Saturday, June 7, 2014

Panitumumab versus Cetuximab - Treatment in Metastatic Colorectal Cancer

Throughout all our research about anti-EGFR treatment in metastatic colorectal cancer, my partner Tien Lu and I often discovered panitumumab and cetuximab as main-line therapies (More in our wiki). Both of these drugs are anti-EGFR treatments. EGFR is the epidermal growth factor receptor, which contains many pathways that lead to cell proliferation and survival. Therefore, it is no surprise EGFR as been important in the study of cancer, as malfunction in its pathways can lead to uncontrollable cell growth, differentiation, and migration. Typically, EGFR ligands bind to the EGFR cell surface receptor to induce cell signaling down the pathway, leading to cell replication. Monoclonal antibodies are anti-EGFR treatment, and bind to the EGFR receptor instead, blocking the downstream signaling and stopping cell proliferation.

Figure 1. Similarity in anti-EGFR treatments in disrupting MAP Kinase pathway.
Figure 1 illustrates the mechanism of the anti-EGFR drugs cetuximab and panitumumab. The pathways affected by the drugs are highlighted in red. In fact, panitumumab and cetuximab use the same mechanism and are virtually interchangeable. Both can bind to either EGFR receptor and inhibit the downstream signaling. Despite the same mechanisms used by cetuximab and panitumumab, a trial showed that patients given both drugs acquired resistance to cetuximab first (Bardelli, et al. 2010). Interestingly, when cetuximab resistance was found after prolonged exposure to the drugs, panitumumab still retained some function. However, this does not lead to panitumumab being a more effective drug because similar resistance can occur in Panitumumab first (Helwick, et al. 2013).

Furthermore, there was a phase 3 study conducted to determine if there was a difference between cetuximab and panitumumab on KRAS wild-type patients with metastatic colorectal cancer. As my partner and I noted in our wiki, KRAS mutations can have negative impact on anti-EGFR therapy, so all participating patients were wild-type KRAS. All 999 patients that were part of the final analysis had chemotherapy-refractory cancer. 499 patients received panitumumab and 500 received cetuximab. The primary analysis was overall survival, defined as the percentage of surviving patients from the start of treatment onward.

Figure 2. Kaplan-Meier plot of overall survival by treatment group.
In the study, the median overall survival was 10.4 months for panitumumab and 10 months for cetuximab (95% CI). The researchers concluded that there is no significant difference in panitumumab and cetuximab treatment. Therefore doctors do not have a particular drug that should be favored over the other when prescribing an intervention for a patient with metastatic colorectal cancer. Going forward it may be best to give patients a cocktail of the two drugs, in case resistance is acquired in one. Or, as is more common, give the drugs in sequential order; prescribing the other drug when resistance is acquired in the first. 

However, it is worth noting that panitumumab is given in 7 doses versus the 14 doses for cetuximab in the study.The minuscule difference in drug response may be attributed to the larger but less frequent doses of panitumumab having more efficacy. Regardless, the researchers concluded that the monoclonal antibody drugs are nearly identical in efficacy and safety (Price, et al. 2014). Yet the issue remains of how one drug's resistance does not occur simultaneously with the others (when the two are given together). If the monoclonal antibodies abide by the same mechanism, the discrepancy in resistance acquisition is possibly due to cetuximab and panitumumab binding to distinct epitopes. That is, the antibodies are binding to different antigen domains, leading to slightly different EGFR-binding capacities. Consequently, the EGFR-binding suppression occurs differently in the two drugs. Nevertheless this is only a hypothesis, and further work is being conducted to discover the difference in panitumumab (brand name Vectibix) and cetuximab (brand name Erbitux).

"Journal of Clinical Oncology." Molecular Mechanisms of Resistance to Cetuximab and Panitumumab in Colorectal Cancer. Journal of Clinical Oncology, n.d. Web. 07 June 2014.
"About FDA." Cetuximab (Erbitux) and Panitumumab (Vectibix). FDA, n.d. Web. 07 June 2014.
"Panitumumab versus Cetuximab in Patients with Chemotherapy-refractory Wild-type KRAS Exon 2 Metastatic Colorectal Cancer (ASPECCT): A Randomised, Multicentre, Open-label, Non-inferiority Phase 3 Study."Panitumumab versus Cetuximab in Patients with Chemotherapy-refractory Wild-type KRAS Exon 2 Metastatic Colorectal Cancer (ASPECCT): A Randomised, Multicentre, Open-label, Non-inferiority Phase 3 Study : The Lancet Oncology. The Lancet Oncology, n.d. Web. 07 June 2014.