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Optimizing mCRC Treatment
Contemporary Management of mCRC: How Experts Select Optimal Therapeutic Strategies

Released: October 31, 2019

Expiration: October 29, 2020

E. Scott Kopetz
E. Scott Kopetz, MD, PhD, FACP
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The treatment landscape for metastatic colorectal cancer (CRC) has evolved significantly in the past decade and now includes several beneficial chemotherapy regimens that can be combined with biologic agents across multiple lines of therapy. Immunotherapy and targeted agents are now also available for specific patients. With the multitude of agents and regimens from which to choose, selecting treatment for individual patients can be complex. Numerous factors must be considered in optimizing systemic therapy; these include primary tumor sidedness (left vs right vs transverse colon), molecular profile (RAS and BRAF mutations, microsatellite instability/mismatch repair defects, NTRK fusions, and HER2 amplifications), previous treatment and response, and patient preferences, fitness, and existing comorbidities.

To assist with patient care and to educate healthcare providers on making informed decisions, CCO developed an online treatment decision support tool with a panel of CRC experts, including Tanios Bekaii-Saab, MD, FACP; George A. Fisher, MD, PhD; Axel Grothey, MD; John L. Marshall, MD; and myself. To access this tool, please click here.

To use this tool, individuals are asked to enter key patient and disease characteristics via predefined menus.

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After submission of the patient case, recommendations from the 5 experts are displayed. In this commentary, I enter various patient cases of interest into the tool and then discuss the rationale behind some of the treatment choices made by the experts.

Case Scenario 1: Patient With No Previous Therapy for Metastatic CRC

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Let’s take a closer look at this patient. Rather than gathering all of the patient’s information, the tool gathers information about factors that the expert panel felt were essential for making treatment decisions. In this case, the patient will require first-line therapy for metastatic CRC, and molecular profiling indicates microsatellite stability and the presence of a RAS mutation (but no BRAF mutation).

For most patients, first-line therapy consists of chemotherapy with an oxaliplatin- or irinotecan-containing regimen plus an EGFR or VEGF inhibitor. For this patient, 4 of the 5 experts would recommend an oxaliplatin-containing regimen and 1 would recommend an irinotecan-containing regimen. In my opinion, all of the chemotherapy regimens listed here would be reasonable, although I would lean toward FOLFOX. Also to note, I would agree with Expert 2 in that I would recommend FOLFOXIRI plus bevacizumab if the patient were very symptomatic or if he/she had a high tumor burden, particularly if the patient’s preference is to maximize survival, with a willingness to tolerate higher initial treatment toxicity.

Per the comments by Experts 1 and 5, maintenance therapy with capecitabine plus bevacizumab can be considered for patients who achieve stable disease or better after initial therapy. This recommendation is based on the survival advantage observed with this regimen (vs observation) in the CAIRO3 study.

For this patient, each expert recommended bevacizumab, a VEGF inhibitor, as biologic therapy. This is based on studies that have demonstrated an improvement in survival when bevacizumab is added to an oxaliplatin-containing regimen. EGFR inhibitors would not be recommended for this patient, as these agents have been shown to be less effective than bevacizumab for patients with RAS mutations. Let’s see what the experts would do if this patient did not have a RAS mutation.

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As you can see, 2 experts would now recommend panitumumab and 1 would recommend cetuximab as a biologic agent, with 2 experts still recommending bevacizumab. This choice is influenced by the fact that this patient has a left-sided primary tumor, for which EGFR inhibitors may be more effective than VEGF inhibitors. For additional data on the use of anti-EGFR vs anti-VEGF agents, click here.

Let’s look at another patient.

Case Scenario 2: Patient Who Previously Received Oxaliplatin- and Irinotecan-Containing Chemotherapy

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As you can see, this patient had already received 2 previous chemotherapy regimens that included oxaliplatin and irinotecan. Note that the patient’s molecular profile indicates no RAS or BRAF mutations, microsatellite instability, HER2 amplification, or NTRK fusion. For these patients, the multikinase inhibitor regorafenib and the chemotherapy doublet of trifluridine and tipiracil (also known as TAS-102) are the primary options. These agents have both been assessed in phase III clinical trials in patients who have progressed on previous treatment regimens (regorafenib in the CORRECT study and TAS-102 in the RECOURSE study) and have both been shown to significantly improve survival vs placebo.

In my practice, when starting a patient on regorafenib, I start with an 80-mg QD dose and titrate up vs starting at the 160-mg QD dose as was done in the CORRECT study. The ReDOS study assessed escalating doses vs standard dosing of regorafenib and determined that escalating dosing was associated with a greater proportion of patients able to start cycle 3 and improved OS. Data from a meta-analysis have also suggested a trend toward improved OS with escalating dosing of regorafenib (starting at 80 mg QD) vs TAS-102.

Your Thoughts
Which patients with metastatic CRC do you find the most challenging to treat? Please answer the polling question on your screen and share your thoughts in the comments box.

To see what 5 experts would recommend for patients with metastatic CRC in different clinical scenarios, visit the Interactive Decision Support Tool here.

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In your current practice, which of the following patients with metastatic CRC do you find most challenging to treat?
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