Thursday, February 13, 2014

BRAF inhibitors for melanoma: Dabrafenib, Vemurafenib, Dabrafenib/trametinib combo. Answers!!!!!

"You have metastatic melanoma." Those words prompt immediate panic, fear, confusion, an onslaught of new tests, new terms, generalized and specific CRAZINESS!!!  The fact that every drug name seems to be some unreal combination of letters derived from a bizarre Czech language crossed with the imaginary "Unobtainium" from Pandora in Avatar only increases confusion.  Granted, even strangely named drugs and their greatly increased effectiveness compared to interferon and even IL-2 is a boon.  Yet, when vermurafenib (Zelboraf) was granted FDA approval in August of 2011, dabrafenib (Tafinlar) in May 2013, and the BRAF/MEK combo (dabrafenib and trametinib [Mekinist]) was approved just this past January, patients were left with even more questions.

What is BRAF??? The BRAF gene tells the cell how to make a protein (B-Raf).  This protein is part of a signaling pathway that regulates cell growth, movement, and death.  When the BRAF gene changes (mutates) and fails to give the correct instructions, cells can become cancerous.

Should I want to have this mutation? Hmmm, well if you didn't have the mutation, about 50% of melanoma patients wouldn't have melanoma.  A lot of folks with cardiofaciocutaneous syndrome, Noonan's syndrome, Langerhans cell histiocytosis, and Leopard syndrome, wouldn't be dealing with their disease either.  But, in order for BRAF inhibitors to work on melanoma, you do need to have that particular mutation in your tumor cells.

Do I have it?  Docs are now routinely sending tumors of melanoma patients (or should be) for mutation testing to include: BRAF, NRAS, and cKIT.  Older BRAF tests were less accurate so folks with tumors tested some time ago may need to have the newer tests done on their tumor to determine their status.

What's with all this V600 business? Most BRAF mutations occur at the same place on the gene... codon 600. At that spot on the gene, the proper amino acid, valine (V), has been changed to either glutamic acid (E) or lysine (K).  {I know...they should be V600G and V600L...right???} Anyhow, if you have BRAF V600E or K your tumor meets the criteria to be treated with BRAF inhibitors (dabrafenib, vemurafenib) or the MEK inhibitor (trametinib).

If one BRAF inhibitor doesn't work for me, will the other one?  Do they work on brain tumors? Short answers....yes.  More info below.


Dabrafenib and its potential for the treatment of metastatic melanoma.  Menzies, Lon, Murali.
Drug Design, Development and Therapy. December 2012. 

Summary points:
  • BRAF mutations occur in 50% of melanomas; 70%–90% are V600E and 10%–30% are V600K.
  • Selective (type 1) BRAF inhibitors (dabrafenib, vemurafenib) target mutant BRAF kinase and inhibit the MAPK pathway.
  • Both drugs provide high response rates and rapid modes of action, but both are limited by the rapid development of acquired resistance. (About 70-80% of BRAF positive patients respond, but most tumors figure out a work around in about 7-8 months, though there are exceptions.)
  • Both dabrafenib and vemurafenib are effective in treating BRAFV600E melanoma patients, with prospective evidence of dabrafenib activity in BRAFV600K melanoma and in those with brain metastases.
  • Both drugs have similar toxicity profiles (Side effects include - arthralgias, rashes, extreme sun sensitivity, development of benign skin cancers and other fun stuff.); dabrafenib appears to have less cutaneous and hepatic toxicity than vemurafenib, but is associated with pyrexia [fever].
  • Emerging combination strategies, such as the CombiDT, [the dabrafenib and trametinib combo] are designed to improve response and delay resistance. [It takes tumors much longer to find  a work-around and patients experience fewer side effects when they take the combo, than when they take a single BRAFi!]
BRAF therapy and BRAIN METS:

Patterns of response and progression in patients with BRAF-mutant melanoma metastatic to the brain who were treated with dabrafenib.  Azer, et al.   Cancer. 2/2014.

23 patients studied. Response rates in intracranial (78%) and extracranial (90%) sites.  Of 20 patients with progressive disease, 6 had IC progressive disease and 6 had progressive disease in EC only and 8 experienced progressive disease in both sites. 5 of 6 with isolated progressive disease to the brain underwent local therapy to the brain and continued on dabrafenib longer than 30 days.  Bottom line:  IC and EC tumors respond similarly to dabrafenib.

Vemurafenib in metastatic melanoma patients with brain metastasis: as open label, single-arm, phase 2 multicenter study.  Kefford, et al.

