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mCRC: Consensus and Controversy
Metastatic Colorectal Cancer: Areas of Consensus and Controversy Among Experts

Released: October 31, 2017

Expiration: October 30, 2018

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New approaches to treating metastatic colorectal cancer (CRC) promise to improve outcomes for patients. This has led to areas of consensus as well as areas of controversy among CRC experts. In particular, the discovery that immune checkpoint inhibitors can be used to greater effect in tumors that are microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR), management of tumors originating in the transverse colon, optimal treatment of tumors with mutated BRAF, and therapy selection for patients who have received multiple lines of therapy. Clinical Care Options’ Interactive Decision Support Tool for metastatic CRC provides evidence-based treatment selections from 5 experts based on multiple patient and tumor characteristics, such as mutation status, and previous treatment history, but the recommendations can vary, even among experts. In this commentary, I explore differences in expert opinions regarding optimal treatment of patients with CRC.

Immune Checkpoint Inhibitors
The indication for the PD-1 inhibitor pembrolizumab was recently expanded to include all patients with solid tumors that are MSI-H or dMMR, as well as MSI-H/dMMR CRC following progression on a fluoropyrimidine, oxaliplatin, and irinotecan. Soon after, the FDA also granted accelerated approval to the PD-1 antibody nivolumab for patients with MSI-H/dMMR CRC in the same postchemotherapy (fluoropyrimidine, oxaliplatin, and irinotecan) setting. However, we do not yet have phase III randomized data for PD-1 antibodies in the first-line setting. As such, many clinicians would not choose an immune checkpoint inhibitor for first-line therapy of patients with MSI-H CRC; instead, clinicians typically select traditional first-line therapy with a cytotoxic regimen with or without a biologic or targeted agent, reserving pembrolizumab or nivolumab for the second line and beyond. However, in my clinic, I have often chosen immune checkpoint inhibition with pembrolizumab as off-label first-line therapy in this population. I am not sure it makes sense for us to wait until the second or third line if we can have access to immunotherapy in the first line since the responses to checkpoint inhibition tend to be solid and durable, and many of these patients actually continue to be in CR for at least 1-2 years, if not longer, which is a phenomenon we rarely observe with chemotherapy. So, in my opinion, it makes sense to use the PD-1 inhibitor first, provided reimbursement is not an issue, and if there is evidence of progression after 8-9 weeks of therapy, one can always switch to chemotherapy. If a durable CR is actually achieved in a disease in which a CR is a rare event and with less overall toxicity than chemotherapy, I personally feel it is unnecessary to delay access to these immunotherapy agents. The KEYNOTE-177 phase III clinical trial is evaluating pembrolizumab vs standard chemotherapy as first-line treatment for patients with metastatic dMMR CRC.

Of note, a recent update of the phase II study of pembrolizumab in previously treated patients showed continuous deepening of responses going beyond 20 weeks with many patients’ responses improved: Some patients with stable disease achieved a PR and many (> 20%) with PR converted to a CR. Responses were durable, with median PFS and OS still not reached. Historically, chemotherapy has been unable to provide the same level of response, even in the first-line setting. Of importance, most MSI-H tumors tend to be right sided, which generally have a worse prognosis than left-sided tumors, and tend to have aggressive and rapid progression. In my opinion, this would represent additional rationale to move PD-1 inhibitors to the first line.

Treatment of Tumors Arising in the Transverse Colon 
Treating cancer that arises in the transverse colon has been controversial, and many of my colleagues would treat these as right-sided colon tumors. However, in recent years, it has become clear that practical treatment of a transverse colon tumor should be based on proximity to either the right or left side. Tumors that arise in the proximal two thirds of the transverse colon share the same embryologic origin (midgut) as the right colon and those in the distal third of the transverse colon, adjacent to the splenic flexure, share the same embryologic origin (hindgut) as the left colon (Figure). So, in my opinion, clinicians need to ensure that patients with left-sided transverse tumors receive appropriate treatment that would include EGFR inhibitors, which are not options for patients with right-sided tumors.

