ESMO CRC Data Showcase 'Beauty' of Precision Medicine

This transcript has been edited for clarity.

I'm David Kerr, professor of cancer medicine from the University of Oxford. Today I'd like to discuss a couple of important, interesting abstracts that were presented in a recent ESMO meeting.

First of all, let me congratulate Solange Peters and my old friends from ESMO for running such a fantastic meeting in such difficult circumstances. I think the leadership of ESMO and ASCO have risen remarkably to adapting to the online delivery of these important meetings. Well done.

The two colorectal talks I'd like to discuss exemplify both the beauty and the increasing complexity of precision cancer medicine. As we understand more about the biology of the disease, we're starting to be able to develop ever-more sophisticated therapeutic interventions.

The first of these was a fantastic presentation from Jenny Seligmann, MD, and colleagues on the FOCUS4 study. The FOCUS group has done a brilliant job with their nested, randomized phase 2 studies looking at particular molecular subtypes.

Here, they focused on an important group of patients with advanced colorectal cancer who had double mutations in RAS and TP53, which was a surprisingly sizable group. About a third of all colorectal cancer patients with advanced disease have these co-terminate mutations in both genes.

They were interested in the role of WEE kinase. This is a kinase which is involved in cell cycle control of the G2/M transition, and control of some of the CDC kinases.

There were 69 patients who were untreated and had the double mutation. They were randomized 2:1 to the potent WEE inhibitor adavosertib vs active monitoring, which is a good expression for best supportive care. They found that the WEE kinase inhibitor adavosertib significantly prolonged progression-free survival, increasing it from about 2 months to about 3.6 months.

They found that the drug was more effective in left- rather than right-sided tumors. In those tumors, there was a hint — given the small patient population — that there might be an improvement in overall survival. There is much more to be done and larger trials are required. I've got to say this was a very clever hypothesis of selecting a subgroup of patients.

It's quite interesting that the KRAS mutations were rather specific to codons 12 and 13 rather than a wider range that we now look for. They did a nice job by pinning down a molecular genotype that allowed us to get this interesting hint of activity that we can follow further in larger randomized trials.

The other study that I'd like to discuss is from a fantastic Italian group, with the presentation by Filippo Pietrantonio, MD. They made a clever observation. They've been using temozolomide to treat colorectal cancer. They investigated a very hyperselected group of patients with advanced colorectal cancer that was microsatellite stable and had methylated MGMT.

That tiny subpopulation of patients was somewhat sensitive to temozolomide, but not really enough for it to emerge as an important therapeutic agent. Even more interestingly, they discovered that the resistance mechanisms that emerged in patients who were treated with temozolomide — in that small group — was a microsatellite-unstable phenotype characterized by increased tumor mutational burden and increased neoantigen load. This is a fantastically interesting observation in terms of emergence of a resistant population.

They hypothesized that, among patients who were microsatellite stable and MGMT silenced, if they primed them with temozolomide, the resistant emergent population would be sensitive to immune checkpoint inhibitors. If the tumors displayed an MSI-type phenotype, then this is exactly the patient group that does well in response to immune checkpoint inhibitors.

They conducted a study in which they primed patients with two cycles of temozolomide followed by combination treatment with low-dose ipilimumab and nivolumab. The results were rather striking. There were small patient numbers, but it was a very well-conducted study. They met their trial endpoint of 32% progression-free survival at 3 months. There was a delayed overall response rate of almost 40%. Therefore, the idea that we can uncloak immunoresistant tumors using these sorts of techniques, such as priming with temozolomide, is absolutely fascinating.

The whole area in which we explore how we can turn tumors that are immunologically cold into tumors that are hot, displaying multiple antigens, is very interesting. In addition to this clever trick to induce an MSI-type phenotype responsive to immune checkpoint inhibitors, there's work that's going on, including work of our own, using a variety of different epigenetic regulators to improve antigen presentation by increased expression of MHC, causing a significant influx of cytotoxic T cells and reducing T regulatory cell numbers within tumors. This is clever stuff.

We have two trials based on a strong, molecularly based hypothesis. We have some very interesting results which need to be exploited and followed up in further and larger trials, of course. Isn't that really lovely work? Isn't this a convincing taste that the future is here to stay?

The more we understand the biology of the disease, the cleverer we will be in our interventions, and the more segmented, narrow, and vertical our cancer treatments will be, where we can match the right drug, the right combination of drug, and the right sequence of drugs to the right patient.

Well done, ESMO. I have discussed two lovely pieces of work, which I recommend to you.

Thanks for listening, as always. I'm very interested if you've got any comments you'd like to make. For the time being, Medscapers, over and out. Thank you.

David J. Kerr, CBE, MD, DSc, is a professor of cancer medicine at the University of Oxford. He is recognized internationally for his work in the research and treatment of colorectal cancer and has founded three university spin-out companies: COBRA Therapeutics, Celleron Therapeutics, and Oxford Cancer Biomarkers. In 2002, he was appointed Commander of the British Empire by Queen Elizabeth II.

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