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Test Your Skills: CRC

CE / CME

Test Your Skills: Understanding the Current Biomarker Landscape for Patients With Advanced Colorectal Cancer

Physician Assistants/Physician Associates: 0.25 AAPA Category 1 CME credit

Nurses: 0.25 Nursing contact hour

Pharmacists: 0.25 contact hour (0.025 CEUs)

Physicians: maximum of 0.25 AMA PRA Category 1 Credit™

ABIM MOC: maximum of 0.25 Medical Knowledge MOC point

Released: September 13, 2024

Expiration: September 12, 2025

CME/CE Information

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In this case challenge, the patient was diagnosed with metastatic CRC. Given this diagnosis, molecular testing is crucial to guide treatment decisions. Both the American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) guidelines offer comprehensive recommendations for testing.1,2 All patients newly diagnosed with CRC, regardless of stage, should be tested for MSI using panel-based NGS or dMMR using IHC. In addition to MSI-high/dMMR, all patients presenting with metastatic disease should be tested using panel-based NGS to identify actionable mutations, such as KRAS, NRAS, and BRAF, and other potentially actionable targets in subsequent lines of therapy such as HER2 amplification, RET fusions, and NTRK fusions.

MSI/dMMR testing is recommended to help guide treatment decisions and to identify patients who may have Lynch syndrome, which is characterized by germline mutations in the DNA repair genes. All patients who present with MSI-high/dMMR disease and patients with CRC younger than 50 years of age should be evaluated for suspected Lynch syndrome using germline sequencing and genetic counseling.2 Lynch syndrome does not typically involve BRAF V600E mutations. In fact, the presence of a BRAF V600E mutation is often used as a negative predictive marker for Lynch syndrome since this mutation is rarely found in Lynch syndrome–associated tumors.3 However, CRCs harboring BRAF V600E mutations can occur in the setting of acquired dMMR. Understanding the distinction between BRAF V600E–mutant CRC with acquired MMR deficiency and Lynch syndrome is crucial for patient management. Sporadic cases of dMMR CRC do occur and are often associated with both somatic BRAF V600E and MLH1 promoter methylation.3 In such cases, immunotherapy is often highly effective because of the MSI-H status. However, these patients do not carry the same inherited cancer risk profile as those with Lynch syndrome, so genetic counseling and testing for hereditary cancer syndromes may not be indicated unless other clinical factors suggest a hereditary component.4

In this case, the patient’s cancer was found to be pMMR (MSS) and harbored a BRAF V600E mutation. This mutation is associated with a poorer prognosis and more aggressive tumor biology, commonly linked to right-sided colon tumors.5-9 Given this patient’s MSS status and BRAF V600E mutation, the initial recommendation is to start systemic chemotherapy. Reasonable regimens include FOLFIRINOX with or without bevacizumab, FOLFOX with or without bevacizumab, and FOLFIRI with or without bevacizumab.1,2 Although targeted therapy with encorafenib plus cetuximab (a BRAF and EGFR inhibitor combination) is highly effective in BRAF V600E–mutated metastatic CRC, it is currently approved by the FDA for patients with metastatic CRC with a BRAF V600E mutation after prior therapy (in the second-line setting or beyond). FOLFIRI plus cetuximab is only recommended for patients with left-sided tumors and is not an effective option for patients with BRAF V600E mutations.10-12 With a cecal mass, this patient’s tumor originated on the right side of the colon.

If this patient’s NGS and MMR testing instead showed a tumor that is MSI-high and dMMR with the presence of a BRAF V600E mutation, the patient would be a candidate for upfront immunotherapy. Upfront immunotherapy options include nivolumab with or without ipilimumab, pembrolizumab, or dostarlimab.2,13 The indication for nivolumab with or without ipilimumab in this setting is based on the phase II CHECKMATE 142 study in dMMR/MSI-high metastatic CRC. In patients who received this regimen for first-line treatment (n = 45), overall response rate (the primary endpoint) was 69%, including 13% with complete response, and the progression-free survival and overall survival rates at 24 months were 74% and 79%, respectively.14

The use of pembrolizumab is supported by the phase III KEYNOTE-177 study in patients with dMMR/MSI-high metastatic CRC and no previous treatment in the metastatic setting where patients were randomized to receive pembrolizumab (n = 153) or standard-of-care chemotherapy (FOLFOX6 or FOLFIRI) with or without bevacizumab or cetuximab (n = 154).15 Pembrolizumab significantly improved PFS compared with chemotherapy (16.5 vs 8.2 months, respectively; HR: 0.59, 95% CI: 0.45-0.79). Although there was a trend toward improved overall survival, it was not statistically significant (HR: 0.74; 95% CI: 0.53-1.03; P =.036). Outcomes favored pembrolizumab across most prespecified subgroups, including BRAF mutation status. Pembrolizumab was associated with fewer treatment-related adverse events. Finally, the indication for dostarlimab in dMMR solid tumors is supported by the phase I GARNET trial, which involved patients with recurrent or advanced solid tumors and MSI-H/dMMR or polymerase epsilon (POLE)–alterations who progressed following systemic therapy and had no satisfactory alternative treatment. In the cohort of patients with CRC (n = 105), dostarlimab resulted in an overall response rate of 43.5%, with a median progression-free survival of 8.4 months and the median overall survival not yet reached.16

In this case challenge, the patient shows an initial favorable response with a reduction in liver lesions after 3 months of receiving FOLFIRI plus bevacizumab. However, repeat imaging at 8 months indicates disease progression in the liver and the appearance of new peritoneal metastases. This progression prompts the need to reassess the treatment strategy and move to second-line therapy. The appearance of new metastases indicates that the current regimen is no longer effective​.

For patients with BRAF V600E–mutated metastatic CRC who have progressed on first-line chemotherapy, switching to targeted therapy is recommended. The phase III BEACON trial compared combination therapy with a BRAF inhibitor, encorafenib, plus cetuximab with or without the MEK inhibitor binimetinib vs standard-of-case chemotherapy plus cetuximab in previously treated patients with BRAF V600E–mutated metastatic CRC.17 The primary endpoint of the study, overall survival with encorafenib plus cetuximab and binimetinib vs chemotherapy, was met. The key secondary endpoint or overall survival for encorafenib plus cetuximab vs chemotherapy was also met with an improvement of approximately 40% with encorafenib plus cetuximab vs chemotherapy (median overall survival: 9.3 vs 5.9 months, respectively; HR: 0.61; 95% CI: 0.48-0.77). Similarly, progression-free survival was also improved with encorafenib plus cetuximab and binimatinib or encorafenib plus cetuximab vs chemotherapy. However, the addition of binimetinib added considerable toxicity. Therefore, the doublet combination with encorafenib plus cetuximab is now a preferred second-line treatment for patients with BRAF V600E–mutated metastatic CRC. Alternative options, such as FOLFOX (oxaliplatin, 5-FU, leucovorin) with or without cetuximab or cetuximab plus irinotecan, might be considered for patients without the BRAF V600E mutation. Of importance, other regimens targeting BRAF V600E mutations, like dabrafenib plus trametinib or vemurafenib plus cobimetinib, are not recommended for CRC because of insufficient efficacy in this specific cancer type.2