowering the irinotecan dose and the 5FU pump, there is significant gastrointestinal toxicity and there are also significant infections. Therefore, this protocol should be used in fit patients, EGOC 0-1. The oldest patients in our trial were 75 years, very fit old patients. There one might use this protocol and it’s very recommended that in the first 4-5 weeks the patients should be visited two times a week in the first cycles. It’s very important to use growth factor support in case of severe infections and neutropenia.

That covers all my questions from the VOLFI trial, was there anything else you’d like to add to round it up?

We will have further data hopefully demonstrated at ASCO next year regarding overall survival, defeces response and early tumour shrinkage and also quality of life. Hopefully then the whole picture gets even stronger than now.