Gastrointestinal cancers: new standards of care from landmark trials

He discussed the two new trials. One is a study called ARGO, which is being done by the National Surgical Adjuvant Breast and Bowel Project, where people get standard adjuvant chemotherapy, and they’re then randomized to either 24 months of regorafenib 120 mg per day or a placebo. This is an attempt to recreate the transient benefit from bevacizumab in the NSABP C-08 trial. It’s accruing slowly because regorafenib has some toxicity associated with it, but it probably will be completed. Will it continue the benefit as seen in the 12 months of bevacizumab and C-08? We’ll see.

The other, more interesting study is being done in the cooperative groups looking at FOLFOX plus atezolizumab, one of the checkpoint inhibitors. The difficulty here is that only 15% of people with stage III disease have microsatellite instability (MSI)-high tumors, but it’s certainly compelling. This is a straight up comparison. It’s 6 months of FOLFOX in the control arm, or 6 months of FOLFOX plus atezolizumab concurrently for 6 months, and then an additional 6 months of atezolizumab. These are both very fascinating ideas.
 

DR HENRY To go back to one of your original points, this 3 versus 6 months: the neuropathy is significantly less in those getting the 3 months?
 

DR HALLER It went to 3%.
 

DR HENRY We all see that is very bothersome to patients. Before we leave colorectal, I must ask about the right-sided versus left-sided colorectal cancer that we hear a lot about now. Could you comment on how right-sided is worse than left-sided, and do we understand why?

DR HALLER There are two things to consider. If you look back even to simple trials of 5-FU or biochemical modulated 5-FU from 20 years ago, there were clear differences showing worse prognosis in patients with right-sided tumors, so that’s one point to be made. It’s been consistently seen but never acted upon. Then, the explanation for it, possibly, is that the right colon and left colon are two biologically different organs – and they are. Embryologically, the right colon comes from the midgut and the left colon comes from the hindgut, and there were several presentations at ASCO and at prior meetings showing that when you look at different mutations, they differ between the right and left colons. The right-sided tumors are more MSI-high and more BRAF-mutated, left-sided mutations less so.

Then, people started analyzing many of the very large colon cancer trials, including the US trial CALB/SWOG C80405 and the FIRE-3 trials in Europe, where backbone chemotherapy of FOLFIRI or FOLFOX was given with either cetuximab or bevacizumab in RAS wild-type patients. For one study, C80405, they saw that for cetuximab, on the right side, the median survival was 16.7 months and on the left side, it’s 36 months – a 20-month difference. In fact, if you look at the totality of the data, 16.7 almost looks like cetuximab is harming them, as if you were giving it to a RAS-mutated patient, but they were not. They were all RAS wild-type.

For bevacizumab, the right side was 24 months; the left side was 31.4 months. If you look at the left, cetuximab was 36 months and bevacizumab was 31.4 months, so it appears left-sided tumors should get more cetuximab than they are now getting in the US with a 5-month difference, but that decrement is much different on the right, where there’s an 8-month benefit for bevacizumab compared with cetuximab. There is a very good review by Dirk Arnold, who looked at a totality of 6 studies to really examine this more carefully.²

The National Comprehensive Cancer Network has chimed in on this, and is suggesting that for the 25% of people who have right-sided tumors, epidermal growth factor receptor (EGFR) agents not be considered in first-line therapy. NCCN did not go as far to say that EGFR agents should be given on the left side. As I said, the differences are much more impressive in the right, so this is a real sea change for people to consider which side of the tumor affects outcome.

Deb Schrag (Dana-Farber Cancer Institute) presented data at last year’s ASCO not only for stage IV disease showing the same thing, but also stage III disease where there are also right-versus-left differences in terms of recurrence, with a hazard ratio on the right side of about 1.4 compared with the left-sided tumors. Maybe it should be true that 3 months is especially good if you’re treating left-sided tumors, and maybe the right-sided tumor needs to be also calculated with the factors we just talked about. These are two big changes in an area in which we literally haven’t made any change since FOLFOX was introduced a decade ago.