“The genetics of gastrointestinal cancers is fairly complex,” said Wells A. Messersmith, MD, speaking at the 2019 NCCN Annual Conference. Even though the mutational burden is high in CRC, similar to other diseases that respond to immunotherapy, “but for whatever reason, this has not worked in microsatellite stable disease,” he said.
There are 4 consensus molecular subtypes of CRC: CMS1, CMS2, CMS3, and CMS4, with overall survival (OS) worst among those with the CMS1 subtype, which has MSI-H as one of its distinguishing features. The subtypes don’t have treatment implications as of yet, “but stay tuned, it might in the future,” said Dr Messersmith, Co-Director of the Developmental Therapeutics Program, University of Colorado Cancer Center, Aurora.
Of the 13 drugs approved by the FDA for the treatment of CRC, until recently only 4 were biomarker-driven, when treatment based on BRAF, MEK, and NTRK fusion targets was added.
First-line bevacizumab added to chemotherapy has improved median OS by 1.4 to 4.9 months compared with chemotherapy alone in phase 3 clinical trials of metastatic CRC.
The 3 targeted agents in the NCCN guideline in the second-line setting are bevacizumab, aflibercept, and
ramucirumab. Adding these agents to standard chemotherapy has resulted in about a 20% reduction in the risk of death compared with chemotherapy, even with prior exposure to bevacizumab.
There are no biomarkers to guide the use of vascular endothelial growth factor receptor inhibitors (VEGFRs), noted Dr Messersmith. “We just don’t have a good idea when these drugs will work,” he said.
The CRYSTAL trial showed that first-line FOLFIRI plus cetuximab improved median OS, but only in patients with KRAS wild-type CRC. Unfortunately, KRAS mutations are common in CRC, he said, and developing drugs that target KRAS has proved elusive. In CRYSTAL, a BRAF mutation was also a negative prognostic predictor, a finding that has since been confirmed.
Mutations in other RAS genes also confer poorer prognosis. KRAS mutations outside of exon 2 on codons 12 and 13 and NRAS mutations constitute about 15% of CRCs. The bottom line, said Dr Messersmith, is that RAS testing, not just KRAS testing at 12/13, should be performed to avoid spending >$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 epidermal growth factor receptor (EGFR) inhibitors.
Based on data from the phase 2 VOLFI trial, the combination of mFOLFOXIRI plus the EGFR inhibitor panitumumab is now listed as an additional option for the treatment of patients with unresectable stage IV metastatic CRC with KRAS/NRAS/BRAF wild-type and left- sided tumors only.
In VOLFI, patients with RAS wild-type metastatic CRC who were randomized to mFOLFOXIRI plus panitumumab had an objective response rate (ORR) of 85.7% compared with 54.5% in those randomized to mFOLFOXIRI alone.
MSI and Mismatch Repair
“We have this relationship between BRAF and microsatellites that’s important to recognize,” said Dr Messersmith. Although MSI-H and dMMR associated with BRAF V600E mutations is usually due to epigenetic mechanisms, and not inherited, it does not rule out Lynch syndrome, which occurs in about 1% of cancers with BRAF V600E mutation, according to the updated guideline. With a strong family history, germline testing is recommended.
Two new first-line immunotherapy options in the NCCN guideline for advanced or metastatic CRC are nivolumab with or without ipilimumab or pembrolizumab for patients with dMMR or MSI-H who are not appropriate for cytotoxic combinations (category 2B recommendation). The same immunotherapy options are also appropriate as second- or third-line therapy for dMMR/MSI-H patients. Dual targeting with nivolumab and ipilimumab in patients with dMMR/MSI-H metastatic CRC resulted in an ORR of 55% compared with 34% for nivolumab monotherapy in the CheckMate-142 study, and responses were observed irrespective of tumor PD-L1 expression. The 12-month OS rate with the combination was 85%.
Only about 1% of patients with metastatic CRC have NTRK fusions. Larotrectinib is a new second-line treatment option in the guideline for patients with metastatic CRC that is NTRK gene fusion positive based on its activity in 4 CRC patients in a pivotal study published in the New England Journal of Medicine. In the overall study population, which included patients with several types of solid tumors, many responses to larotrectinib were prolonged.
About 8% to 15% of colorectal 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 8.0 months and an estimated median OS 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 combination option in this setting as second-line therapy is dabrafenib plus trametinib plus either cetuximab or panitumumab.