Abstract Body: The PI3K/AKT/mTOR and Ras/Raf/MEK/ERK are interlinked growth and survival signaling pathways that are often constitutively activated in human tumors as a result of amplifications and/or mutations in PIK3CA, RAS and BRAF genes. In the present work, we have investigated the anti-tumor activity and documented the steady state pharmacodynamic impact of combinations between 2 selective pan PI3K Class I inhibitors, SAR245408 (XL147) and SAR245409 (XL765) with the selective allosteric inhibitor of MEK1/2, pimasertib (AS703026; MSC1936369B) against several different patient derived colorectal cancer (CRC) xenograft models harboring either KRAS mutations, dual KRAS and BRAF mutations or dual KRAS and PIK3CA mutations.
In the BRAF driven CRC model, effects of the combinations were not significantly different from that of single agent treatment of pimasertib alone. In the G12V KRAS or G12D KRAS mutant CRC models, both combinations led to significantly greater anti-tumor activity than that of single agent treatment. In the dual PIK3CA/KRAS mutant tumors, combination therapies lead to a potent inhibition of both TORC1 and TORC2 pathways, in addition to inhibition of the MAPK pathway in contrast to single agent treatments. Overall, pimasertib combined with either SAR245409 or SAR245408 showed a significantly greater anti-tumor activity as compared to single agent treatment alone in primary models bearing KRAS mutations or dual PIK3CA/KRAS mutations. The combination of pimasertib and SAR245409 is currently being investigated in patients with PIK3CA/KRAS mutant colorectal cancer as part of an ongoing Phase Ib dose escalation trial of oral combination therapy with pimasertib (MSC1936369B) and SAR245409 in subjects with locally advanced or metastatic solid tumors.