UNASSIGNED: 2502 Background: The dual targeting strategy involving @entity10160 and MAPK pathways is compelling, as it has become increasingly clear that both pathways are interconnected. Nevertheless, the clinical impact of this strategy remains uncertain. METHODS: A pooled analysis of advanced @entity5 @entity1 (pts) treated with phase I study drugs targeting @entity10160 /MAPK pathways from 06/07 to 11/10 was conducted. Pts treated with either single pathway inhibition (S) or dual pathway inhibition (D) were evaluated for safety, efficacy, and correlations between @entity5 genetic alterations and response. Response was assessed by using waterfall plot analysis (WPA) which included both average enlargement in @entity5 burden (AETB) and @entity5 ( @entity5 ). Tumor genetic alterations were analyzed using DNA array-based CGH/PCR-based DNA sequencing. RESULTS: A total of 225 pts in 11 first-in- @entity1 phase I clinical trials were analyzed; 66 pts (30%) received D, while 122 (54%) and 37 (16%) received inhibitors of either @entity10160 or MAPK pathways (S); 159 (71%) had measurable disease. The rates of drug-related grade 3/4 adverse events (AEs) were 17% (28/159) for S and 46% (30/66) for D (p<0.0001); rates of DLTs were 10% (16/159) for S and 17% (11/66) for D (p=0.17). The most frequent grade 3/4 AEs were @entity1910 and transaminase elevation. WPA displayed AETB(%) / @entity5 (%): 21/17(S) and 13/14(D). Ninety-two of the 225 (41%) pts had available @entity5 genomic profiling data. @entity10160 pathway genetic alterations were detected in 17 of the 92 pts (18%; @entity983 deletion, n=11; @entity23698 amplification, n=5; @entity10160 mutation, n=1). Nine of the 17 (53%) pts with @entity10160 pathway genetic alterations had simultaneous @entity984 or @entity817 mutations (colorectal, n=8; @entity320 , n=1). Of these 9 pts, all 5 pts who treated with D had @entity5 regression ranging from -2% to -64%. CONCLUSIONS: These preliminary results suggest that D of @entity10160 /MAPK pathways exhibits favorable efficacy compared to S of either pathway, at the expense of higher rates of Gr 3/4 AEs. This strategy may be especially important in pts with coexisting @entity10160 pathway genetic alterations and @entity984 / @entity817 mutations. Validation in the context of larger studies is recommended.

The clinical effect of the dual-targeting strategy involving @entity10160 /AKT/mTOR and RAS/MEK/ERK pathways in first-in- XXXX phase I study: The START Center experience.

@entity1 :: ('9606', 'Species') :: ['human', 'patients'] @entity1910 :: ('MESH:D005076', 'Disease') :: ['rash'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor', 'METB', 'cancer', 'median enlargement in tumor burden'] @entity984 :: ('3845', 'Gene') :: ['KRAS'] @entity983 :: ('5728', 'Gene') :: ['PTEN'] @entity23698 :: ('208', 'Gene') :: ['Akt2'] @entity817 :: ('673', 'Gene') :: ['BRAF'] @entity10160 :: ('5290', 'Gene') :: ['PI3K', 'PIK3CA'] @entity320 :: ('MESH:D008545', 'Disease') :: ['melanoma']
@entity1 :: (9606,Species) :: ['human']
