Pharma Strategy Blog

Hot on the heels of last week's New England Journal of Medicine article on ipilimumab (BMS) comes another article on metastatic melanoma, this time from Keith Flaherty's group in Pennsylvania and Boston on BRAF inhibition with PLX4032, an exciting compound being developed by Plexxikon/Roche (see link below in the references for the article).

I've written a few posts on this interesting compound recently (e.g. here and here), for those interested in getting up to speed on the concept and data.

The basic concept is that a while back it was noticed that some tumours such as melanoma develop the V600E BRAF mutation and induce resistance or a poorer prognosis, so common sense says why not find a targeted agent to inhibit the activity to see what happened?

In the August 26th edition of the NEJM, Flaherty et al., described the updated phase I results in two phases:

• 55 patients (49 with melanoma) in the dose escalation phase
• 32 additional people with metastatic melanoma who had BRAF with the V600E mutation in the extension phase

Now, remember, a phase I trial usually seeks to define the maximum tolerated dose (MTD), which is used in the phase II studies and looks at the general tolerability and side effects.  Efficacy is not the primary end point, but of course, we all secretly look at the activity to see if there is any sign of a response!

First things first.  After some palaver with the crystalline formulation, it was finally settled on a "micro-precipitated bulk powder" since that offered superior bioavailability. I'm paraphrasing a bit and taking liberties here, but no doubt regular readers will sense my excitement and tendency to skip to the bottom line and find out what it all means, although we have all been there with those kind of challenging problems, especially as they add delays and frustrations all around!

Anyway, as a result of these changes, the final recommended dose that emerged for the phase II studies was 960mg BID, with increases in the dose limited by grade 2 or 3 rash, fatigue or arthralgia. These kind of side effects are fairly typical of oral TKI's and very different from what we saw with last week's NEJM article on immunotherapy with ipilimumab in a similar population.

Potentially, the biggest concern is the appearance of squamous-cell carcinoma that appeared in 10 of 32 patients (31%) in the dose escalation cohort.  While normally well differentiated and of low invasive potential, it is something to note.  The authors noted that recent data earlier this year (see references below) suggest BRAF inhibitors can activate the MAP kinase pathway in cells that lack a BRAF mutation and may explain some of the peculiar side effects seen with PLX4032.

Previously, Flaherty et al., reported nine responses in the second PLX4032 cohort and median PFS of 6 months.  For comparison with the updated data, see the last report before reading on. Over half of the people in both cohorts had received 2 or more therapies, so these are a mix of relapsed and refractory patients:

• In the first cohort of 55 people, there were 16 with the BRAF V600E mutated melanoma and received 240mg or more of PLX-4032.  The efficacy?  Well, there were 10 partial response and 1 complete response (69%).
• In the extension cohort of 32 people, 24 were partial responders and 2 had a complete response (81%), which is pretty impressive all around.  No wonder Dr Flaherty was very excited when interviewed for an article in the NY Times earlier this year!

My first reaction was slight disbelief, after all, this is a very difficult to treat and highly aggressive disease, thus sadly, people do tend to relapse early. In short, if there were three cancers I absolutely wouldn't want to get, this would be one of them.

On closely checking the data carefully including the 81% response rate in the second cohort (yes, it's correct!), I noticed that the researchers reported across all patients in the phase I study, the median progression free survival (PFS) was now improved to 7 months.  That means that 50% did worse and 50% did better than 7 months, way better than one might expect so early in a trial.  I did double check again and pinch myself, as it was late on Tuesday night when I penned the draft.

If you are interested in this area, do check out the link to the article below because the water plots and anti-tumour responses over time are well worth looking at, especially as some people are clearly achieving responses approaching a year, despite having advanced disease.

"Responses were observed at all sites of the disease, including the bone, liver, and small bowel."

Yes, it is still very early, but how awesome is it to read that?

As an aside, a number of readers have written asking why sorafenib hasn't shown to be effective in melanoma, despite inhibiting BRAF.  Flaherty et al., had an answer for that. They suggested that  because it also inhibits other pathways, it may well be that the non-BRAF effects of the drug mediate side effects that limit the ability to achieve enough drug concentration and thus the drug concentration isn't high enough to effectively inhibit the V600E BRAF mutation.  An interesting theory that also speak to the idea that several specific inhibits may be more effective that more promiscuous multi-kinase inhibitors.

The good news is that for now at least, we seem to be on the right track with PLX4032 and ipilimumab in metastatic melanoma.  It will be interesting to see what the mechanisms of resistance are down the road, and whether we have some options in the works for either combination or sequencing of different targeted agents for this disease.

Flaherty, K., Puzanov, I., Kim, K., Ribas, A., McArthur, G., Sosman, J., O'Dwyer, P., Lee, R., Grippo, J., Nolop, K., & Chapman, P. (2010). Inhibition of Mutated, Activated BRAF in Metastatic Melanoma New England Journal of Medicine, 363 (9), 809-819 DOI: 10.1056/NEJMoa1002011

Heidorn, S., Milagre, C., Whittaker, S., Nourry, A., Niculescu-Duvas, I., Dhomen, N., Hussain, J., Reis-Filho, J., Springer, C., & Pritchard, C. (2010). Kinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF Cell, 140 (2), 209-221 DOI: 10.1016/j.cell.2009.12.040

Poulikakos PI, Zhang C, Bollag G, Shokat KM, & Rosen N (2010). RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature, 464 (7287), 427-30 PMID: 20179705

Hatzivassiliou, G., Song, K., Yen, I., Brandhuber, B., Anderson, D., Alvarado, R., Ludlam, M., Stokoe, D., Gloor, S., Vigers, G., Morales, T., Aliagas, I., Liu, B., Sideris, S., Hoeflich, K., Jaiswal, B., Seshagiri, S., Koeppen, H., Belvin, M., Friedman, L., & Malek, S. (2010). RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth Nature, 464 (7287), 431-435 DOI: 10.1038/nature08833