Efficacy of vemurafenib (V), a selective V600EBRAF inhibitor, as monotherapy or in combination with erlotinib (Erl) or erbitux (Erb) and irinotecan (Iri) doublets and triplets in a colorectal cancer (CRC) xenograft model.

Abstract

494 Background: B-Raf mutations, particularly at V600 occur in 10% of CRCs resulting in constitutive activation of the MAPK pathway. V (RG7204, PLX4032) is a first-in-class, V600B-Raf-selective small molecule inhibitor previously shown to potentiate anti-tumor effects in the V600E CRC xenograft model HT29 in combination (combo) with capecitabine ± bevacizumab (ASCO GI, 2008). V600E CRC respond poorly to EGFR inhibition (EGFRi) both preclinically and clinically. We aimed to determine whether antitumor activity could be potentiated by combining V with EGFRi. Methods: The monotherapy (mono) activities of V, Erl, Erb and Iri were compared to combo of these agents in the HT29 model. V was tested as a mono at its optimal dose (OD), Erl was tested at its MTD or 2/3 MTD, and a combo of V OD + 2/3 MTD Erl were tested. V was subsequently tested as mono or combo at the OD and suboptimal-OD with OD Erb. A final study included Iri as mono, doublets of Iri + V or Erb, and triplet combo of Iri, V, and Erb. Results: Tumor growth inhibition (TGI) and increase in life span (ILS) for combo of OD V + 2/3 MTD Erl was superior to all mono arms. TGI in mono arms was equivalent for V, Erb and Iri. ILS was better for V vs Iri and Erb mono, while Iri vs Erb ILS were equivalent. TGI and ILS for Iri + Erb doublet was equivalent to V mono. Otherwise, TGI and ILS in all other doublets and triplets were superior to mono groups. TGI in V + Erb and V + Iri were equivalent, but ILS was better for V + Iri. TGI and ILS for V + Iri was better than Iri + Erb. TGI in V + Erb was better than Iri + Erb, but ILS was equivalent. TGI in the triplet was superior to all doublets except V + Erb, however ILS was superior to all doublets tested. Conclusions: V potentiates anti-tumor activity in a V600E CRC model when used in combo with Erl, Erb and Iri. Although a V + Erb doublet provided impressive TGI equivalent to a triplet with Iri, the triplet yielded sustained antitumor activity as demonstrated by a significant increase in survival as compared to the doublet. Combo with V may afford V600E CRC patients a differential response to what is seen traditionally with single agent EGFi and is worthy of clinical exploration.