Wednesday, May 24, 2017

Management of Adverse Events with Targeted Therapy (BRAF/MEKi)

BRAF inhibitors combined with MEK inhibitors have been an amazing targeted treatment option for BRAF positive melanoma patients (about half of us).  They rarely have durable responses, though occasionally they can remain effective therapy for years, but are incredibly useful in our treatment arsenal.

Here is a post that gives a basic primer on BRAF and targeted therapy:  BRAF inhibitors for melanoma

Here is a post on several BRAF/MEK combo's  The coBRIM trial with links to other reports

And of course....there are always side effects.  Here is a report from Weber and Agarwala:  Side effects and how to manage them

Now there is this with specific plans re management of adverse events.....

Management of Treatment-Related Adverse Events with Agents Targeting the MAPK Pathway in Patients with Metastatic Melanoma. Daud, Tsai. The Oncologist. May 18, 2017.

Tremendous progress has been made in the clinical landscape of advanced-stage BRAF V600–mutant melanoma treatment over the past 5 years. Targeted therapies that inhibit specific steps of the mitogen-activated protein kinase pathway have been shown to provide significant overall treatment benefit in patients with this difficult-to-treat disease. Combination therapy with BRAF and MEK inhibitors (dabrafenib plus trametinib or vemurafenib plus cobimetinib, respectively) has become standard of care. These agents are administered until disease progression or unacceptable toxicity occurs; thus, some patients may remain on maintenance therapy for an extended period of time, while toxicities may result in early discontinuation in other patients. Because the goal of treatment is to prolong survival with minimal impairment of quality of life, drug-related adverse events (AEs) require prompt management to ensure that patients derive the best possible benefit from therapy. Proper management depends on an understanding of which AEs are most likely BRAF or MEK inhibitor associated, thus providing a rationale for dose modification of the appropriate drug. Additionally, the unique safety profile of the chosen regimen may influence patient selection and monitoring. This review discusses the toxicity profiles of these agents, with a focus on the most commonly reported and serious AEs. Here, we offer practical guidance derived from our clinical experience for the optimal management of key drug-related AEs.  

Recommended dosage adjustments....
LATE NOTE:  Thanks to the sharp eyes of Mike Brooks and a note he left me....I think he is correct in having found a typo in the dose reduction chart above regarding the trametinib dose.  It appears they have simply copied the dose reduction for vemurafenib....which comes in 240 mg tabs and is usually dosed at 960 mg taken twice a day.  However, trametinib (Mekinist) comes in 0.5, 1 and 2 mg tabs and is usually dosed at 2 mg once a day, either alone or in combination with a BRAFi. Therefore, Mike is probably right that a dose reduction regimen is likely to be something along the lines of:  2 mg, to 1.5 mg, to 1 mg, to 0.5 mg. It takes a village!!!
Management of fever...

Management of rash....

Management of cardiac side effects....
Again, as I noted in my last post, I hope this is information for which you will find no need...but here it is....if you do. - c

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