Cetuximab for EGFR-expressing Metastatic Colorectal Cancer

Cetuximab

As a recombinant chimeric human/mouse IgG1 monoclonal antibody. Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor drug used to treat metastatic colorectal cancer and head and neck cancer.

• In July 2009, cetuximab (Erbitux) was approved for wild-type KRAS for colon cancer.

Fig.1 The structure of cetuximab. (Wikipedia)

Function of Cetuximab

• Enhanced NK cell-mediated ADCC
• Activate the link between natural killer cells (NK) and dendritic cells
• Promote phagocytosis of cancer cells by dendritic cells
• Increases the expression of major histocompatibility complex (MHC) class II molecules and tumor microenvironment T cell aggregation

Background

Studies have shown that the re-use of anti-EGFR monoclonal antibodies (mAbs) can still benefit patients with metastatic colorectal cancer (mCRC) who are sensitive to first-line therapy. The rationale lies in the assumption that cetuximab or panitumumab can kill most RAS wild-type (WT) cancer cells. However, during EGFR monoclonal antibody therapy, cancer cells developed RAS mutations, leading to disease progression. In the previous analysis of plasma ctDNA in mCRC patients, it was found that the interruption of anti-EGFR therapy led to an increase in RAS WT cancer cells and the decay of RAS mutant cancer cells. IgG1 monoclonal antibodies, such as cetuximab, enhance antibody-dependent cytotoxicity (ADCC) and activate innate and adaptive immune responses. Among ICI drugs, Avelumab (anti-PD-L1 IgG1 monoclonal antibody) has ADCC properties.

The primary purpose of this article was to evaluate the efficacy and safety of Avelumab plus cetuximab in patients with RAS WT mCRC.

Methods

This study is a multicenter, open-label phase II clinical trial. Seventy-seven patients with metastatic colorectal cancer treated with RAS WT were included. All of these patients achieved some degree of remission during cetuximab combined with chemotherapy. Similarly, all patients were treated with Cetuximab plus Avelumab. The dose of Cetuximab is 400 mg/m2, followed by 250 mg/m2/week, and Avelumab is given once each time for 2 weeks until disease progression or intolerable adverse effects.

Results

• The mOS for both the intention-to-treat (ITT) population and the microsatellite stable (MSS) population was 11.6 months. (Fig.2A & 2C)
• The mPFS of both the ITT population and the MSS population was 3.6 months. (Fig.2B & 2D)

Fig.2 Kaplan-Meier estimates.

• The mOS of RAS/BRAF wild-type patients was significantly better than that of RAS/BRAF mutant patients. (17.3 months vs 10.4 months, HR=0.49). (Fig.3A)
• The mPFS of RAS/BRAF wild-type patients was significantly better than that of RAS/BRAF mutant patients (4.1 months vs. 3.0 months, HR=0.42). (Fig.3B)
• The mOS of RAS/BRAF wild-type patients in the MSS population was significantly better than that of RAS/BRAF mutant patients. (17.3 months vs 10.4 months, HR=0.50). (Fig.3C)
• The mPFS of RAS/BRAF wild-type patients in the MSS population was significantly better than that of RAS/BRAF mutant patients (3.9 months vs 3.0 months, HR=0.42). (Fig.3D)

Fig.3 Kaplan-Meier estimates

• ORR for ITT population: 7.8%, DCR: 65%.

Table.1 Activity and efficacy in the intention-to-treat population and in patients

• Safety assessment results: rash (14%) and diarrhea (4%).

Conclusion

The results of this study showed that Cetuximab combined with Avelumab had good efficacy and safety in patients with RAS WT MCRC. The results of this study can be explained from their structure. Cetuximab and avelumab are both IgG1 isotypes with ADCC-inducing properties. In the Cetuximab plus Avelumab for Non-small Cell Lung Cancer unit, cetuximab plus avelumab selectively induces ADCC in human non-small cell lung cancer (NSCLC) cell lines in vitro and has antitumor activity in patients with refractory NSCLC, while activating NK cell-driven ADCCs.

References

1. Martinelli, E.; et al. Cetuximab rechallenge plus avelumab in pretreated patients with RAS wild-type metastatic colorectal cancer: The phase 2 single-arm clinical CAVE trial. JAMA oncology. 2021, 7(10): 1-7.