As of April 2013, 146 patients with melanoma brain mets (Patients had an average number of 3 mets...though the range was from 1-30.) were treated with vemurafenib.  In patients with previously untreated MBMs, vemurafenib produced a response in 61% of those patients. The median progression free survival was 3.7 months and the overall survival median was 7 months.  So...Vemurafenib works on brain tumors, too.


Switching therapy pre-emptively from vermurafenib (Zelboraf) to ipilimumab (ipi/Yervoy) in patients with BRAF-mutated melanoma.  Angelo et al.  Memorial Sloan Kettering.

"Median time to progression on Zel is 6.9 months; 75% of patients progress by 1 year.  Once patients progress on Zel, melanoma sometimes grows too quickly for patients to benefit from subsequent ipi treatments.  In July 2011, researchers adopted a strategy of treating previously untreated patients with BRAF-mutated melanoma with Zel for a limited time, then, after maximal response but before developing resistance, switching to ipi. Review of 19 patients:  Initial plan = 4 months of Zel, was changed to 2 months after some patients progressed at 4.  All patients were switched to ipi and received a median of 4 doses starting at a median of 1 week after last dose of Zel. At the time of the first ipi dose, 8 patients had progressed on Zel, 11 had not, but 5/11 ultimately progressed on ipi and were retreated with Zel.  Among the 11 patients switched to ipi before progression, there have been no melanoma specific deaths to date (median follow-up = 1 year) compared to 7/8 deaths among patients who had progressed at the time of the switch.  There is potential selection bias in this small, on-going experience.  However, the results are consistent with a benefit of switching patients pre-emptively from a BRAF inhibitor to ipi prior to onset of resistance."

Response to BRAF inhibition in melanoma is enhanced by the addition of immune checkpoint blockade.  Cooper, Hodi, Flaherty, et al.  Mass General, Harvard, Dana Farber.

"BRAF targeted therapy results in objective responses in the majority of patients, however responses are short lived (about 6 months).  In contrast, treatment with immune checkpoint inhibitors results in lower response rates, though responses tend to be more durable.  We...have preliminary evidence that these two strategies may be combined to provide more durable responses. ...BRAF inhibition results in a more favorable tumor microenvironment in patients, with an increase in CD8+ T cell infiltration and a decrease in immunosuppressive cytokines.  However, there may also be an increased expression of the immunoinhibitory molecule PD-L1, which may contribute to resistance.  ...[So] we sought to test the hypothesis that responses to BRAF-targeted therapy would be enhanced by the addition of immune checkpoint blockade (like anti-PD1, anti-PDL1 and ipi).  [So....when poor ratties (really....rats) were given a BRAF(V600E) melanoma tumors, then BRAF targeted therapy combined with anti-PD1 and anti-PDL1], they demonstrated enhanced response, significantly prolonging survival and slowing tumor growth....suggesting that the addition of PD1 pathway blockade may augment responses to BRAF-targeted therapy. Clinical trials combining these two strategies are ongoing..."

COMBO of Dabrafenib and Trametinib (BRAF/MEK):

Note:  From Jan 22, 2014 post - I've mentioned before various trials have demonstrated that the combination of these meds created better responses and fewer side effects than when they were used alone.  Approval of the combination was based on the demonstration of durable objective responses in trials where objective response rates and response durations were 76% and 10.5 months with the combo and only 54% and 5.6 months in the single agent arm.  Squamous cell carcinoma was 7% in the combo arm, but was 19% in the single agent arm. The most common (at least 20% incidence) side effects experienced with the combination were:  fever, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough, headache, arthralgia, night sweats, decreased appetite, constipation, and myalgia.  The most frequent complicated adverse events (with at least a 5% incidence) were:  acute renal failure, fever, hemorrhage, and back pain.

Phase I/II expansion cohort of BRAF inhibitor GSK2118436 + MEK inhibitor GSK1120212 in patients with BRAF mutant metastatic melanoma who progressed on a prior BRAF inhibitor.  Flaherty, Infante, Falchook, et al. Pigment Cell Melanoma Res. 2011;24 (1022):  Abstract.

"Additionally, in the Part B expansion cohort of patients with prior disease progression during [single] BRAF inhibitor treatment, an impressive 19% response rate was seen with CombiDT therapy."

I realize that for the uninitiated, non-medical person this is just a bunch of mess.  But, I tried to simplify things as much as possible and hope it helps answer some of the basic questions about BRAF, BRAF-inhibitors, and how researchers are trying to make them work better for melanoma patients.  Best - c

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