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The Which: Clinical Evidence and Ongoing Trials in Anti-Angiogenic Treatments - Colorectal Cancer

I. Chau (United Kingdom)

Ian Chau covers the challenges of treating colorectal cancer, looking at the molecular characterization and current systemic therapies. The presentation includes relevant clinical trials and considers different treatment paradigms.


Disclosure statement

I would like to thank Elsevier for the kind invitation.  Colorectal cancer really is becoming quite a complex disease to treat.  

Full transcription

Full transcription

Disclosure statement

I would like to thank Elsevier for the kind invitation.  Colorectal cancer really is becoming quite a complex disease to treat. 

Systemic therapy for mCRC (ESMO guideline)

We now have many systemic therapy options for metastatic colorectal cancer.

This is a diagram from the ESMO guideline that was published in the Annals of Oncology 2012.  You can see this almost looks like a mess, you know, just one line leading to another – a horrible, complicated tube map around major world cities.

Current systemic therapy for mCRC (ESMO guideline)

A few years afterwards, Eric Van Cutsem published his in the Annals of Oncology which looks a bit simpler in terms of how you add the paradigm or the treatment algorithm you use in mCRC.

Current systemic therapy for mCRC (2015)

But this was published in 2014 and of course since then we have other agents that have become available that have become available; ramucirumab which is now licensed, at least in the US in conjunction with FOLFIRI in the second line and then TAS-102 was of course licensed I think only last week in the US based on another successful Phase III study.

So there are even more agents to be put into the mix of treating mCRC and that’s actually not even taking into account maintenance chemotherapy which we now know is of course a very important strategy in the treatment of mCRC.  And in among all this we also still need to think about some of the locoregional treatments for oligometastasis; resection, radiofrequency ablation, microwave ablation, SIRT as well as external beam radiation.

Comprehensive molecular characterization of human colon and rectal cancer

So really in looking at this complex time, we need to think about what else is important in colorectal cancer, so the Cancer Genome Atlas published three or four years ago now for colorectal cancer using exome sequencing, messenger as well as micro RNA and promoter methylation analysis and really have identified all these very important signalling pathways for colorectal cancer. Yet if you look at the therapeutic effort, it is mainly concentrated on this RAS/RAF pathway.

Slide showing world map

If you look at the Genome Atlas and imagine this is actually the world atlas and then you look at this thinking ‘Well actually, it looks like we are only concentrating in the North-East corner of the world’ - Japan may be a very, very important country but that’s not really the only country that one should focus on. You really have to look at the whole world.

71% of the Earth’s surface is covered by the ocean

In fact, if you think about it, 71% of the earth’s surface is actually covered by the ocean and in order to conquer this world one of the most important things is we have to conquer the ocean.

The empire on which the sun never sets

You probably know that the empire on which the sun never sets first referred to the Spanish empire and then subsequently to of course Great Britain in the 19th Century and in order to conquer this world, what did they need?  They needed a navy.  Okay, so we really need to harness the microenvironment of the cancer in order to be able to move forward with this,

Agents targeting the tumour microenvironment

Of course immuno-oncology or targeting the immune system is one of the most important or most exciting areas that we are concentrating on.

But another part of the tumour microenvironment is of course the subject of today’s symposium which is the angiogenesis and of course angiogenesis has been a very successful strategy in treating metastatic colorectal cancer really for a decade now.

Efficacy of bevacizumab in randomized phase III trials in first-line mCRC

The first-line study which you are all very familiar with has been reported now.  The original IFL study was back in 2004 when it was published. But perhaps more recent data which is the TRIBE data which is comparing FOLFIRI plus bevacizumab versus FOLFOXIRI plus bevacizumab has really taken us back to again looking at the molecular subtypes. In this particular situation, the BRAF mutation, there is a suggestion that combining FOLFOXIRI with bevacizumab may be a strategy for BRAF mutation.

TRIBE treatment effects differ in molecular subgroups


So maybe not everything has to be targeted towards the actual gene but in fact targeting the microenvironment is also important, but this is of course very, very hypothesis-generating because of the small number of patients in the TRIBE data.

Efficacy of anti-angiogenic drugs in second- and subsequent-line mCRC

Now moving on to the second and subsequent line mCRC, there are of course several very large-scale randomised controlled trials addressing or targeting the angiogenesis; the original ECOG 3200 and then subsequently, or more recently the ML18147 so-called TML study, the VELOUR study, the RAISE study and then looking at regorafenib, the CORRECT study.

But maybe if you just concentrate on the hazard ratio for overall survival of the more recent TML study, the VELOUR study and the RAISE study, you can see the hazard ratio in fact was very similar among all these three studies.

Baseline characteristics in trials of anti-angiogenic drugs in second-line mCRC

But if you look at the eligibility criteria of these three studies, there are actually some subtle but very important differences that may really give some clues in the day-to-day clinical practice about what one may need to do.

In the TML study, or the ML18147, first of all patients are only allowed in if their first-line progression was more than three months, so if in your first-line treatment you had a disease progression within three months, you are not eligible.

