Molecular Advances in Colorectal Cancer Are "Only the Tip of the Iceberg"

Tanios Bekaii-Saab, MD

There has been a significant evolution in the care of patients with metastatic colorectal cancer over the past 20 years. It’s been amazing. When I finished my fellowship around 2002, we had a few drugs—5-FU (5-fluorouracil) was our only option and irinotecan (Camptosar) was just approved. The average survival for patients was—with a stretch—about 11-12 months. Irinotecan pushed it a little bit. It was given with fluorouracil/leucovorin as a bolus, and it was tough for most patients. Then came oxaliplatin (Eloxatin), which added 1 cytotoxic option, and then capecitabine (Xeloda), an alternative option for a fluoropyrimidine. Following all this, it was essentially the era of biologics.

After 2004, we saw the introduction of bevacizumab (Avastin) and then cetuximab (Erbitux), panitumumab (Vectibix), and a number of other monoclonal antibodies that essentially target VEGF very similarly, but not the same. We started moving that needle from 1-year to 2-year survival, which is pretty amazing, if you think about the timeline of change. We were shifting the whole curve positively.

With EGFR inhibitors, the story started a little bit different. We started using them mostly without selecting for a gene but selecting for expression of EGFR, which did not make sense since this is an inducible protein that we measure by immunohistochemistry. Shortly after this, we learned that EGFR expression does not really matter, and in time we learned that the KRAS gene, if mutated, will exclude those patients from receiving EGFR inhibitor therapy given the lack of benefit.

When we started expanding our understanding of the genomic drivers for colorectal cancer, we understood further contribution from NRAS mutations that exclude patients from EGFR inhibitors beyond KRAS. That pie of patients who would have a likelihood of benefit from EGFR inhibitors continued to shrink. Today, we understand that BRAF mutations and HER2 amplifications additionally exclude those patients from receiving EGFR inhibitors.

As this research progressed, 2 other agents were introduced in later lines of therapy: regorafenib (Stivarga), which is a multikinase inhibitor, and TAS-102 (trifluridine and tipiracil hydrochloride; Lonsurf), which is another cytotoxic agent belonging to the superfamily of fluoropyrimidines. This progress continues to happen on a large scale. With all these additions and refinements, we observe that average survival has shifted to 3-plus years, and we are starting to get closer to 4 years for many patients. For example, we now have evidence that in a subset of patients with HER2 amplification, HER2 inhibition with tyrosine kinase inhibitors plus trastuzumab (Herceptin) may bring incredible benefits for some patients — with responses lasting beyond 2 to 3 years with great tolerability.

Another subgroup of patients includes patients with a BRAF mutation; those patients do incredibly poor and live an average of 1 year or less with doublet therapy. However, they seem to respond better with FOLFOXIRI (leucovorin [folinic acid], 5-FU, oxaliplatin and irinotecan), at the expense of added toxicity. We have improved targeting the genetic alteration and/or its downstream effects in patients with BRAF V600E mutations and added options with irinotecan, vemurafenib, and cetuximab or panitumumab and now a biologic triplet—encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab. What we’ve seen from this biologic triplet combination in the first 30-plus patients is a response rate close to 50%, when we expect an almost 0% response rate from EGFR inhibitors.

Patients with microsatellite instability—high (MSI-H) colon cancer benefit tremendously from immunotherapy with the PD-1 inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo), and ipilimumab (Yervoy) added to nivolumab for some patients. With single agent pembrolizumab, more than half of the exposed patients remain progression free for at least 3 years. That is an incredible achievement. Imagine that for that 4% of a subgroup of patients with MSI-H disease, we are able to pull the survival beyond 5 years. In fact, I think we can safely start making the claim that we are curing many of these patients from their cancer with a PD-1 inhibitor.

To add further complexities to all this, we add the impact of sidedness—right versus left—which relate to different molecular and all genetic aspects of colorectal cancer. For example, it seems that patients with right-sided tumors do incredibly worse than those with left-sided tumors, and even in the presense of all RAS wild-type/BRAF wild-type tumors do not respond well to EGFR inhibitors. We are piecemealing the advanced colorectal cancer into multiple molecular, genetic, and immune subsets to continue advancing the care of patients.

As such, when we put all these things together, it is at least a 4-fold improvement in the median overall survival of patients. Even more so for certain subgroups that typically did not have a chance to respond to chemotherapy and where the needle has moved significantly further than for the general population. I believe that this is only the tip of the iceberg and we are going to see more and more of these subgroups being defined and refined with many more rationally targeted agents matching these alterations. One of the largest platforms aimed at redefining the landscape of colorectal cancer is a study focusing on selecting patients through “liquid biopsy” screening and matching them to molecularly assigned therapy (COLOMATE; NCT03765736) which will run through the Mayo Clinic-supported research consortium, Academic and Community Cancer Research United. There are very exciting times and I have never been more optimistic about the positive changes that are coming.

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