ASCO 2012-DABRAFENIB EFFECTIVE FOR BRAF+ MELANOMA PATIENTS WITH BRAIN METASTASES 

May 17, 2012 — The efficacy of the investigational cancer agent dabrafenib (GlaxoSmithKline) evidently extends beyond its targets of solid tumors and melanomas that harbor BRAF mutations, according to a phase 1 trial.

The agent also reduced the size of brain metastases in 9 of 10 patients with advanced melanoma and asymptomatic brain lesions, and led to complete resolution in 4 of these patients, according to lead coauthors Gerald Falchook, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, and Georgina Long, MD, from Melanoma Institute Australia in Sydney, and their colleagues.

Results from their dose-escalation study of dabrafenib were published online May 17 in the Lancet.

The results in these 10 patients are relatively dramatic, the study authors report.

"Patients with melanoma and brain metastases typically survive for less than 5 months; yet in this study, all 10 patients were alive at [5 months] and 2 patients had durable antitumor activity with survival beyond 12 months. One patient remains on treatment at 19 months," they write.

"No previous systemic treatment has shown this degree of clinical activity against melanoma brain metastases," write Geoffrey Gibney, MD, and Vernon Sondak, MD, from the H. Lee Moffitt Cancer Center in Tampa, Florida, in their comment.

The impact on brain metastases is unprecedented, according to experts writing in an accompanying comment

In terms of safety and melanoma response, dabrafenib appears to be comparable to vemurafenib, which is the first approved inhibitor of BRAF-mutant melanoma, they point out.

"Importantly, the proportion of patients with Val600Glu BRAF-mutant melanoma treated at the recommended phase 2 dose with confirmed objective responses (15 [56%] of 27 patients) was similar to that reported in a phase 3 trial of vemurafenib (106 [48%] of 219 patients)," they write.

The authors explain that the Val600Glu mutation is the most common type of BRAF mutation. The study designers purposely included patients with non-Val600Glu mutations, which do not respond as dramatically and have not been studied in trials of vemurafenib. Overall, these various BRAF mutations occur in about half of melanomas.

Brain lesions are fairly common in advanced melanoma, the authors note. "In patients with stage IV disease, brain metastases are present in 20% at diagnosis and in 40% to 45% of patients overall, and contribute to death in 20% to 54%," they write.

Brain metastases also affect survival; melanoma patients with them have a median survival of 5 months, but patients without them live an average of 9 to 11 months, the authors report.

Standard approaches for managing brain metastases are resection, stereotactic radiosurgery, and whole-brain radiotherapy, write Drs. Gibney and Sondak.

Some systemic therapies for melanoma, including ipilimumab, have demonstrated a positive but limited impact on brain metastases, as reported by Medscape Medical News.

"Clearly, systemic agents of increased effectiveness are needed for this patient population," Drs. Gibney and Sondak argue.

The effect of dabrafenib on brain metastases is "impressive," in part because it "was not predicted to cross the blood–brain barrier in substantial quantities," they add.

"Our study supports the inclusion of patients with brain metastases in future drug trials in melanoma," say the study authors.

Further Study Details

The initial stage of this phase 1 study was designed to establish dosage. A total of 156 patients with metastatic melanoma and 28 with incurable solid tumors received escalating doses of dabrafenib, which resulted in a recommended phase 2 dose of 150 mg twice daily.

In the second stage, efficacy at the recommended phase 2 dose was studied in 3 groups of patients with BRAF-mutant tumors: those with advanced melanoma, those with untreated melanoma brain metastases, and those with other BRAF-mutant solid tumors.

In the 36 patients with Val600 BRAF-mutant melanoma, half had tumor shrinkage. In 27 patients with Val600GluBRAF-mutant melanoma, the overall confirmed response rate was 56%, as noted above.

Confirmed responses to treatment were also noted in 4 of 18 patients (22%) with Val600Lys BRAF-mutant melanoma.

No responses were reported in patients with tumors with Lys601Glu or Val600_Lys601delinsGlu BRAF mutations.

The 3 patients with wild-type BRAF tumors did not respond to BRAF inhibition with dabrafenib; therefore, they are not candidates for future treatment, as was the case in clinical trials of vemurafenib.

In the 28 patients with nonsmall-cell lung, colorectal, papillary thyroid, and ovarian carcinomas, and gastrointestinal stromal tumors, the results indicate that dabrafenib has antitumor activity (partial responses and disease stabilization) in Val600Glu BRAF-mutant versions of these tumors, the authors note.

This trial helps establish exactly which patients with BRAF mutations are the best candidates for future study.

"The high response rate in melanoma brain metastases and the near-equivalent progression-free survival in patients with Val600Lys or Val600Glu BRAF-mutant melanoma justify the inclusion of such patients in further trials of potent BRAF inhibitors," write the authors.

The most common grade 2 or higher adverse effects were cutaneous squamous cell carcinoma (a nonlethal form of skin cancer; 11%), fatigue (8%), and pyrexia (6%).

"Although the adverse-event profiles of dabrafenib and vemurafenib are much the same, subtle differences seem to exist. Little or no skin photosensitivity was reported with dabrafenib, but it might cause more pyrexia than does vemurafenib," write Drs. Gibney and Sondak.

Funding was received from GlaxoSmithKline. Dr. Falchook and Dr. Long report financial relationships with GlaxoSmithKline. Some coauthors report financial relationships with GlaxoSmithKline, and some are employees of the company. Dr. Gibney and Dr. Sondak have disclosed no relevant financial relationships.

Lancet. Published online May 17, 2012. Abstract, Comment