The new generation of genetically targeted anticancer agents is being developed for melanoma patients with specific mutations
The new generation of genetically targeted anticancer agents work in specific subpopulations of patients whose malignancies have specific mutations. Two such mutations, present in some melanoma patients, are at the BRAF and NRAS genes on the mitogen-activated protein kinase signalling pathway. These can both have an oncogenic effect, and have great potential as therapeutic targets. One way to do this is via selectively inhibiting mitogen-activated protein kinase kinases, or MEKs, which both inhibit growth and cause cell death in melanoma cell lines with these mutations.
A MEK inhibitor, binimetinib, is being developed by Array Pharma. The drug is a potent and selective inhibitor of MEK1/2. Various clinical trials have been carried out.
About 15% of melanoma patients have the NRAS mutation, associated with higher tumour proliferation and a worse prognosis. Its potential in these melanomas has been evaluated in a Phase II trial in 117 patients, who were given twice-daily 45mg oral doses.1 The median progression-free survival was 3.6 months, and the objective response rate was 14.5%; one patient achieved a complete response. The median overall survival was a shade over 12 months. The most common adverse events leading to discontinuation of therapy were decreased ejection fraction, retinal vein occlusion and a deterioration in general physical health; these three accounted for eight patients in total.
A Phase III trial is now underway to compare its activity with dacarbazine in patients with unresectable or metastatic NRAS mutated cutaneous melanoma, which was either untreated or had progressed after first line immunotherapy.2 Again, subjects are being given 45mg oral doses twice a day, with the parallel group receiving 1,000mg/m2 intravenous doses every three weeks.
Its potential is also being investigated in combination with the selective CDK4/6 inhibitor LEE011. Preclinical studies indicated that LEE011 inhibited tumour growth, and when combined with binimetinib regressions were seen in models of NRAS mutant melanoma.
A Phase Ib/II open label study is underway in patients with this form of melanoma.3 Early results from the Phase Ib part showed there was no evidence of drug–drug interaction. Six of the first 14 evaluable patients achieved a partial response, and a further six had stable disease. Several had early tumour shrinkage along with major improvements in symptoms.
It may also have potential in other solid tumours. In a Phase Ib dose escalation study, it is being combined with the PI3K(alpha) inhibitor BYL719, in patients who have one of more than 10 types of RAS or BRAF mutant advanced solid malignancy. Subjects were given orally co-administered doses of 30 or 45mg of binimetinib twice a day, alongside doses of between 80 and 270mg BYL719 once a day, in 28 cycles.4 The most common adverse events were diarrhoea and elevated creatine phosphokinase, with dose-limiting toxicities observed in nine out of 58 patients. Three KRAS mutant ovarian cancer patients achieved a partial response, plus another partial response in each of NRAS mutant melanoma and KRAS mutant endometrial cancer. About a third of the patients achieved stable disease for at least six weeks as their best response. Trials continue.
1. C.M.L. van Herpen et al. ESMO Ann. Meet. 2014 (26–30 September, Madrid), Abst. LBA 35
2. K. Flaherty et al. J. Clin. Oncol. 2014, 32 (suppl.) Abst. TPS 9102
3. J.A. Sosman et al. J. Clin. Oncol. 2014, 32 (suppl.) Abst. 9009
4. D. Juric et al. J. Clin. Oncol. 2014, 32 (suppl.) Abst. 9051