BRIM-3

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Chapman BP, et al. "Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation". The New England Journal of Medicine. 2011. 364(26):2507-2516.
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Clinical Question

In patients with metastatic melanoma with a BRAF V600 mutation, does vemurafenib improve overall and progression-free survival compared to dacarbazine?

Bottom Line

Vemurafenib substantially improved overall and progression-free survival for metastatic melanoma patients with a BRAF V600 mutation.

Major Points

Metastatic melanoma carries a poor prognosis with conventional therapies including dacarbazine and interleukin-2. The finding that some half of patients with melanoma harbor a BRAF V600 mutation which drives their disease led to the development of BRAF inhibitors including vemurafenib and dabrafenib.

Published in 2011, the BRAF Inhibitors in Melanoma 3 (BRIM-3) study was the first phase 3 randomized trial to demonstrate the clinical effectiveness of BRAF inhibitors in patients with metastatic melanoma harboring a BRAF V600 mutation. BRIM-3 randomized 675 patients with metastatic or unresectable stage IIIC melanoma and a BRAF V600 mutation to either vemurafenib 960 mg twice daily or to dacarbazine 1000 mg/m2 every 3 weeks, continued until disease progression or intolerance to therapy. At a median follow-up of 12.5 months in the vemurafenib arm and 9.5 months on the dacarbazine arm,[1] vemurafenib improved overall survival (13.6 vs. 9.7 months) and progression-free survival (6.9 vs. 1.6 months). An analysis of outcomes stratified by BRAF mutation demonstrated that vemurafenib improved survival in patients with either BRAF V600E or V600K mutations. Objective responses were observed in 57% of vemurafenib-treated patients, and 9% of patients receiving dacarbazine; complete responses by RECIST were seen in 6% in the vemurafenib arm and 1% in the dacarbazine arm. Important to the analysis of overall survival, the study allowed crossover and approximately 25% of patients in the dacarbazine arm crossed over to vemurafenib. In addition, approximately 20% of patients in each arm received the anti-CTLA4 antibody ipilimumab.

Vemurafenib was generally well-tolerated, with arthralgia (21%), cutaneous squamous cell cancer or keratoacanthoma (20%), rash (18%), and photosensitivity (12%) the most common side effects. The skin cancers and keratoacanthomas deserve special attention, since these generally require local excision. Post-marketing experience suggests that BRAF inhibition is associated with electrolyte abnormalities and acute renal injury, highlighting a need for electrolyte and renal function monitoring during therapy.[2]

Two additional agents have been approved for the treatment of BRAF-mutated melanoma. In a phase 3 study published in 2012, the BRAF kinase inhibitor dabrafenib demonstrated improved OS and PFS when compared to dacarbazine, with effect sizes similar to those seen with vemurafenib in BRIM-3.[3] In METRIC (2012), the MEK inhibitor trametinib improved PFS and OS when compared to dacarbazine in BRAF-mutated melanoma.[4] Combination therapy with a BRAF inhibitor plus a MEK inhibitor was studied in COMBI-v (2015), in which dabrafenib plus trametinib improved median OS and PFS when compared to vemurafenib alone, without significantly increasing toxicity.[5] Interestingly, combination therapy was associated with fewer secondary skin cancers compared to vemurafenib monotherapy.

Guidelines

NCCN Guidelines Melanoma (2016, adapted)[6]

  • For patients with metastatic or unresectable disease and BRAF mutation, combination therapy are preferred first-line options, with dabrafenib/trametinib or vemurafenib/cobimetanib
  • For patients with metastatic or unresectable disease and BRAF mutation, monotherapy with dabrafenib or vemurafenib are also first-line options
  • The above combination therapies and monotherapies are also recommended for subsequent therapy if evidence of disease progression or maximium clinical benefit of initial BRAF therapy

Design

  • Multicenter randomized, controlled trial
  • N=675
    • Vemurafenib (n=337), 960 mg orally twice daily
    • Dacarbazine (n=338), 1000 mg/m2 IV every three weeks
  • Setting: 104 centers in 12 countries
  • Enrollment: January-December 2010
  • Median follow-up: Interim analysis at 2-4 months, and subsequent analysis at 9-12 months
  • Analysis: Intention-to-treat
  • Coprimary outcomes: Overall survival (OS) and progression-free survival (PFS)

Population

Inclusion Criteria

  • Age ≥18 years
  • Untreated metastatic or unresectable stage IIIC melanoma
  • Presence of BRAF V600E mutation (by Cobas 4800 BRAF V600 Mutation Test, which is known to detect the V600K mutation as well)
  • Life expectancy ≥3 months
  • ECOG performance status of 0-1

Exclusion Criteria

  • Untreated or active CNS metastases or carcinomatous meningitis
  • Severe cardiovascular disease within prior 6 months
  • Previous malignancy within 5 years prior to study, except for basal or squamous cell carcinoma of the skin, melanoma in-situ, or carcinoma in-situ of the cervix

Baseline Characteristics

From the vemurafenib group.

