Some of the most frequently searched words on this blog or those that arrive via organic Google searches centre around:

  • Melanoma
  • Ipilimumab
  • PLX4032

Interestingly, few are searching for RG7204, the Roche code for their compound being developed in partnership with Plexxikon or BRAF, the actual kinase target involved.

As background, you can read up on the past developments with BRAF V600 mutated melanoma herehere and here, including the phase II NEJM data, mechanisms of resistance (MEK or AKT) and how targeting CRAF as well as BRAF can lead to the development of squamous cell lesions in some patients.

This morning, Roche and Plexxikon announced the long awaited results of the phase III study (BRIM3) in newly diagnosed patients with metastatic melanoma:

“RG7204 (PLX4032) met its co-primary endpoints showing a significant survival benefit in people with previously untreated BRAF V600 mutation-positive metastatic melanoma.

Study participants who received RG7204 lived longer (overall survival) and also lived longer without their disease getting worse (progression-free survival) compared to participants who received dacarbazine, the current standard of care.”

The good news is that the survival benefit observed in the Phase II trials appears to be confirmed although the press release was rather short on specifics, presumably because the actual data will be presented at a cancer meeting later this year. However, given the current timing, I’m thinking this may augur well for an ASCO data submission. If so, ASCO is going to be interesting in metastatic melanoma this year with data anticipated from PLX4032 and ipilimumab (BMS).

Clearly, Roche intend filing the positive data with the Health Authorities, and in the meantime, they have announced plans to expand the access to PLX4032:

“Roche is now working closely with global health authorities to expand the recently announced RG7204 Early Access Program (EAP). The global EAP will be extended to include people with previously untreated, BRAF V600 mutation-positive metastatic melanoma.”

Now that we know more about the mechanisms of BRAF V600 resistance in metastatic melanoma, I’m also wondering when we might see some logical new trials evolve with PLX4032 in combination with a MEK or AKT inhibitor or perhaps sequenced, but to me it would make more sense to combine them.  It will be very interesting to see:

  • What the final survival advantage for PLX4032 is over dacarbazine
  • If a BRAF-MEK combination would further improve the OS

Fortunately, Genentech actually have two MEK inhibitors in development, GDC-0623 and GDC-0973 in solid tumours, so this approach is certainly feasible for them.

We’ll have to wait and see, but to put things in context, the phase II trial reported by Flaherty et al., (2010) in the NEJM demonstrated an approx. 6 month survival advantage in favour of PLX4032 before resistance set in.