Pharmacodynamic Elegance: Combination of BRAF and MEK Inhibitors

From Pharmaceutical to Pharmacodynamic Elegance

Traditional: Pharmaceutical Elegance

We all have the phrase pharmaceutical elegance firmly engrained in our brains from our respective university/college/school days (at least most of us – I’ve talked to a couple of my colleagues who are recent grads and I got a “deer in the headlights” look.)

A quick poll of colleagues on what they think of when they hear the term pharmaceutical elegance revealed descriptors such as:

  • “pretty product”
  • “nicely labeled”
  • “neat, straight and tidy label”
  • “neatly compounded cream and placed in jar cleanly”
  • “no lumps in the cream/ointment”
  • “absence of physical flaws”
  • A couple colleagues named 2 co-workers who have excellent penmanship

Technically, this is all fine and dandy and I feel appropriate when applied to the preparation of pharmaceutics. Those in the pharmacy field often exhibit the trait of having close attention to detail and thus being pharmaceutically elegant is a natural offshoot.

 

Progressive: Pharmacodynamic Elegance

As the profession of a clinical pharmacist continues to evolve, I am enamoured with another form of elegance – one that cannot be seen, at least not in the traditional sense.

The elegance I speak of, I will coin pharmacodynamic elegance.

{Disclaimer: I have not previously seen this phrase; feel free to notify me if you seen it utilized before. Healthcare professionals always seem to feel the need to add disclaimers…}

Over the past six months, I’ve attended three outstanding talks on the exciting developments in metastatic melanoma and the treatment thereof. Although, I’m sure it was mentioned in the first talk, I was a little sleep deprived and jet-lagged in Quebec City at NOPS and must have missed it (many of you may therefore be already aware of the following unique treatment combination). During the second talk, an excellent presenter from Germany talked at ground rounds and I thought I heard right, but upon second thought really could not believe what I was hearing. This past Wednesday, yet another grand rounds speaker highlighted this item quite clearly – an incidence of pharmacodynamic elegance  in its finest form.

 

The Eureka Moment: combine two targeted agents with a resulting synergistic efficacy and a paradoxical decrease in toxicity with the combination as compared to either one as monotherapy.

This is exactly what happens with the combination of the oral MEK inhibitor GSK212 and the oral BRAF inhibitor GSK436.

Acneiform rash:

  • MEK Inhibitor alone: 75% incidence
  • BRAF Inhibitor alone: 18% incidence
  • Combination of both: 2% incidence!!!

SCC (squamous cell carcinoma)

  • BRAF Inhibitor alone: 11% incidence
  • Combination of both: <1% incidence!!!

Read on from the following references for more details:

'Compelling' Activity With Combo Targeted Therapies for Melanoma (Reference: Nick Mulcahy, Medscape)

Excerpts:

“June 10, 2011 (Chicago, Illinois) — Two oral targeted therapies might be better than 1 in the treatment of patients with advanced melanoma and BRAF V600 mutation-positive disease, according to early research presented here at the American Society of Clinical Oncology 2011 Annual Meeting.

In a phase 1 trial, the combination of the oral MEK inhibitor GSK212 and the oral BRAF inhibitor GSK436 appeared to provide a synergistic boost to efficacy and a paradoxical reduction in toxicity, said lead author Jeffrey Infante, MD, from Sarah Cannon Research Institute in Nashville, Tennessee.

As monotherapies, the BRAF inhibitor GSK436 had a response rate of 63% and the MEK inhibitor GSK212 had a response rate of 40% in earlier testing in patients with advanced melanoma, said Dr. Infante. The responses to the combination therapy included 5 complete responses, which stunned one expert.

Resistance and Toxicities

"One of the goals of the trial is to determine if the addition of the MEK inhibitor can overcome or prevent BRAF resistance via activation of the MAPK pathway," said Dr. Infante, referring to the mitogen-activated protein kinase. However, resistance is a matter of long-term durability and cannot be answered at this point.

Dr. Infante explained that the addition of the MEK inhibitor was thought to be a potential way to decrease the incidence of BRAF-induced hyperproliferative skin lesions.

Thus far, among the study's 109 patients receiving combination therapy, there has only been 1 case of squamous cell carcinoma, a hyperproliferative skin condition that is not malignant and occurs in 7% to 15% of treated patients, reported Dr. Infante.

Another hyperproliferative condition, treatment-related rash, only occurred in 25% of patients, which is a much lower proportion than is typically seen. For instance, about 75% of patients treated with the MEK inhibitor GSK212 will have rash, he said.

At the press conference, a disbelieving reporter asked Dr. Infante if he heard correctly: Did the 2 drugs — combined and at full doses — have less toxicity than the agents as monotherapies? Yes, said Dr. Infante, admitting that it is "paradoxical."

"Cutaneous biologists will have a lot of fun" attempting to figure out the reason behind the reduction in dermatologic events with the combination therapy, said discussant Dr. Dummer.

The dose-escalation part of the study indicates that both drugs can be given together at the full monotherapy dose, Dr. Infante said. The MEK inhibitor GSK212 was ultimately given at 2 mg once daily, and combined safely with the BRAF inhibitor GSK436 at 150 mg twice daily.

In the phase 1 study, investigators found no significant drug–drug interactions in 7 patients evaluated.”

***

Another reference link which looks at the combination: Clinical Care Options

Excerpt:

“Background

  • Approximately 50% of melanomas harbor mutations in BRAF  {Chris: I’ve read 40- 60% and 7-8% in all of cancers.}
  • Suggests that inhibition of mutated BRAF kinase possibly clinically beneficial
  • GSK436, an oral BRAF inhibitor
    • Induces > 60% response rate
    • Key toxicity squamous cell carcinoma
  • GSK212, an oral MEK1/2 inhibitor
    • Induces 40% response rate
    • Key toxicity acneiform rash
  • Combination therapy with GSK436 and GSK212 attractive to dually inhibit Ras signaling pathway
  • Hypotheses {which turned out to be the case}:
  • Combining 2 agents with activity as monotherapy will have synergistic activity
  • Adding MEK1/2 inhibitor will prevent or overcome potential resistance to monotherapy
  • Adding MEK1/2 inhibitor will decrease incidence of hyperproliferative skin lesions associated with BRAF inhibition”

***

I’m looking forward to seeing many more of these unique pharmacodynamic elegant combinations.

Feel free to share your encounters with pharmacodynamic elegance.

- Chris

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Christopher Ralph - Communications Committee Chair