Figure. Embryologic origins of the transverse colon.

The challenge for busy clinicians in the clinic is how to identify where the tumor is in the transverse colon, which is impossible to ascertain with exact certainty. The most practical way is to visually determine if it is closer to the left or right side, and then treat accordingly. However, once patients progress and require second-line treatment and beyond, the effect of sidedness on treatment selection tends to wane. Of note, and unlike considerations for the use of EGFR inhibitors, sidedness does not appear to be a concern with the use of bevacizumab as first-line therapy, which may translate into less concern regarding choice of therapy in patients with cancers arising from the transverse colon.

BRAF-Mutant Tumors
Patients with CRC in the presence of a BRAF V600E mutation will likely benefit from specific approaches. Many clinicians are now choosing vemurafenib (an inhibitor of BRAF kinase) combination regimens over more traditional chemotherapy following failure to respond to first-line therapy. This is based on the promising results of the phase II SWOG S1406 study, which randomly assigned patients with BRAF V600E–mutated metastatic CRC who had been treated with 1-2 lines of chemotherapy to receive irinotecan and cetuximab (IC) or IC plus vemurafenib (VIC). The trial met its primary endpoint of PFS: The triple combination (VIC) was associated with a significantly longer median PFS of 4.3 months vs 2.0 months with IC (HR: 0.48; P = .001). The disease-control rate was 67% vs 22% with VIC vs IC, respectively.

For first-line treatment, FOLFOXIRI plus bevacizumab probably makes the most sense for eligible patients. Nevertheless, in my opinion, if a patient with BRAF V600E–mutated CRC fails first-line FOLFOXIRI plus bevacizumab, and in the absence of a clinical trial, it is not unreasonable to consider the VIC regimen, only because second-line chemotherapy simply will not be effective in this population.

Regorafenib vs TAS-102
With the advent of both regorafenib (a pan-VEGFR kinase inhibitor) and trifluridine/tipiracil (TAS-102) (chemotherapy), clinicians may be challenged to choose between these different agents for third-line treatment and beyond, and no directly comparative data yet exist. However, both are relatively effective in patients with CRC and the choice can be made mostly based on the safety profiles (regorafenib is associated with predominately hand–foot skin reaction, fatigue, and diarrhea whereas patients receiving TAS-102 typically experience myelosuppressive toxicities). In the prospective phase III RECOURSE study of TAS-102 vs placebo in refractory, metastatic CRC (N = 800), approximately 20% of the patients had previously received regorafenib. Results showed a significant OS benefit for TAS-102: Median OS was 7.1 months vs 5.3 months for placebo (P < .001). In a subgroup analysis, it appeared that previous exposure to regorafenib did not affect the PFS or OS benefit gained from TAS-102. Regorafenib was approved in 2012 based on the phase III CORRECT trial, which reported that among patients with metastatic CRC progressing after all available standard therapy was given, regorafenib was associated with a significant improvement in median OS vs placebo (6.4 vs 5.0 months, respectively; P = .0052) and PFS (1.9 vs 1.7 months with placebo; P < .0001).

Two other phase III studies have shown a survival benefit to these 2 agents in patients with refractory, metastatic CRC and less pre-exposure to biologic agents or other treatment: CONCUR (regorafenib) and TERRA (TAS-102). Taken together, the CORRECT, CONCUR, RECOURSE, and TERRA studies suggest that previous treatment did not seem to dilute benefit from TAS-102 whereas less pretreated patients seem to derive more benefit historically from regorafenib. In my clinic, I typically choose regorafenib before TAS-102, for most patients, but frankly, I think that there is little difference one way or the other.

Your Thoughts?
How do you select therapy for your patients with MSI-H, BRAF V600E–mutant, or chemotherapy-refractory metastatic CRC? Have you begun using these new findings and agents in the clinic?

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Which of these novel approaches do you feel has the most impact on your treatment of patients with metastatic CRC?
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