The other thing to say is patients who would progress very shortly after adjuvant chemotherapy were again not eligible in the ML18147 and I think these subtle differences may need to be taken into account when we think about how to treat patients on a day-to-day basis.

Unresectable mCRC treatment paradigm

So now if you look at patients who actually progressed very shortly after adjuvant oxaliplatin-based chemotherapy then of course most clinicians would not like to re-use oxaliplatin so quickly, so they probably would use FOLFIRI plus bevacizumab, or if they are RAS wild type of course one of the other treatment options is FOLFIRI plus cetuximab.

It does actually fit into the patient population for VELOUR, so of course another option would be to use FOLFIRI plus aflibercept.

Now if they progress through this FOLFIRI regimen, some may rechallenge them with FOLFOX plus bevacizumab and for those who have not had an EGFR antibody, then using the cetuximab or panitumumab as monotherapy is an accepted treatment option.

Unresectable mCRC treatment paradigm

If you look at the benefits of EGFR antibody you can argue that the hazard ratio is in fact more in favour if you treat it at a later line.  If you look at the NCIC CO.17, the hazard ratio is still 0.55.  When you look at the first-line CRYSTAL study, the hazard ratio is 0.796, so therefore one may be able to reserve EGFR antibody until later on and of course we have regorafenib or TAS-102.

Unresectable mCRC treatment paradigm

Now if you look at the patients who have not had adjuvant oxaliplatin chemotherapy and then they then develop metastatic disease, one would consider either CapOx or FOLFOX plus bevacizumab as a first-line treatment option.

For those who now have disease progression less than three months, remember I said in this particular population the TML study results actually do not apply, so really now it gives you the options of using either FOLFIRI plus ramucirumab according to RAISE date or FOLFIRI plus aflibercept according to the VELOUR study.

So in this situation one would still now need to think about if they still have oligometastases but they are unresectable, you may still want to think whether other locoregional treatment may be useful and then by having a higher response rate may be the way to go for.

Unresectable mCRC treatment paradigm

In this situation maybe FOLFIRI plus aflibercept is the treatment option to go for whereas if you think about that no locoregional treatment is worthwhile, you really are trying to give the patient the best quality of life with probably the least toxicity.

Grade 3/4 AEs in trials of anti-angiogenic drugs in second-line mCRC

Then if you look at the differences – this is of course cross-trial comparison, but if you look at the toxicity profile between the RAISE data and the VELOUR data you can see that with aflibercept there is a higher instance of diarrhoea, neutropenia and stomatitis compared to chemotherapy whereas in the RAISE data the ramucirumab do not really add huge amounts of side effects compared to chemotherapy alone.  Neutropenia is a bit more but not febrile neutropenia.

Unresectable mCRC treatment paradigm

Of course for those who have disease progression over three months, then bevacizumab is an option.

Subgroup analysis on overall survival: by timing of first-line disease progression

Here perhaps the resistance mechanism is where we really need to play a role.

VELOUR post-hoc analysis: by timing of first-line disease progression

If you look at the clinical data you can see that if you had disease progression within a very short time on your first-line, then you don’t actually benefit as much on continued bevacizumab compared to say the ramucirumab data or the VELOUR data.

Preclinical model demonstrates the advantage for bevacizumab resistance of switching different anti-angiogenic drugs

In a preclinical model, this is looking at DC101 which is a murine antibody for ramucirumab and then the S12 is mimicked more towards bevacizumab.

So if you have oxaliplatin plus a ligand bevacizumab antibody, S12 and then you progress, you switch and then you switch to DC101, then you do actually seem to do better than continuing with S12, which is bevacizumab. So these preclinical data are really saying that a switch may be a good idea when you have a short progression with a bevacizumab-based chemotherapy.

Continuing bevacizumab led to significantly increased circulating angiogenic factors, especially on progression

And of course clinically, as we heard, placental growth factor also goes up when we have a resistance on bevacizumab.

Aflibercept activity in CRC model progressing on bevacizumab treatment

Again there are preclinical data that switching to perhaps aflibercept may be a good idea when it’s a short-term benefit on bevacizumab alone.

Aflibercept activity in CRC model progressing on bevacizumab

Here is another set of preclinical data on patient-derived xenograft in support of switching to aflibercept and not continuing on bevacizumab.

Unresectable mCRC treatment paradigm

Again, these are the options.

Unresectable mCRC treatment paradigm

Very lastly, another first-line option when you are RAS wild type and are using FOLFOX + panitumumab based on the PRIME data, here it is a bit more difficult as there is no randomised control evidence to guide second and subsequent line therapy and therefore you can use FOLFIRI plus probably any of the anti-angiogenics and of course really leading to the paradigm that I mentioned before.

Unresectable mCRC treatment paradigm

Of course with this treatment paradigm we still need to put in maintenance therapy as well as the locoregional treatment or in a mix, so it is a complex story but there are different anti-angiogenic therapy options and we really need to try to do all this in order to benefit our patients.

Thank you very much.