New Targeted Therapies for Metastatic Colorectal Cancer Recommended in the Updated NCCN Guideline

A growing number of targeted therapies and immunotherapies are now recommended in the updated National Comprehensive Cancer Network (NCCN) guideline for metastatic colo­rectal cancer (CRC). New first-line immunotherapy options for patients with mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H) CRC are also listed in the new guideline.

Wells A. Messersmith, MD, FACP, Program Co-Leader, Developmental Therapeutics, University of Colorado Cancer Center, Aurora, presented the updated guideline at the 2019 NCCN Conference.

“The genetics of gastrointestinal cancers is fairly complex,” Dr Messersmith said. Even though the mutational burden is high in patients with CRC, as in other tumors that respond to immunotherapy, “but for whatever reason, this has not worked in microsatellite stable disease,” he said.

Of the 4 molecular subtypes of CRC—CMS1, CMS2, CMS3, and CMS4—the overall survival is worst among patients with the CMS1 subtype, which has MSI-H as one of its distinguishing features. These subtypes still don’t have treatment implications, according to Dr Messersmith, “but stay tuned, it might in the future,” he advised.

Of the 13 drugs approved by the FDA for the treatment of patients with CRC, only 4 were biomarker-driven until 2019, when treatments targeting BRAF, MEK, and NTRK fusion mutations were added.

Drugs Targeting VEGF Receptors

First-line bevacizumab (Avastin) added to chemotherapy has improved the median overall survival by 1.4 to 4.9 months compared with chemotherapy alone in phase 3 clinical trials of patients with metastatic CRC.

The 3 targeted agents in the updated NCCN guideline recommended for the second-line setting are beva­cizumab, ziv-aflibercept (Zaltrap), and ramuciru­mab (Cyramza). Adding these agents to standard chemotherapy has resulted in approximately a 20% reduction in mortality risk compared with chemotherapy alone or even in patients with previous exposure to bevacizumab therapy.

However, because there are no biomarkers to guide the use of VEGF inhibitors, “We just don’t have a good idea when these drugs will work,” Dr Messersmith said.

Drugs Targeting EGFR

The CRYSTAL clinical trial showed that the use of the FOLFIRI regimen plus cetuximab (Erbitux) as first-line treatment improved the median overall survival, but only in patients with KRAS wild-type CRC. However, KRAS mutations are common in CRC, and developing drugs that target KRAS mutations has proved elusive. In the CRYSTAL study, the presence of a BRAF mutation was also a negative prognostic predictor, which has since been confirmed.

Mutations in other RAS genes also confer poorer prognosis. KRAS mutations other than exon 2 on codons 12 or 13 and NRAS mutations constitute approximately 15% of CRCs. The bottom line, Dr Messersmith said, is that RAS testing, not just KRAS testing at 12 or 13, should be performed to avoid spending more than $200 million to harm patients.

“Sidedness” may also serve as a marker of prognosis and response, with right-sided CRC associated with a worse prognosis and less benefit from treatment with EGFR inhibitors.

Based on data from the phase 2 VOLFI clinical trial, the combination of mFOLFOXIRI plus the EGFR inhibitor panitumumab is now recommended as an option for the treatment of patients with unresectable metastatic (stage IV) CRC and KRAS/NRAS/BRAF wild-type and left-sided tumors only.

In the VOLFI study, patients with RAS wild-type metastatic CRC who were randomized to mFOLFOXIRI plus panitumumab chemotherapy had an objective response rate of 85.7% compared with 54.5% in those randomized to mFOLFOXIRI alone.

Targeting MSI and Mismatch Repair

“We have this relationship between BRAF and microsatellites that’s impor­tant to recognize,” Dr Messersmith said. Although MSI-H or dMMR that is associated with BRAF V600E mutation is usually a result of epigenetic mechanisms, and is not inherited, it does not rule out Lynch syndrome, which occurs in approximately 1% of cancers with BRAF V600E mutation, according to the updated NCCN guideline. For patients with a strong family history of CRC, germline testing is recommended.

Two new first-line immunotherapy options recommended in the updated guideline for advanced or metastatic CRC are nivolumab (Opdivo), with or without ipilimumab (Yervoy) or pembrolizumab (Keytruda) for patients with dMMR or MSI-H who are not candidates for cytotoxic combinations (Category 2B recommendation). These same immunotherapy options are also appropriate as second- or third-line treatment for patients with dMMR or MSI-H CRC.

Dual immunotherapy with nivolumab and ipilimumab in patients with dMMR or MSI-H metastatic CRC resulted in an objective response rate of 55% versus 34% with nivolumab alone in the CheckMate-142 study, and responses were observed regardless of tumor PD-L1 expression. The 12-month overall survival rate with the immunotherapy combination was 85%.

Targeting NTRK Fusion

Only approximately 1% of patients with metastatic CRC have NTRK fusions. Larotrectinib (Vitrakvi) is a new second-line treatment option in the updated guideline recommended for patients with metastatic CRC and NTRK gene fusion, based on its activity in 4 patients with CRC reported in a pivotal study. In the overall study population, which included patients with several types of solid tumors, many responses to larotrectinib were prolonged.

Targeting BRAF Mutations

Approximately 8% to 15% of CRC tumors have a BRAF mutation. BRAF inhibitor monotherapy is disappointing, said Dr Messersmith. The triplet of binimetinib, encorafenib, and cetuximab resulted in an estimated median progression-free survival of 8 months and an estimated median overall survival of 15.3 months in the phase 3 BEACON CRC trial, which led to this triplet’s inclusion in the NCCN guideline for patients with a BRAF V600E mutation who received previous oxali­platin therapy.

Another second-line combination option in this setting is dabrafenib plus trametinib plus either cetuximab or panitumumab.

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