COMMENTARY

David Kerr on ESMO's Most Important Colorectal Cancer Trials

David J. Kerr, CBE, MD, DSc

Disclosures

October 09, 2020

This transcript has been edited for clarity.

Hello. I'm David Kerr, professor of cancer medicine at University of Oxford.

Today I want to talk about a couple of interesting presentations from the recent virtual meeting of the European Society for Medical Oncology (ESMO).

All of us are becoming used to tapping into streamed-live major cancer meetings, and the ESMO team has done a fantastic job of pulling together a great program and delivering it on a technical platform that works well. So, a big thumbs-up for ESMO.

As always with these meetings, one finds an eclectic mixture of presentations to capture one's attention.

Chemo Alone or Surgery Plus Chemo for Stage IV Colorectal Cancer?

Our Japanese colleagues presented updated results of their randomized phase 3 trial in which they randomly assigned 165 patients with incurable stage IV colorectal cancer to receive chemotherapy alone or surgery to remove the primary tumor, followed by chemotherapy.

The primary outcome was overall survival. The study found no survival benefit for resection. In fact, there were three postoperative deaths due to complications in the resection arm. Their very firm conclusion was that resection of a primary tumor is not recommended for patients with an asymptomatic primary colorectal tumor and synchronous unresectable metastases.

This is an influential study, even though it is small and we'd love to have seen larger numbers. We've debated this in our multidisciplinary team. Some observational studies give conflicting results, suggesting benefits from having resection of the primary tumor; but in this first randomized trial, there are no benefits at all. Therefore, we would now hesitate to make a recommendation for surgery.

Circulating Tumor DNA

Quite a bit of work at the meeting looked at the low copy number circulating DNA and its role in the adjuvant setting in early disease.

This is an area where we need a lot of help. We know that [in the oligometastatic colorectal cancer setting] the disease recurs in 70% of patients following hepatic or pulmonary metastasectomy, but there's a big question mark as to whether we should be offering adjuvant chemotherapy. In our multidisciplinary team, we do not. We don't think there's sufficient evidence of the benefits of post-metastasectomy quasi-adjuvant chemotherapy to offer it routinely.

An interesting study from an Italian group examined circulating tumor DNA for the detection of minimal residual disease (MRD) in patients after resection of metastases. They looked at a total of 100 patients and used a nested PCR methodology for detecting the circulating DNA. The results were rather compelling: MRD positivity, determined by measuring the low copy number [circulating] DNA, was observed in about half the patients, of whom 86.5% eventually relapsed.

MRD-positive status was also associated with an inferior overall survival, with a huge hazard ratio. At the time of the analysis, 98% of patients in the MRD-negative arm were alive, compared with only around 57% in the MRD-positive arm. Without any doubt, the circulating DNA status was the most significant prognostic factor and was associated with a hazard ratio between 4 and 5.

We've been searching for tissue biomarkers that might allow us to identify patients who are at high risk for relapse and for whom we would want to offer post-metastasectomy chemotherapy. To be honest, looking at tumor burden, RAS status, and so on has been somewhat helpful but has not resulted in hazard ratios that would make a difference. The results of this study look fascinating. It needs to be replicated and expanded to larger numbers, but it is very interesting indeed.

Regorafenib Plus Toripalimab

An early-phase clinical trial from China looked at combining regorafenib, a multitargeted kinase inhibitor approved for third-line treatment in colorectal cancer, with toripalimab, a PD-1 inhibitor, in patients with microsatellite-stable disease who had progressed through two or more lines of therapy.

They found that the combination of regorafenib (80 mg) and toripalimab (3 mg/kg) induced an overall response rate of nearly 14%, a disease control rate of around 35%, and a progression-free survival of 3 months. There is other work looking at different combinations of regorafenib with other PD-1 and PD-L1 inhibitors.

This gives us a feel for the sorts of results we're seeing, with disease control rates at 30%-50% and an overall response rate in the low teens. This is something that may be worth considering in combination, but always with an eye on the potential toxicity of regorafenib.

Fluoropyrimidine Cardiotoxicity

Finally, I want to talk about the cardiotoxicity associated with fluoropyrimidine chemotherapy.

A study from Italy included only 135 patients, but interestingly, in this cohort, 20% of patients suffered a cardiac event: dysrhythmia, destabilizing angina, or heart attack. I believe that all of us who give a lot of fluoropyrimidines are becoming anxious about their cardiac side effects. We do need to better understand which patients would be most sensitive to that adverse effect.

This study showed that there seemed to be no relationship with preexisting cardiovascular comorbidities. They looked at BNP (brain natriuretic peptide) and some other markers with microRNA that haven't been sufficiently informative, but this is a small cohort.

Our group has been looking at germline polymorphisms, and we think we may have identified a lead from one of our larger genome-wide association studies that identifies patients at risk.

This is an awful effect, but it happens. We've had a slow but entirely memorable number of patients with sudden cardiac death, usually with the first exposure to fluoropyrimidine. Ours have been relatively young patients treated in the adjuvant setting, and one never forgets that. So, anything we can do to understand the biology and to come up with biomarkers, the better.

As always, I'm interested in your feedback on the ESMO meeting and also about attending these larger meetings virtually. Does it work for you? Is it better than having to travel to Chicago or Madrid or wherever? Is the virtual meeting here to stay?

Thanks for listening. For the time being, Medscapers, over and out.

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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