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Metastatic melanoma patients with BRAF V600K mutations may benefit more from first-line immunotherapy than targeted BRAF/MEK inhibition, according to researchers in Australia.

While more melanoma patients with V600K melanoma received combination BRAF/MEK inhibition, those with this mutation had a numerically lower median degree of response to therapy (-31% vs -52%, P=0.154), as well as a lower rate of complete response (0% vs 10%), reported Alexander M. Menzies, MBBS, PhD, of the University of Sydney, and colleagues.

V600K patients also had a median progression-free survival (PFS) of 5.7 months, and no patient remained progression free beyond 9 months, whereas V600E patients had a median PFS of 7.1 months, with approximately 20% remaining progression free at 5 years, they wrote in .

Despite these numerical differences in response rates and PFS, overall survival (OS) was similar in both groups, the authors noted.

The study confirmed previous research suggesting that while V600K melanomas have a lower response rate and shorter PFS with BRAF/MEK inhibition compared with V600E melanomas, OS is similar.

"If our results are validated, the best treatment for patients with BRAF-mutant melanoma may well differ based on V600E and V600K genotypes," the authors wrote.

V600E and V600K BRAF-mutant melanomas are considered biologically distinct subtypes, with different clinical phenotypes, different molecular features, and differing responses to systemic therapies.

"All V600 BRAF-positive melanoma patients -- V600E, V600K, or the rare subtypes V600R/D/M -- are suitable for either targeted or immunotherapy," Menzies told 乌鸦传媒. "Most clinicians prefer to start with immunotherapy where possible, as this provides the greatest chance of long-term disease control or cure. But patients with bad symptoms, or those in need of a rapid near-guaranteed response, may start with targeted therapy."

He added that the study's results will also likely be of relevance to the adjuvant setting, where a similar treatment decision process is made about targeted or immunotherapy. "Trials have not presented data on V600E versus V600K outcomes as yet, and I expect they never will," Menzies stated.

He noted that both treatments cost approximately $100,000 per year, but immunotherapy is considered to be of better value as it is given for no longer than 2 years, while BRAF/MEK is ongoing until progression. Immunotherapy has a much higher chance of durable control or cure, but it doesn't work in about 50% patients. Targeted therapy works, albeit usually briefly, in almost everyone.

"It is complicated," he said.

Some 40% of melanoma patients bear mutations in the gene BRAF -- 70-80% V600E and 20-30% V600K. V600K melanomas, most commonly found in older patients with chronic sun damage, have less activation of the ERK pathway via BRAF mutation than V600E melanomas. That feature might explain their relatively greater resistance to BRAF inhibition, with or without MEK inhibition, the authors explained, but these tumors also have a higher mutational load and respond better to immunotherapy.

Study Details

The investigators examined 78 consecutive clinical trial patients (58% male) treated at two Australian centers with BRAF inhibition with or without MEK inhibition. Pretreatment tumor samples were examined by gene expression profiling and DNA sequencing. The researchers also studied 15 consecutive V600E/K patients (67% male) treated with anti-PD-1 immunotherapy. The median ages in the two groups were 56.5 (V600E) and 58 (V600K).

Patients were typical of those enrolled in clinical trials of melanoma. In both groups, 40% had an Eastern Cooperative Oncology Group performance status of >1 and 80% had American Joint Committee on Cancer M1c disease. Lactate dehydrogenase was elevated in 27% of V600E patients and in their V600K counterparts. Only 20% of the V600E group received combination BRAF/MEK inhibitors, whereas 33% of V600K patients did.

Compared with V600K patients, those harboring V600E mutations had significantly higher expression of ERK pathway genes and significantly lower expression of PI3K-AKT pathway genes, suggesting that their tumors relied more on this pathway for progression and survival.

The researchers also evaluated an unrelated cohort of 103 BRAF-mutant patients treated with anti-PD-1 immunotherapy using pembrolizumab (Keytruda) or nivolumab (Opdivo). Of these, 84 had V600E BRAF-mutant melanoma, while 19 had the V600K type. Response to immunotherapy based on BRAF genotype was correlated with clinical outcomes.

With a median 31.7-months of follow-up, the authors found a trend toward a higher response rate to immunotherapy in patients with V600K compared with V600E melanomas at 53% versus 29% (P=0.059). Moreover, PFS lasted longer in V600K melanoma patients at a median 19 versus 2.7 months (P=0.049). Prolonged OS for V600K did not reach statistical significance at 20.4 versus 11.7 months (P=0.081).

Study limitations included the small number of patients with V600K BRAF-mutant melanoma, relatively short follow-up, and the absence of validation in more patients treated with immunotherapy. The authors called for validation in larger cohorts, such as a post-hoc analysis of the CheckMate-067 and Keynote-006 trials.

'Choosing an Alternative Treatment'

Melissa A. Wilson, MD, PhD, of the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, told 乌鸦传媒 that "The study's findings are very interesting. They actually support what we see in the clinic -- that patients with the BRAF V600K mutation do not respond as robustly or as long to targeted therapy as those with the V600E mutation. And the authors have found an underlying mechanism or etiology for this in the greater mutational load."

She added, however, that targeted therapy is still a potential option for V600K patients as they may derive some benefit from it.

"These findings give clinicians information for potentially choosing an alternative treatment, which would be immunotherapy," said Wilson, who was not involved in the study. "It will help them recommend treatment for patients in the adjuvant setting as well as the metastatic setting."

Results from a 2018 study showed that adjuvant pembrolizumab for resected high-risk melanoma led to an almost 20% absolute improvement in recurrence-free survival, irrespective of a tumor's BRAF or PD-L1 expression status, and supported a role for earlier use of immunotherapy. In two studies reported in 2017, adjuvant nivolumab significantly improved PFS in resected high-risk melanoma compared with ipilimumab (Yervoy), while targeted adjuvant therapy with a dabrafenib (Tafinlar) and trametinib (Mekinist) combination significantly reduced recurrence versus with placebo.

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