CME Author: Vicki Brower
Study Authors: Inês Pires da Silva, Kevin Y.X. Wang, et al.
Target Audience and Goal Statement:
Oncologists, dermatologists, internists
The goal was to determine whether there are distinct molecular profiles, or subtypes, in BRAF-mutated advanced melanoma, specifically, in the V600K and V600E genotypes, which might explain why some patients do better with targeted BRAF/MEK inhibition than other patients.
- What are the treatment outcomes in advanced melanoma patients with the V600K and V600E genotypes when treated with BRAF/MEK inhibitors?
- What are the molecular features of these two melanoma genotypes?
- What do clinical results with BRAF/MEK inhibitors and immunotherapies tell us about treating advanced melanoma with these drugs?
Study Synopsis and Perspective:
In a two-part study, researchers studied baseline tissue and clinical outcomes in 93 advanced melanoma patients treated with BRAF/MEK inhibitors to determine why BRAF V600K melanomas did not respond as well to BRAF/MEK-targeted treatment as BRAF V600E cancers.
Few comparisons of the two genotypes and their respective responses to different treatments have been conducted in the past.
The first part of the study demonstrates that the two genotypes have distinct molecular subtypes and mutational loads: BRAF V600K has lower expression of the ERK pathway, higher expression of the P13AKT genes, and a significantly greater mutational burden than the V600E genotype, which explains why it is less responsive to BRAF/MEK inhibition, according to Alexander M. Menzies, MBBS, PhD, of the University of Sydney, and colleagues in Clinical Cancer Research.
Conversely, the V600E genotype, with greater ERK pathway activation, responds well to BRAF/MEK inhibition, they noted.
While more melanoma patients with V600K melanoma in the trial received combination BRAF/MEK inhibition, patients 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%), than patients with the V600E subtype.
V600K-genotype patients 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.
Despite these numerical differences in response rates and PFS, overall survival (OS) was similar in both groups, the authors noted. This part of the study confirmed previous research that V600K melanomas have a lower response rate and shorter PFS with BRAF/MEK inhibition compared with V600E melanomas. OS was 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.
Patients with the V600E mutation tended to be slightly younger, with median age 58, and tumors arising on the skin without chronic sun-induced damage, versus those with the V600K mutation, which is characterized by chronic sun damage and a slightly older age.
In the second part of the study, the researchers evaluated an unrelated cohort of 103 BRAF-mutant patients treated with immunotherapy using the checkpoint inhibitors 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 the V600K subtype compared with V600E melanoma patients (53% vs 29%, P=0.059). Moreover, PFS lasted longer in V600K melanoma patients, for a median of 19 versus 2.7 months (P=0.049). However, prolonged OS for the V600K patients did not reach statistical significance at 20.4 versus 11.7 months (P=0.081).
The V600K and V600E genotypes represent new subtypes. The former subtype is characterized by having a high mutational burden, and a more favorable response to immunotherapy than to targeted therapy. Immunotherapy can therefore be used as first-line treatment in these patients, the authors wrote.
Source Reference: Clinical Cancer Research, Jan. 10,2019; DOI:10.1158/1078-0432.CCR-18-1680
Study Highlights: Explanation of Findings
Australian researchers highlighted that V600E and V600K BRAF-mutant melanomas are biologically distinct subtypes, with different clinical phenotypes, different molecular features, and differing responses to systemic therapies.
The investigators studied 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).
All 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 the V600K patients, those harboring V600E mutations had significantly higher expression of the 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.
About 40% of melanoma patients have mutations in the BRAF gene — 70-80% V600E, and 20-30% V600K. V600K melanomas 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, but these tumors also have a higher mutational load, and hence are more immunogenic and responsive to immunotherapy.
The two subtypes represent differential activity of pathway signaling, “potentially explaining the relative resistance of V600K melanoma to BRAF/MEK inhibition,” according to the researchers. Along with the higher mutational load in BRAF V600K melanomas, several groups of genes — those with tumor-suppressor functions and proto-oncogenes — are more frequently mutated in this genotype, they noted.
“All V600 BRAF-positive melanoma patients — V600E, V600K, or the rare subtypes V600R/D/M — are suitable for either targeted or immunotherapy,” Menzies told MedPage Today. “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.”
Menzies added that the study’s results will also likely be relevant 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.
Menzies noted that both treatments cost approximately $100,000 per year, but immunotherapy is considered to have better value because it is given for a limited period of time, usually no longer than 2 years, while BRAF/MEK is given in an ongoing manner until progression. Immunotherapy also has a much higher chance of durable control or cure, but it works in about 50% of patients. Targeted therapy works, albeit usually briefly, in almost everyone.
“It is complicated,” Menzies said.
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.
Melissa A. Wilson, MD, PhD, of the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, told MedPage Today 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, a PD-L1 inhibitor given in 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.
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco