A Phase I Dose Defining Study for MK-2206 Combined with Gefitinib in NSCLC Population Enriched with EGFR Mutation

Abstract

BACKGROUND: The PI3K/AKT pathway is one of the key pathways of EGFR signaling in NSCLC. We hypothesize that combination of gefitinib with MK-2206, an allosteric oral AKT inhibitor, will overcome the development of EGFR TKI resistance and further increase the therapeutic efficacy of gefitinib. Preclinical data support the synergistic effect of this combination. The purpose of this study (NCT01147211) is to define the MTD of MK-2206 when combined with gefitinib in NSCLC. METHODS: The main eligibility criteria include metastatic NSCLC patients who previously failed and progressed through more than 3 months' use of EGFR TKI (e.g. erlotinib, gefitinib, afatinib) and >1 line of chemotherapy. Cohorts of 3 + 3 patients will be enrolled on escalating doses (level -1, 90 mg; level 1, 135 mg; level 2 200 mg QW) of MK-2206 administered followed by gefitinib (250 mg QD). Dose-limiting toxicity (DLT) is Gr 4 ANC >7 d, Gr >3 febrile neutropenia, Gr 4 platelets; Gr >3 non-hematologic toxicity except inadequately treated vomiting, diarrhea, asymptomatic uncomplicated hyperglycemia without Gr >3 electrolytes (but AC >250 mg/dL, PC >500 mg/dL), hypersensitivity, ALT >1 wk; and toxicity leading to a dose modification or causing a >3 wk delay. RESULTS: A total of 14 patients (median age 62, range 35 - 84; median prior treatments 4, range 2 - 6) who had been treated with gefitinib (n = 4), erlotinib (alone or with afatinib; n = 7), or both (n = 2) were enrolled, starting at MK-2206 QW 135 mg (n = 3) with 1 DLT (grade 3 vomiting). MK-2206 was de-escalated to 90 mg (n = 3) without DLT. MK-2206 was then escalated to 135 mg (n = 5) with 1 DLT (grade 2 erythema multiforme). No DLTs were observed at 200 mg (n = 3) QW. The most common toxicities of all grades for the combination of gefitinib and MK-2206 were eosinophil increase (n = 9), rash (n =9), diarrhea (n = 7), hyperglycemia (n = 4), and mucositis (n = 4). The RP2D identified was gefitinib 250 mg QD and MK-2206 200 mg QW. Two pts with MK-2206 200 mg QW had minor responses (-18, -20%) with symptomatic improvement for 8 and 27 wks, respectively. CONCLUSIONS: Gefitinib combined with MK-2206 is well tolerated and had shown preliminary activity in NSCLC patients with acquired resistance to EGFR TKIs.