Addressing the Needs of Molecular Subgroups in CRC

Benjamin Weinberg, MD

With a variety of molecular subsets in colorectal cancer (CRC) that require different treatment approaches, Benjamin Weinberg, MD, recommends that oncologists perform next-generation sequencing (NGS) and determine tumor sidedness upon diagnosis.

“There are important subpopulations in patients with metastatic colorectal cancer and it's not just a monolithic entity,” explained Weinberg. “We need to be testing for these things. There are certain things we need to know upfront, including RAS, BRAF, microsatellite instability, and HER2 status. Even if we don’t use [the NGS] to guide therapy immediately, it would steer how I structure a sequencing of treatments.”

For patients with BRAF V600E—mutant metastatic colorectal cancer (mCRC), for example, the BEACON study evaluated the triplet regimen of encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux) versus encorafenib/cetuximab alone versus investigator’s choice of standard therapy with cetuximab plus either irinotecan or FOLFIRI. Results showed that the median overall survival for the triplet therapy was 9.0 months versus 5.4 months with the standard regimens, which translated to a 48% reduction in the risk of death (HR, 0.52; 95% CI, 0.39-0.70; 2 sided &#8239;P&#8239; <.0001).&#8239;

The FDA previously granted the triplet regimen a breakthrough therapy designation for the treatment of patients with &#8239;BRAF &#8239;V600E—mutant mCRC as detected by an FDA-approved test, following failure of 1 or 2 prior lines of treatment.&#8239;

In an interview with OncLive, Weinberg, an assistant professor of medicine and attending physician at Georgetown University, discussed the treatment options available for the various subpopulations in mCRC.

OncLive: How do you currently treat patients with mCRC in the first-line setting?

Weinberg: There are many treatment options for frontline mCRC. All of these typically involve fluoropyrimidine-containing chemotherapy, usually with the addition of oxaliplatin and/or irinotecan. The options for chemotherapy backbones include FOLFOX, CAPOX, FOLFIRI, CAPIRI, FOLFIRINOX, or CAPIRINOX, which typically have a biologic agent added to them. Patients also benefit from bevacizumab (Avastin), a VEGF-targeting therapy. For patients with left-sided RAS and BRAF wild-type tumors, we believe the benefit of an EGFR-directed antibody like cetuximab is beneficial in the frontline setting.

Could you expand on the different molecular subsets in CRC?

In mCRC, there are many different molecular genotypes that we need to be aware of. We think BRAF V600E is a bad mutation to have, but we have drugs that target BRAF, including the regimen using vemurafenib (Zelboraf) in combination with irinotecan and cetuximab and, more recently, the BEACON regimen of encorafenib, binimetinib, and cetuximab. These therapies are not in the upfront setting but are very useful in later-line settings and have shown benefit in patients who otherwise have a very poor prognosis.

We also are aware of patients who have HER2 amplification, which is mostly in rectal cancer. These patients may benefit from HER2-targeting therapies—not necessarily the frontline setting, but in the later-line settings.

The other important groups we need to be aware of are the 4% of patients who have microsatellite instability—high (MSI-H) tumors. Those patients benefit from immunotherapy with pembrolizumab (Keytruda) or nivolumab (Opdivo), or even a combination of nivolumab with the CTLA-4 inhibitor ipilimumab (Yervoy).

Finally, the NTRK story has fully emerged and drugs, such as larotrectinib (Vitrakvi) and entrectinib (Rozlytrek), seem to benefit this very rare patient population that we need to be aware of; we need to look for those types of rare fusion events.

How frequently are these different subsets identified?

The BRAF story tends to be [found in] more right-sided colon cancers at around 5% to 15% [of patients], depending on where in the colon the tumor comes from. They are still pretty rare. MSI-H is even more rare, at about 4% of mCRC. The HER2 story is very narrow, at about 5% of rectal cancer and less common throughout the colon. The NTRK story is even rarer, at approximately 0.2% or 0.3% of all mCRC.

Could you expand on the targeted therapies used in these subsets?

As of now, we don't usually use much of these targeted therapies in the frontline setting. The ongoing ANCHOR trial is going to look at the BEACON regimen upfront for patients with BRAF V600E—mutated mCRC. We eagerly await the results of those types of trials.

The HER2 story is going to be [explored in] more refractory disease. There are some ongoing trials that look into using immunotherapy upfront for the MSI-H population. The jury is still out [on immunotherapy], but in patients who are having trouble with frontline chemotherapy, it's very reasonable to move to one of these more targeted options.

How would you define the use of cetuximab?

We used to think that cetuximab only works in patients who have RAS and BRAF wild-type mCRC. For a long time, we have known that patients with right-sided CRC—tumors that arise from the cecum, ascending colon, hepatic flexure, or beginning of the transverse colon—have a worse prognosis than patients who have mCRC that comes from left-sided and primary splenic flexure, descending colon, sigmoid, rectosigmoid, and rectum.

We also now know that even for patients with RAS wild-type tumors, the EGFR-directed drugs only seem to work upfront in patients with left-sided primaries. I would be remiss to use anti-EGFR therapy on a patient with right-sided CRC until a much later-line setting and only in patients who are RAS or BRAF wild-type, the exception being the BRAF V600E—mutated patients. Now, we have these combination regimens that include cetuximab, but I wouldn't use EGFR-directed therapies without also inhibiting BRAF and/or MEK.

Tabernero J, A. Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab with or without binimetinib for BRAF V600E—mutant metastatic colorectal cancer: expanded results from a randomized, 3-arm, phase III study vs. the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). Ann Oncol. 2019;30(suppl_5):v851-v934. doi: 10.1093/annonc/mdz394.