May is Melanoma Month-Part II, "Research is Hope"

When I read this article from The Lancet today,  I literally started crying.  After a long drought and many warriors lives lost, there are finally some newer drugs in the metastatic melanoma arsenal that bring us hope!!! 

The hour is late, so I will post more on these later.  But Melanoma Warriors,  check out this article below!!!

Yes, I know that these drugs are not for everyone, but they are a great start.  And to all of  you out there....when they unlock the key for one subset of patients, let's hope the next subset is not far behind.

Vemurafenib, Ipilimumab and now Dabrafenib (early phase, but promising!!).  Have hope Melanoma patients!!!  Long ago I was at a Southwest Oncology Group Meeting and I heard someone say, "Research is Hope", and that is the truth.

One of the doctors mentioned in the article below was one of the co-chairs of the Southwest Oncology Group Melanoma Committee for 20 years.  Dr. Vernon Sondak.  A truly good person,  a great surgical oncologist, and a researcher who has been fighting the war on melanoma for many years with his other amazing co-chair Lawrence Flaherty, MD.  Two great men doing great work (and they both are unbelievably humorous to boot!!)

http://www.swog.org/Visitors/newsletters/2011/10/index.asp?a=melanoma

Hopefully we will be hearing a lot more about all of these drugs (and many other drugs and other types of cancer) when reports start coming out of ASCO in two weeks.
http://chicago2012.asco.org/

Here's The Lancet article:

Dabrafenib Safe in Melanoma With Brain Mets

By Shalmali Pal, Contributing Editor, MedPage Today Published: May 18, 2012
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, BSN, RN, Nurse Planner 

For a second time this week, a study has shown the BRAF inhibitor dabrafenib to be active and safe in advanced melanoma, with positive results in patients with brain metastases.

In a phase I trial, dabrafenib treatment (150 mg twice daily) elicited responses in 69% (95% CI 51.9 to 83.7) and confirmed responses in 50% (95% CI 32.9 to 67.1) of 36 patients with the most common form of BRAF-mutated metastatic melanoma, reported Gerald Falchook, MD, from MD Anderson Cancer Center in Houston, and colleagues.

The patients in this study carried the BRAF mutation Val600Glu, which is the substitution of valine with glutamic acid at amino acid position 600. This mutation locks in BRAF activity, making it at least 10 times more active than wild-type BRAF, the authors explained in The Lancet.

Earlier this week, results were released from another trial that combined dabrafenib with the MEK inhibitor trametinib, and demonstrated an acceptable safety profile and objective responses in patients with metastatic melanoma.

In addition to responses across all patients in the Falchook trial, dabrafenib showed efficacy in melanoma patients with untreated brain metastases, with nine of 10 patients demonstrating a reduction in the size of brain lesions and four experiencing complete resolution.

"This finding is impressive for two reasons," explained Geoffrey Gibney, MD, and Vernon Sondak, MD, in an accompanying Lancet commentary.

"No previous systemic treatment has shown this degree of clinical activity against melanoma brain metastases, and dabrafenib was not predicted to cross the blood-brain barrier in substantial quantities," wrote Gibney and Sondak, who are from the H. Lee Moffit Cancer Center and Research Institute in Tampa, Fla.

Patients with metastatic melanoma have a median overall survival of 9 to 11 months and those with brain metastases fare even worse, with a median survival of 4 to 5 months. Systemic treatments are not effective in these patients and they have been excluded from previous trials of other BRAF inhibitors, such as vemurafenib (Zelboraf).

The current dabrafenib dose-escalation study took place between 2009 and 2012 at eight centers in the U.S. and Australia. The authors enrolled 156 patients with incurable solid tumors including metastatic melanoma, melanoma with asymptomatic, untreated brain metastases, and nonmelanoma solid tumors.

Among melanoma patients without brain metastases, 75% carried Val600Glu BRAF mutations while 25% had the less common Val600Lys (lysine) mutation. Among patients with brain metastases, 90% had Val600Glu mutations and 10% had Val600Lys mutations.

"We deliberately enriched for patients with non-Val600Glu BRAF-mutant metastatic melanoma and are the first, as far as we are aware, to report progression-free survival in this group," the authors wrote.

They began with a dose of oral dabrafenib at 12 mg daily in a 21-day cycle. The dosage was escalated up to 300 mg twice daily. On the basis of pharmacokinetic and response data, they chose 150 mg twice daily as the phase II dose.

Among 27 patients with Val600Glu BRAF-mutant melanoma, 78% (95% CI 57.7 to 91.4) responded to treatment and 56% (95% CI 35.3 to 74.5) had confirmed responses. Among 18 patients with Val600Lys mutant melanoma, 22% (95% CI 6.4 to 47.6) responded to treatment.

In all cases of Val600 BRAF-mutant melanoma, the responses were durable, with 47% remaining on treatment for more than 6 months.

The median progression-free survival (PFS) for patients with brain metastases was 4.2 months (95% CI 3.3 to 5.3). While this result is impressive, Gibney and Sondak pointed out that the PFS was longer for those who only had active extracranial disease, at 5.5 months (95% CI 4.1 to 8.3).

In patients with BRAF-mutant nonmelanoma tumors, anti-tumor activity was seen in gastrointestinal stromal tumors, papillary thyroid cancers, and non-small cell lung cancer (NSCLC), as well as ovarian and colorectal cancers, the authors stated.

At all doses, the most common grade 2 or higher treatment-related adverse events were cutaneous squamous-cell carcinoma or keratoacanthoma, fatigue, and fever. Squamous-cell carcinoma was seen in 11% of patients given 50 mg or more of dabrafenib twice daily, with a median onset of 67 days. Treatment-related fever of any grade was seen in 20% of the participants with a median onset of 31 days.

The authors stressed that there were no cases of photosensitivity, which is commonly reported with vemurafenib. Again, the result is laudable, Gibney and Sondak noted, but dabrafenib did seem to cause more fever compared with vemurafenib.

Falchook and colleagues acknowledged that their study was limited by sample size, as is the case with most phase I trials. Larger studies that includes patients with non-Val600Glu mutant melanoma, as well as those with melanoma brain metastases, will give more accurate estimates of dabrafenib's anti-tumor activity, they said.

There currently are two trials in the works with dabrafenib in melanoma: a phase II study in patients with asymptomatic brain metastases and a phase III randomized, controlled trial of dabrafenib compared with dacarbazine (Dtic-Dome).

The study was funded by GlaxoSmithKline (GSK).
Many of the study authors reported financial relationships with GSK, Roche, Merck, Sharp and Dohme, Pfizer, Genentech, Bristol-Myers Squibb, Arqule, the Cancer Council Trials, and Sir Charles Gairdner Hospital.
Some of the study authors are past or present employees of GSK and hold stock options.
The editorialists declared no conflicts of interest.

Primary source: The Lancet
Source reference:
Falchook G, et al "Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial" Lancet 2012;379:1893-1901.
Additional source: The Lancet
Source reference:
Gibney GT, Sondak VK "Extending the reach of BRAF-targeted cancer therapy" Lancet 2012;379:1858–1859.