Search

Supplementary Tables S1-S4 and Figures S1-S3. Tables S1/S2: % tumor response in mice with HCT116 and A2058 tumor xenografts following treatment; Table S3: Diagram showing dose-decision guidelines utilized in the MK-2206 clinical study based on observed toxicities; Table S4: number of patients with drug-related AEs in all courses of treatment; Figure S1/S2: Line graph showing the relative tumor volume and body weight observed in patients over time expressed in terms of days following treatment; Figure S3: Patient presenting with Grade III rash

Purpose: This study evaluated the clinical relevance of the dual-targeting strategy involving PI3K/AKT/mTOR and RAF/MEK/ERK pathways.Experimental Design: We investigated safety, efficacy, and correlations between tumor genetic alterations and clinical benefit in 236 patients with advanced cancers treated with phase I study drugs targeting phosphoinositide 3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways in our Phase I Clinical Trials Program.Results: Seventy-six (32.2%) patients received a PI3K pathway inhibitor in combination with a MAPK pathway inhibitor (D), whereas 124 (52.5%) and 36 (15.3%), respectively, received an inhibitor of either the PI3K or MAPK pathways (S). The rates of drug-related grade >III adverse events were 18.1% for (S) and 53.9% for (D; P < 0.001); the rates of dose-limiting toxicities were 9.4% for (S) and 18.4% for (D; P = 0.06). The most frequent grade >III adverse events were transaminase elevations, skin rash, and mucositis. In our comprehensive tumor genomic analysis, of 9 patients who harbored coactivation of both pathways (colorectal cancer, n = 7; melanoma, n = 2), all 5 patients treated with (D) had tumor regression ranging from 2% to 64%.Conclusions: These results suggest that dual inhibition of both pathways may potentially exhibit favorable efficacy compared with inhibition of either pathway, at the expense of greater toxicity. Furthermore, this parallel pathway targeting strategy may be especially important in patients with coexisting PI3K pathway genetic alterations and KRAS or BRAF mutations and suggests that molecular profiling and matching patients with combinations of these targeted drugs will need to be investigated in depth. Clin Cancer Res; 18(8); 2316–25. ©2012 AACR.

CCR Translation for This Article from The Clinical Effect of the Dual-Targeting Strategy Involving PI3K/AKT/mTOR and RAS/MEK/ERK Pathways in Patients with Advanced Cancer

Purpose: KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies.Experimental Design: We conducted a dose/schedule-finding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumors. Recommended dosing schedules were defined as MK-2206 at 135 mg weekly and selumetinib at 100 mg once daily.Results: Grade 3 rash was the most common dose-limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug–drug interactions. Clinical antitumor activity included RECIST 1.0–confirmed partial responses in non–small cell lung cancer and low-grade ovarian carcinoma.Conclusion: Responses in KRAS-mutant cancers were generally durable. Clinical cotargeting of MEK and AKT signaling may be an important therapeutic strategy in KRAS-driven human malignancies (Trial NCT number NCT01021748). Clin Cancer Res; 21(4); 739–48. ©2014 AACR.

Purpose: KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies. Experimental Design: We conducted a dose/schedule-finding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumors. Recommended dosing schedules were defined as MK-2206 at 135 mg weekly and selumetinib at 100 mg once daily. Results: Grade 3 rash was the most common dose-limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug–drug interactions. Clinical antitumor activity included RECIST 1.0–confirmed partial responses in non–small cell lung cancer and low-grade ovarian carcinoma. Conclusion: Responses in KRAS-mutant cancers were generally durable. Clinical cotargeting of MEK and AKT signaling may be an important therapeutic strategy in KRAS-driven human malignancies (Trial NCT number NCT01021748). Clin Cancer Res; 21(4); 739–48. ©2014 AACR.