Dr. Weeks’ Comment: Melanoma is a stealth agent, poorly understood (made worse by sunlight or not? made worse by low fit D3 or not?) – here is some new research of combination agents to consider.
However, in what seems counterintuitive, the combination is less toxic, especially with regard to secondary skin cancers.
All of the study participants had a BRAF V600 mutation. About 50% of melanoma patients have this type of BRAF mutation, which does not occur in normal cells.
The combination of the BRAF inhibitor dabrafenib (GlaxoSmithKline) and the MEK inhibitor trametinib (GlaxoSmithKline) provided a median progression-free survival of 7.4 months in 77 patients, which is comparable to results from studies of single-agent vemurafenib (also a BRAF inhibitor), said lead study author Jeffrey Weber, MD, PhD, from the Moffitt Cancer Center in Tampa, Florida.
He spoke at a presscast in advance of the annual meeting of the American Society of Clinical Oncology, being held in Chicago, Illinois.
The main focus of Dr. Weber’s comments was the dermatologic toxicities of grade 3 or more associated with the targeted therapies.
Only 3% of the patients developed squamous cell carcinomas; in contrast, the incidence in patients treated with either single-agent dabrafenib or vemurafenib is 15% to 25%.
Only 5% of patients in the study developed premalignant actinic keratosis lesions, and 2% developed skin papilloma. These numbers also compare favorably with single-agent BRAF inhibition.
In 22% of the study sample, rash developed.
“There was significant diminution of the dermatologic toxicities,” said Dr. Weber.
At the same time, there was an 8% incidence of grade 3 or more pyrexia, which is “more than would be expected” with single-agent BRAF inhibition, he added.
He described the take-home message as the “dramatic and significant reduction in dermatologic toxicity with a slightly corresponding increase in pyrexia.”
The adverse-event profile was unexpected when it first emerged, Dr. Weber noted. Researchers have since come to understand that the MEK inhibitor suppresses the dermatologic adverse effects of BRAF inhibition, he said.
The secondary skin tumors associated with BRAF inhibition are relatively benign, compared with melanoma, and are no reason to discontinue therapy, according to Ashani T. Weeraratna, PhD, from the molecular and cellular oncogenesis program at The Wistar Institute in Philadelphia, Pennsylvania, who was not involved with the study.
Dr. Weeraratna told Medscape Medical News that the logic behind combining a BRAFinhibitor with a MEKinhibitor was to create “a one-two punch” to improve efficacy. “The tumor cell is clever enough to bypass the inhibition of a single player in the pathway,” she said.
“Just inhibiting player number 1 at the top of the pathway has not proven to have durable effects,” Dr. Weeraratna explained, referring to BRAF and the development of treatment resistance seen with vemurafenib.
The idea behind inhibiting a “second player” is to “overcome some of the resistance,” she added.
Until phase 3 data are in, the jury is out as to whether or not the combination targeted therapy is more effective than vemurafenib alone, Dr. Weeraratna suggested.
More Study Details
This analysis of a relatively large dose-escalation study of the combination therapy (more than 400 patients) involved only patients who were treatment-naÃ¯ve for BRAF inhibition (n = 77).
Dr. Weber’s presentation is an update of phase 1/2 data of BRAF-inhibitor-naÃ¯ve patients, which were reported at the ASCO meeting last year.
In the new analysis, the researchers report an overall response rate of 57% (n = 44). There were 6 complete responses (8%), 38 partial responses (49%), and 29 patients with stable disease (38%). Only 3 patients (4%) had progressive disease during the study period.
According to Dr. Weber, the subset of 24 patients who received dabrafenib 150 mg and trametinib 2 mg had the best outcomes. This is the dose that will be tested in the phase 3 trial. This cohort had a median progression-free survival of 10.8 months, which Dr. Weber called “impressive.”
The study was funded by GlaxoSmithKline. Dr. Weber reports financial relationships with GlaxoSmithKline. Some coauthors report financial relationships with GlaxoSmithKline, and some are employees of the company. Dr. Weeraratna has disclosed no relevant financial relationships.
2012 Annual Meeting of the American Society of Clinical Oncology®: Abstract 8510. To be presented June 4, 2012.