Targeted therapy for colorectal cancer

17 years ago, the number of drugs available for advanced colorectal cancer was very limited. There were only a few chemotherapeutic drugs and almost no targeted drugs. Once diagnosed, the survival period is only between half a year and one year. But now, cancer treatment is entering the era of precision treatment, and more and more targeted and immune drugs are on the market.

In the 2017 version of the colorectal cancer treatment guidelines, the recommendations for genetic testing only involve KRAS, NRAS, dMMR, and MSI-H. In the latest treatment guidelines for 2019, new targets such as BRAF, HER2, and NTRK are newly included points. Through genetic testing, understanding more molecular information about colorectal cancer can help us find more medication options. The average patient survival rate is more than 3 years, which is a huge improvement brought by precision medicine.

After diagnosis, doctors must genetically test each patient with metastatic colorectal cancer (mCRC) as early as possible to determine the subgroup of the disease, as this information may predict treatment prognosis, such as HER2 amplification suggesting anti-EGFR therapy resistance. The following genes must be tested!

MSI, BRAF, KRAS, NRAS, RAS, HER2, NTRK.

The indications for bevacizumab : metastatic colorectal cancer and advanced, metastatic, or recurrent non-small cell lung cancer.

The indications for trastuzumab: HER2-positive metastatic breast cancer, HER2-positive early breast cancer, and HER2-positive metastatic gastric adenocarcinoma or gastroesophageal junction adenocarcinoma.

Pertuzumab’s indications: This product is suitable for combination with trastuzumab and chemotherapy as an adjuvant treatment for patients with HER2-positive early breast cancer with a high risk of recurrence.

Nivolumab’s indications: negative epidermal growth factor receptor (EGFR) gene mutation and anaplastic lymphoma kinase (ALK) negative, disease progression or intolerable locally advanced or metastatic disease after previous platinum-containing chemotherapy Adult patients with non-small cell lung cancer (NSCLC).

Regorafenib’s indications: previously treated metastatic colorectal cancer patients. Durvalumab, Tremelimumab, Ipilimumab, lapatinib are not yet available in China.

1. Kras-negative colorectal cancer targeted therapy

KRAS wild-type colon cancer is a standard first-line treatment for targeted chemotherapy in combination with chemotherapy. So what kind of chemotherapy is chosen?

While selecting a targeted drug, it is recommended to choose a chemotherapy regimen with a longer OS; that is, cetuximab is more suitable for FOLFOX, and bevacizumab is more suitable for FOLFIRI. Which plan to choose depends on specific clinical analysis:

If there is hope for cure, cetuximab combined with chemotherapy is generally preferred because the recent objective effectiveness of cetuximab is higher than that of bevacizumab.

For patients with advanced incurable disease, bevacizumab combined with chemotherapy can be used first-line, followed by cetuximab or panitumumab.

2. Treatment of Kras-positive colorectal cancer

Patients with metastatic colon cancer need to be tested for RAS mutation status, including KRAS and NRAS, and at least the status of KRAS exon 2 needs to be clear.

If possible, the status of the other exons except KRAS Exon 2 and the NRAS mutation status should be clarified.

Bevacizumab combined with two-drug chemotherapy can bring PFS (median progression-free survival) and OS (overall survival) benefits to patients with KRAS mutations.

For patients with RAS mutations, the use of cetuximab may have a negative impact on overall efficacy. Patients with KRAS or NRAS mutations should not use cetuximab or panitumumab.

3. Treatment of BRAF mutant colorectal cancer

7-10% of patients with colon cancer carry the BRAF V600E mutation. The BRAF V600E mutation is a BRAF-activated mutation and has the highest proportion of BRAF mutations. Has unique clinical characteristics: mainly appears in the right hemicolon; dMMR ratio is high, reaching 20%; BRAF V600E mutation has a poor prognosis; atypical metastatic patterns;

Studies have found that FOLFOXIRI + bevacizumab may be the best treatment for patients with BRAF mutations. 2019 V2 NCCN guideline recommends BRAF V600E second-line treatment options for metastatic colorectal cancer: verofinib + irinotecan + cetuximab/panitumumab, and dabrafenib + trametinib + cetuximab/panitumumab.

Encorafenib + Binimetinib + Cetux / Pan

4. HER2 amplification

HER2 amplification or overexpression is found in 2% to 6% of patients with advanced or metastatic colorectal cancer. Pertuzumab and trastuzumab bind to different HER2 domains to produce synergistic inhibitory effects on tumor cells. MyPathway is the first clinical study to investigate the efficacy of Pertuzumab + Trastuzumab in patients with HER2 expansion metastatic colorectal cancer (regardless of KRAS mutation status). This study shows that HER2 dual-targeted therapy, Pertuzumab + Trastuzumab, is well tolerated or could be used as a treatment option for patients with HER2 expansion metastatic colorectal cancer. Early genetic testing to identify HER2 mutations and consider early use of HER2-targeted therapy may benefit patients.

5. Treatment of NTRK fusion colorectal cancer

NTRK fusion occurs in about 1 to 5% of patients with colon cancer, and NGS testing is recommended. Lorarectinib was approved for NTRK rearrangement in patients with solid tumors, with an ORR of 62%, and 3 of them with CRC. The emergence of TRK inhibitors such as larotinib and emtricinib provides new therapeutic ideas for NTRK gene fusion CRC.

A 75-year-old woman with metastatic colorectal cancer (CRC) is very lucky:

Primary colon tumor.

Peritoneal cancer.

Liver metastases.

1600 mg/m² of emtricitabine is administered orally once a week for 4 consecutive days (i.e., 4 days / 3 days off) and 3 consecutive weeks every 28 days. Aft

After eight weeks of treatment, the lesions significantly reduced.

Concluding Remarks

Entering the era of targeted therapy, every patient with colorectal cancer should pass MSI testing, RAS and BRAF mutation analysis, and perform HER2 amplification as much as possible. Detection of genes such as NTRK and genetic testing (NGS) will be included in the large initial examination criteria for most patients.

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