New Data Support De-escalating Chemotherapy in Colorectal Cancer

David J. Kerr, CBE, MD, DSc


June 29, 2021

This transcript has been edited for clarity.

I'm David Kerr, professor of cancer medicine at University of Oxford in England. It's come to that time of year when we consider what we've learned from the American Society for Clinical Oncology (ASCO) annual meeting. In terms of colorectal cancer news, there wasn't a huge amount of new practice-changing information that came out. We know that for any tumor type, information waxes and wanes. And this was a rather lean year.

I picked up on one or two interesting studies. KEYNOTE-177 reaffirmed what we knew when comparing pembrolizumab vs chemotherapy in frontline treatment for patients who've got mismatch repair–deficient colorectal cancer: The treatment of choice is pembrolizumab.

This was a much-touted final report of the overall survival benefits, which weren't seen because a significant number of the patients who had received chemotherapy crossed over, at some stage during their patient journey, to an immune checkpoint inhibitor. Of course, that obfuscated any overall survival benefit, But every other element of clinical activity that we look at, including safety, hugely favors pembrolizumab. So it was a reaffirmation, if you like, of the importance of the immune checkpoint inhibitors as first-line treatment in this setting.

A theme we come back to from time to time, and something I'm interested in, is the idea of stopping or de-escalating chemotherapy in patients with advanced and metastatic disease. We know that there is a good literature of randomized trials in which chemotherapy is initiated for 2, 3, 4 months, followed by a chemotherapy holiday, and then restarting chemotherapy when the tumor starts to regrow, or of de-escalating chemotherapy — usually taking oxaliplatin out of the combination regime — and continuing with an infusion of 5-FU/leucovorin/capecitabine.

Two interesting studies bear on this issue. The first study was reported by an excellent German group who looked at maintenance therapy with panitumumab. These patients had wild-type RAS metastatic disease and were treated initially with an infusion of chemotherapy — oxaliplatin (FOLFOX) plus 5-FU/leucovorin and panitumumab. After the induction period, they were randomly assigned to receive 5-FU/leucovorin alone or 5-FU/leucovorin plus panitumumab. The study found a significant benefit in progression-free survival (PFS). Those patients who continued with 5-FU/ leucovorin plus panitumumab had a PFS of around 8.8 months compared with 5.7 months in those who received 5-FU/leucovorin alone. It was difficult to discern any impact on overall survival.

Make of those details what you will. This was a trial with about 250 patients, and in those patients with wild-type RAS, PFS can be extended if the antibody is continued in combination with a de-escalated infusion of 5-FU/leucovorin. Of course, that will likely have a negative impact in terms of quality of life and safety.

The final study I want to discuss is in the same broad area. The study was from our own FOCUS4 group in the United Kingdom. This is a complicated trial that seeks to put patients into different genetic categories following a period of induction therapy. Those patients for whom there wasn't an obvious precision medicine–tailored treatment went into a randomized trial of capecitabine vs active monitoring (undergoing CT scan every couple of months).

This was a randomized trial with around 250 patients, and the results were not enormously compelling. They showed that oral capecitabine maintenance treatment improved PFS by around 4 months vs 2 months in the active monitoring group (doing nothing but following up with CT scans). There was no impact on overall survival, which was around 13.9 months in the capecitabine group vs 13.3 months in the active monitoring group.

Let me tell you what I do. When I see patients who present initially with a large metastatic tumor burden, regardless of the degree of response, I tend to use de-escalated chemotherapy. When patients present initially with an oligometastatic tumor burden, stable disease, and a good treatment response, I tend to give them a chemotherapy holiday, without any impact on overall survival, and with somewhat of an improvement in quality of life. I have no hard evidence to support doing that, apart from the fact that when we look at depth of response and initial disease burden, those are the patients who tend to progress more rapidly and therefore in whom improving PFS just might — again, no hard evidence; this is me being "old Doc Kerr" — but in that setting, this approach just might improve overall survival.

Thanks very much indeed for listening. I would be very interested in any comments you have about anything important you've picked up at ASCO that I've missed.

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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