Blocking EGFR is an interesting strategy for cancer therapy; as well as leading to proliferation, its activation is also thought to be associated with angiogenesis and the inhibition of apoptosis
Epidermal growth factor receptor, or EGFR, is commonly upregulated in squamous non-small cell lung cancer, among other cancer types. The receptor is activated by ligands including the tyrosine kinase EGF, and when upregulated can lead to uncontrolled cell division.
Thus, blocking EGFR is an interesting strategy for cancer therapy, and as well as leading to proliferation, its activation is also thought to be associated with angiogenesis and the inhibition of apoptosis. Several drugs that act as EGFR inhibitors are already on the market, including cetuximab, gefitinib and erlotinib.
Another, necitumumab, is being developed by Lilly. First invented by ImClone as a follow-on to cetuximab, it was the subject of a battle over development rights between Lilly and Bristol-Myers Squibb, finally won by Lilly. The recombinant human IgG1 antibody is thought to have a lower hypersensitivity reaction risk than cetuximab while initiating cell-mediated cytotoxicity. Its anticancer activity is being evaluated in combination with chemotherapy drugs.
A Phase I open label study was carried out in 60 patients with advanced solid tumours to determine the maximum tolerated dose.1 Non-escalating doses of 100 to 1000mg were given to 29 patients weekly, and every other week to the remaining 31.
Two patients given the highest dose every two weeks experienced dose-limiting toxicities, and the half-life was about seven days at 800mg in both arms of the trial. Two patients achieved a partial response, and a further 16 stable disease. The recommended dose was set at 800mg, either weekly or fortnightly depending on the clinical setting.
It is furthest advanced in squamous NSCLC, in which indication the full results of a Phase III trial have recently been reported.2 In the randomised, open label Phase III study, 1,093 patients with stage IV NSCLC were given 800mg of necitumumab 1250mg/m2 on days 1 and 8 plus 1250mg/m2 gemcitabine and 75mg/m2 cisplatin on day 1, or the chemotherapy regimen alone, in 21 day cycles for up to six cycles. Those given the combination with no progression continued to receive the antibody on its own until disease progression or intolerable toxicity occurred. Median survival for the antibody group was 11.5 months, and 9.9 months for those given just chemotherapy.
1. B. Kuenen et al. Clin. Cancer Res. 2010, 16, 1915
2. N. Thatcher et al. J. Clin. Oncol. 2014, 32 (Suppl.), Abst 8008