David J. Kerr, CBE, MD, DSc, FRCP, FMedSci


May 31, 2016

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Hello. I am David Kerr, professor of cancer medicine from the University of Oxford. It is that time of year again, when all eyes, roads, and feet move toward Chicago and the American Society of Clinical Oncology (ASCO) Annual Meeting. I would like to give you an idea of some highlights, particularly focusing on the colorectal cancer oral session. There are some interesting clusters of abstracts on immune checkpoint inhibitors and some novel prognostic markers for advanced disease, as well as a couple of interesting surgical trials.

Doubling Up on Immune Checkpoint Inhibitors

For immune checkpoint inhibitors, there is a randomized phase 2 study[1] in which we see the report of nivolumab versus a combination of nivolumab and ipilimumab. We know that these are immune checkpoint inhibitors that function in different molecular pathways. For patients who have microsatellite unstable disease with advanced metastatic colorectal cancer, there is definite activity here. It's too early to see whether the combination is superior to single-agent nivolumab, but it does look as if both regimens are pretty well tolerated. We await the results with interest to see if the combination gives some hint of superiority.

Some interesting work is being done in patients with metastatic refractory squamous cell cancer of the anus.[2] Again, the results are showing a very reasonable phase 2 response rate to nivolumab. Not surprisingly, these squamous tumors look as if they may also be responsive to immune checkpoint inhibition.

One study caught my eye and I found it quite fascinating in terms of the logic of combination. Everybody seems to agree that the future of immune oncology is with combinations, to see if they can push up response rates and make a longer, more sustainable response. There is a very interesting piece of work in which the clinical activity and safety of a MEK inhibitor, cobimetinib, was combined with another PD-L1 inhibitor, atezolizumab, in patients with advanced colorectal cancer.[3] Why is this interesting? Because there is some preclinical work suggesting that the MEK inhibitor can upregulate MHC class 1. It can reduce regulatory T-cell infiltrations. The MEK inhibitor primes the colorectal cancer and makes it more of an immune target.

We know that colorectal cancers tend to be heavily immuno-edited. They downregulate everything in terms of neo-antigen presentation. So, in this study they only took patients with microsatellite stable disease, and it did look as if there were hints of activity. The combination with the MEK inhibitor did do what it said in the tin. It did upregulate MHC 1 and 2. It also had a reasonable response rate. It was a very clever idea.

Prognostic Markers for Advanced Disease

In prognosis, there is quite a lot of interest in the Immunoscore, which has been validated in a worldwide study with 39 laboratories and 1400 patients—not an incredibly huge number, but enough to suggest that it may be of some use in stage II disease.[4] There is a lot of work going on in the sidedness of tumors. Tumors that are left-sided in patients with advanced disease carry a better prognosis than right-sided tumors. We have confirmation of that from a randomized clinical trial.[5]

Then, we have an expanded version, in which investigators went to cancer registries to show that patients with stage IV disease in which the primary tumor is right-sided carry a significantly worse prognosis than those with left-sided tumors.[6] Left-sidedness is from the splenic flexure down to the rectum. Right-sided tumors are obviously from the cecum to the transverse colon.

What is the molecular basis of this? It may have to do with a greater number of BRAF mutations on the right side. There may be a greater degree of methylation. People are starting to try to unravel the molecular basis of sidedness and why it carries a significant difference in prognosis.

Surgical Trials

Finally, there are two well-conducted surgical studies. There is a nice study from the United Kingdom in which they compared immediate operation vs endoluminal stenting as a bridge to operation.[7] Still in the United Kingdom, 20% of patients with colorectal cancer present as emergencies; 80% of those present with obstruction. Should we proceed to do a primary operation or colostomy or can we use endoluminal stenting? Are there any advantages to stenting? It looks as if there are.

Patients who were endoluminally stented had a significantly lower colostomy rate. If you look at indices of recurrent survival, there is no difference whatsoever. At least we can say that endoluminal stenting, which successfully relieves symptoms of obstruction in about 80% of patients, is a very reasonable bridge to undertake.

Finally, there is a study from Japan with about 700 patients who were randomized to total mesorectal excision (TME) or TME and lateral lymph node dissection.[8] This has been a Japanese gold standard for some time, some would say. It was a smallish study, and therefore there are caveats. It was designed along the lines of noninferiority, suggesting that TME would be noninferior to TME plus the more complex lateral lymph node dissection.

I found the results slightly difficult to interpret from the abstract, which suggested that for overall recurrence-free survival, there was no difference between the two groups. However, when you count the number of recurrences, they seem to be statistically significantly higher in the group that received only TME. There is a confusing lack of concordance between the overall big-picture figures for which the trial was powered and the actual number of recurrences. Perhaps those recurrences happened, but upon subsequent treatment—perhaps reoperation—they had no negative impact on overall survival. I guess we need to hear the presentation to understand.

It is going to be a good meeting. I am going to give some talks myself. I'm going to do something in the educational section about better value in cancer care, which is something close to my heart. I have a couple of posters. I would love to meet you.


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