The Lancet is currently taking votes for the paper of the year – with six papers nominated for the award. My interest was piqued by a paper published in the New England Journal of Medicine by Karapetis et al. As the title of the paper suggests, “K-Ras Mutations and Benefit from Cetuximab in Advanced Colorectal Cancer” essentially looks at the association between mutations in the K-Ras gene and the efficacy of a cetuximab (brand name Erbitux) in treating colorectal cancer.
Like the blockbuster cancer drugs bevacizumab (Avastin) and trastuzumab (Herceptin), cetuximab is an example of a newer, targeted therapeutic agents now being used for cancer treatment, often in combination with conventional chemotherapy. Cetuximab is a monoclonal antibody that targets the epidermal growth factor receptor (EGFR), which is often overexpressed in colorectal tumor cells. EGFR is a cell surface receptor with downstream signalling cascades involved in cell migration and proliferation, so a number of relatively new anti-cancer drugs inhibit EGFR in an attempt to curb the growth of cancer cells. One of the downstream signalling proteins is K-Ras, and certain activating mutations in the K-Ras gene can dissociate the protein from EGFR signalling. As a result, treatments that target EGFR are rendered ineffective by these mutations.
In all fairness, the Karapetis et al. paper was not the first to investigate the role of K-Ras mutations in the efficacy of anti-EGFR therapy. Scientists from biotech company Amgen found that K-Ras mutations reduced the benefit of their own anti-EGFR agent, panitumumab (Vectibix). Amado et al. reported in the Journal of Clinical Oncology that of patients treated with panitumumab, those with wild-type K-Ras tumors had better response rates and median progression free survival.
Karapetis et al. were able to establish that the same holds true for cetuximab treatment. In a clinical trial conducted in 572 advanced colorectal cancer patients who did not respond to conventional chemotherapy regemins including fluoropyrimidines, oxaliplatin and/or irinotecan, patients treated with cetuximab monotherapy were found to have better overall survival and progression-free survival than patients receiving best supportive care only. At diagnosis, samples of the tumor were taken from each patient and these samples were fixed in formalin and then stored at a facility at Queen’s University in Kingston, Ontario. Researchers did blinded analyses of tissue samples from 394 of the 572 patients in the trial by sequencing the K-Ras gene and labelled them as having wild-type or mutant status. 198 of these samples were from patients who received cetuximab, while 196 were from patients who received only best supportive care. 40.9% (81) of samples from patients from the cetuximab group and 42.3% (83) of those from the best supportive care group had K-Ras mutations.
Amongst patients with K-Ras mutant tumors, there was no benefit in overall survival (OS) amongst those who received cetuximab compared to those who received best supportive care alone (median OS: 4.5 months vs. 4.6 months). In contrast, median OS for patients with wild-type tumors was 9.5 months for those who were treated with cetuximab and 4.8 months for those who received best supportive care. Median progression-free survival (PFS) was 1.8 months for the K-Ras mutant group regardless of whether or not they received cetuximab. In comparison, median PFS was 1.9 months of the K-Ras wild-type group that received best supportive care and 3.7 months for those treated with cetuximab. Response rates were also different between the two K-Ras status groups; 13.2% of K-Ras wild type patients treated with cetuximab had an objective response, compared to just 1.2% of those with mutant K-Ras status (none of the patients receiving best supportive care only had an objective response).
The findings of this study as well as the Amado et al. paper suggest that K-Ras status can be used to select patients for whom treatment with an anti-EGFR agent is more likely to be successful. Given the fact that roughly 40% of colorectal cancer patients have a tumor with mutant K-Ras and the high cost of biologics like cetuximab and panitumumab, these results will enable doctors to tailor treatments for patients that will be more cost-effective. Therefore, patients with wild-type status who are refractory to standard treatments might be prescribed cetuximab, while those with K-Ras mutant status may receive other therapies or best supportive care only. In fact, ImClone (developer of cetuximab) and Amgen filed a request for FDA permission to modify their product labels to include the results from these trials and recommend that use be limited to patients with wild-type K-Ras status.
With the ongoing development of more targeted cancer therapies as well as advances in genomics, biomarkers such as the K-Ras gene promise smarter and more cost-effective treatment approaches for cancer. Hurdles such as the logistics and reliability of the test still exist, although I anticipate that they will be overcome with time.