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Background This multicenter, open‐label, phase Ib study investigated the safety and efficacy of binimetinib (MEK inhibitor) in combination with buparlisib (phosphatidylinositol 3‐kinase [PI3K] inhibitor) in patients with advanced solid tumors with RAS/RAF alterations. Materials and Methods Eighty‐nine patients were enrolled in the study. Eligible patients had advanced solid tumors with disease progression after standard therapy and/or for which no standard therapy existed. Evaluable disease was mandatory, per RECIST version 1.1 and Eastern Cooperative Oncology Group performance status 0‐2. Binimetinib and buparlisib combinations were explored in patients with KRAS‐, NRAS‐, or BRAF‐mutant advanced solid tumors until the maximum tolerated dose and recommended phase II dose (RP2D) were defined. The expansion phase comprised patients with epidermal growth factor receptor (EGFR)‐mutant, advanced non‐small cell lung cancer, after progression on an EGFR inhibitor; advanced RAS‐ or BRAF‐mutant ovarian cancer; or advanced non‐small cell lung cancer with KRAS mutation. Results At data cutoff, 32/89 patients discontinued treatment because of adverse events. RP2D for continuous dosing was buparlisib 80 mg once daily/binimetinib 45 mg twice daily. The toxicity profile of the combination resulted in a lower dose intensity than anticipated. Six (12.0%) patients with RAS/BRAF‐mutant ovarian cancer achieved a partial response. Pharmacokinetics of binimetinib were not altered by buparlisib. Pharmacodynamic analyses revealed downregulation of pERK and pS6 in tumor biopsies. Conclusion Although dual inhibition of MEK and the PI3K pathways showed promising activity in RAS/BRAF ovarian cancer, continuous dosing resulted in intolerable toxicities beyond the dose‐limiting toxicity monitoring period. Alternative schedules such as pulsatile dosing may be advantageous when combining therapies. Implications for Practice Because dysregulation of the mitogen‐activated protein kinase (MAPK) and the phosphatidylinositol 3‐kinase (PI3K) pathways are both frequently involved in resistance to current targeted therapies, dual inhibition of both pathways may be required to overcome resistance mechanisms to single‐agent tyrosine kinase inhibitors or to treat cancers with driver mutations that cannot be directly targeted. A study investigating the safety and efficacy of combination binimetinib (MEK inhibitor) and buparlisib (PI3K inhibitor) in patients harboring alterations in the RAS/RAF pathway was conducted. The results may inform the design of future combination therapy trials in patients with tumors harboring mutations in the PI3K and MAPK pathways.

Mouse L5178Y strain LY-S and its parental strain LY-R differ in their comparative sensitivities to the cytotoxic effects of various mutagenic agents-i.e., strain LY-S has been found to be more sensitive, less sensitive, or similarly sensitive to individual agents in comparison to strain LY-R. Nevertheless, strain LY-S has been found to be uniformly less mutable than strain LY-R at the hypoxanthine (guanine) phosphoribosyltransferase (Hprt) locus following treatment with x-radiation, UV radiation, or alkylating agents. In the present work we have isolated subclones of strains LY-R and LY-S that are heterozygous at the thymidine kinase (Tk) locus (chromosome 11). We have found that a heterozygous LY-S Tk+/Tk-strain shows as high or higher mutability at the Tk locus than do heterozygous LY-R strains following treatment with x-radiation, UV radiation, or ethyl methanesulfonate.Mutability of all heterozygous strains at the Tk locus is much higher than at the Hprt locus following treatment with these mutagenic agents, with the exception ofone heterozygous LY-R strain that possesses only one chromosome 11 and that is poorly mutable at the Tk locus by x-radiation. On the basis of these results, we have suggested that (i) because of a repair deficiency, multilocus lesions are formed in the DNA of LY-S strains following treatment with radiation or alkylating agents; (ii) multilocus lesions lead to poor recovery of viable mutants when the target locus is closely linked to essential genes and situated on a hemizygous chromosomal region (e.g., the Hprt locus on the X chromosome or the Tk locus in strains monosomic for chromosome 11); and (iii) x-radiation is a relatively poor mutagen at loci situated on hemizygous chromosomal regions, in repair-efficient and repair-deficient cells, because of its tendency to form multilocus lesions.Mouse lymphoma strain L-5178Y-S (LY-S) was first isolated by Alexander and Mikulski (1) following a spontaneous increase in the x-radiation sensitivity ofL5178Y cells growing in vitro. The parental strain was named L5178Y-R (LY-R) to differentiate it from the newly isolated sensitive strain. In spite of the greater sensitivity of strain LY-S to the cytotoxic effects of x-radiation and alkylating agents (2-5), strain LY-S is less mutable than strain LY-R by UV radiation and x-radiation and by alkylating agents at the hypoxanthine (guanine) phosphoribosyltransferase (Hprt) and Na+,K+-ATPase loci (4-6). In the present work we have compared the mutability of the two strains at the thymidine kinase (Tk) locus situated on chromosome 11 (7, 8) using heterozygous Tk+/Tk-strains of LY-R and LY-S. We have found the mutability of the heterozygous LY-S strain (LY-Si) to be as high or higher than that of LY-R heterozygous strains (LY-R16 and LY-R83) at the Tk locus following treatment with x-radiation, UV radiation, or ethyl methanesulfonate (EtMes). Mutant frequencies are much higher at the Tk locus than at the Hprt and Na',K+-ATPase loci for LY-S and LY-R heterozygous strains treated with these age...

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