  • Demographics: Age 56 years, 41% female, 99% White race
  • Geographic region: 26% North America, 61% Europe, 12% Australia or New Zealand
  • ECOG performance status: 0 (68%), 1 (32%)
  • Disease extent: M1c (66%), M1b (18%), M1a (10%), unresectable IIIC (6%)
  • LDH elevated: 58%

Interventions

Patients were randomized to:

  • Vemurafenib, 960 mg twice daily orally, or
  • Dacarbazine, 1000 mg/m2 of body surface area delivered via IV infusion every 3 weeks

Patients and investigators were both aware of treatment allocation. Patients were allowed to cross-over from dacarbazine to vemurafenib, and several received additional therapy (e.g., about 20% received ipilimumab).

Patients were examined every 3 weeks, with tumor assessments (via RECIST v1.1) performed at weeks 0, 6, 12, and every 9 weeks thereafter.

Outcomes

Comparisons are vemurafenib vs. dacarbazine.

Primary Outcomes

From the interim analysis:

Overall survival at 6 months
84% vs. 64% (HR 0.37; 95% CI 0.26-0.55; P<0.001)
Median PFS
5.3 vs. 1.6 months (HR 0.26; 95% CI 0.20-0.33; P<0.001)

With longer-term follow-up:[1]

Median OS
13.6 vs. 9.7 months (HR 0.70; 95% CI 0.57-0.87; P=0.0008)
Median PFS
6.9 vs. 1.6 months (HR 0.38; 95% CI 0.32-0.46; P<0.0001)

Secondary Outcomes

Response rate
48% vs. 5% (P<0.001)
Median time to response
1.45 months vs. 2.7 months

Subgroup analysis

Subgroup analysis demonstrated superior outcomes with vemurafenib therapy across groups including age, female sex, ECOG performance status, extent of disease, and LDH status.

Adverse Events

Grade 2 or greater.

Arthralgia
21% vs. <1%
Rash
18% vs. 0%
Cutaneous squamous cell carcinoma
12% vs. <1%
Keratoacanthoma
8% vs. 0%
Neutropenia
<1% vs. 9% (3% of which were grade 4-5 neutropenia)

Criticisms

  • Unblinded study; may exhibit some degree of observer bias.
  • The BRIM-3 trial had a short follow-up period due to the dramatic improvement in OS seen at the 6-month interim analysis. Patients were allowed to crossover from dacarbazine to vemurafenib at this time, which 25% elected to do, but their data was appropriately censored at this point.
  • While not a criticism per se, BRIM-3's inclusion criteria required a BRAF V600E mutation. However, the test used to determine BRAF mutation status is known to detect V600K mutations as well. Indeed, a small minority of patients in BRIM-3 were found to have V600K mutations, which were confirmed on Sanger sequencing.

Funding

Funded by Hoffmann–La Roche, producers of Zelboraf (vemurafenib).

Further Reading

  1. 1.0 1.1 McArthur GA, Chapman PB, Robert C, et al. "Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study." Lancet Oncol. 2014 Mar;15(3): 323-32.
  2. Jhaveri KD, et al. Nephrotoxicity of the BRAF Inhibitors Vemurafenib and Dabrafenib. JAMA Oncol. 2015 Jun 25.
  3. Hauschild A, Grob JJ, Demidov LV, et al. "Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial." Lancet. 2012 Jul 28;380(9839):358-365.
  4. Flaherty KT, Robert C, Hersey P, et al. "Improved survival with MEK inhibition in BRAF-mutated melanoma." N Engl J Med. 2012 Jul 12;367(2):107-1.
  5. Robert C, Karaszewska B, Schachter J, et al. "Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib." N Engl J Med. 2015 Jan 1;372(1):30-39.
  6. NCCN Guidelines for Melanoma version 3.2015.