AZD6244 is a potent and selective MEK1/2 inhibitor that has shown excellent preclinical activity in a range of tumor models4
with an acceptable toxicology profile, and this phase I study demonstrates that AZD6244 is well tolerated up to 100 mg bid. In part A, the MTD was 200 mg bid, but because of an increase in the frequency and severity of rash in part B, the lower dose level (50% of the MTD; 100 mg bid) was recommended as the tolerable phase II dose. The most common treatment-related toxicities observed with AZD6244 were rash, diarrhea, nausea, and fatigue, which are consistent with those observed for PD0325901 and CI-1040.9,10,16
Seven patients developed transient and reversible blurred vision while receiving AZD6244, an adverse effect also observed with PD0325901 and CI-1040.9,10,16
Five of these ocular events were observed at doses greater than the recommended phase II dose. When conducted, ophthalmologic examinations were unrevealing in regard to etiology. Rigorous physical examination and laboratory tests did not identify any other significant toxicities observed with other MEK inhibitors, including syncope and neurotoxicity.16,17
Despite a growing clinical literature on MEK inhibitors, there is only limited evidence to date that MEK can be inhibited consistently in patient tumors at tolerable inhibitor doses. In addition, it is unclear whether such inhibition correlates with clinical outcome and whether MEK inhibition in surrogate tissues corresponds to MEK inhibition in tumors. Accordingly, we determined whether tolerable doses of AZD6244 would inhibit MEK in PBMCs, skin, and patient tumors. Skin biopsies were generally uninformative because of the variable and minimal baseline levels of pERK. We observed a dose-dependent inhibition of ERK phosphorylation in PBMCs, as well as consistent inhibition of ERK phosphorylation when comparing pre- and post-treatment tumor biopsies, but there were insufficient data to suggest a correlation between surrogate tumor tissue PD. We also demonstrated inhibition of Ki-67 in patient tumors, but again, there were insufficient data to conclude whether PBMC samples are suitable surrogate tissues for tumor samples. Because activating mutations in NRAS, KRAS, and BRAF genes correlate in preclinical studies with sensitivity to MEK inhibitors, mutational analysis of these genes was performed in 26 available tumors. In this small sample size, there was a nonsignificant trend towards delayed progression on study in patients with mutations compared with wild-type tumors.
AZD6244 displayed less than dose-proportional PK with increasing Cmax and AUC as doses increased from 50 to 300 mg bid. There was a high degree of interpatient variability, which is not surprising for an oral agent. No food effect study was performed, and no guidance for food intake was given except for PK assessments that were performed in the fasting state (1 hour before and 2 hours after dosing). The PK profile supports a bid dosing scheme that results in exposures that adequately inhibit the drug target.
The best clinical response was SD that lasted for 5 or more months in nine patients. Two patients maintained SD for 19 and 22 cycles. One patient with malignant melanoma had a 70% tumor shrinkage after three cycles of AZD6244 but developed symptomatic brain metastases before confirmatory scans could be performed. This patient had an NRAS mutation and showed 100% inhibition of ERK phosphorylation and 97% inhibition of Ki-67. Thus, the present phase I study provides preliminary evidence of antineoplastic activity in humans.
In summary, this study establishes that the MEK inhibitor AZD6244 has a manageable safety and tolerability profile and identifies a suitable dose for subsequent clinical trials (100 mg orally, twice daily continuously) that results in target inhibition. Although this study demonstrates that the MEK1/2 target can be safely inhibited in vivo in humans, our data also suggest that target inhibition may be necessary but not sufficient for antineoplastic activity. These findings support future clinical development of AZD6244, and phase II studies are in progress.