Vemurafenib (brand name Zelboraf) NEW DISCOVERY

New research on mice shows that drug-resistant melanoma tumors shrink when treatment is interrupted, or given a "holiday", suggesting that altering the dose pattern of cancer drug treatment in this manner could be a simple way to extend survival in human patients with late-stage disease. However, only human trials can verify if this is the case.

Co-lead researcher Martin McMahon, a cancer biologist at UCSF, and colleagues, found that one mechanism by which melanoma cancer cells become resistant to the anti-cancer drug vemurafenib (brand name Zelboraf), also makes them become addicted to it.

The consequence of this simultaneous resistance-cum-addiction to vemurafenib is that the cancer cells then proceed to use the compound to boost the growth of deadly, fast growing, drug-resistant tumors.

Once they made this discovery the team proceeded to experiment with changing patterns of drug dosage to see what effect this might have on mice implanted with melanoma tumors.

Drug combinatorial screening was used to identify effective combinations for mutant BRAF melanomas, including those resistant to vemurafenib, and mutant RAS melanomas that are resistant to many therapies.



Roche recently disclosed a decision to start phase III with GDC-0973 (formerly XL518), a MEK inhibitor licensed from Exelixis (EXEL) to Genentech 6 years ago. The trial is expected to start next month, and will evaluate GDC-0973 in combination with Roche's Zelboraf in patients with BRAF-mutated melanoma. This is an extremely positive catalyst for Exelixis, who now has a second drug in pivotal studies with a high likelihood of success and a substantial market opportunity.

Large commercial opportunity - The commercial opportunity for GDC-0973 in advanced melanoma is ~$1.5B globally, based on pricing and sales estimates for Zelboraf. MEK inhibitors have potential for many additional cancers, including lung and ovarian cancer.

Favorable deal terms - Deal entails a profit share agreement and an option for Exelixis to co-promote the drug in the US. Exelixis is eligible for additional milestones and royalties on ex-US sales.

Short timelines - The phase III trial will start next month with progression-free survival as the primary endpoint. Enrollment should be very quick, given Roche's experience in the indication (Zelboraf was the 1st approved drug for BRAF-mutated melanoma) and the fact that melanoma patients are routinely screened for BRAF status and treated with Zelboraf. Top line results could be available in mid-2014, and Roche expects to submit the combination for approval in 2014.


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