Friday, January 13, 2012

Beyond the Glitter of the Abstract: Analysis of Vemurafenib (Zelboraf) Phase 3 Study


Title/ Citation

·   Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-16.

·   Hoffman-La Roche
Trial Design
·   Randomized, open-label, controlled, multicenter study with parallel assignments
·   Whether vemurafenib prolongs rate of overall survival (OS) or progression-free survival (PFS) as compared with dacarbazine in metastatic melanoma patients


·   Melanoma is a form of skin cancer that typically arises from epidermal melanocytes, but can arise in other sites in which melanocytes are found such as the retina[1]
·   Although curable if treated in early stage, malignant melanoma has a poor prognosis1
·   The median survival from diagnosis for stage IV melanoma is 8-18 months depending on substage1
·   68,130 new cases and 8700 deaths due to melanoma in the US in 2010[2]
·   Risk factors: positive family history; prior melanoma; multiple atypical moles or nevi; genetic mutations (rare); sunburns; light skin color2
·   Most patients (85%) present with localized disease, 10-13% with regional disease, and 2-5% with distant metastases2
·   5 year survival rates: > 90% for patients with localized disease; 20-70% for regional disease depending on lymph node tumor burden; < 10% for those with distant metastases2
·   Clinical Staging2:
o    Stage 0: melanoma in situ
o    Stage IA: < 1 mm in thickness, mitotic rate < 1/mm2, and no ulceration
o    Stage IB-II: < 1 mm thickness with ulceration or mitotic rate > 1/mm2
o    Stage III: positive nodes and/or in-transit disease
o    Stage IV: distant metastatic disease
·   TNM staging2,[3]:
o    M0: no evidence of distant metastases
o    M1a: metastases to skin, subcutaneous, or distant lymph nodes with normal lactate dehydrogenase (LDH)
o    M1b: metastases to lung
o    M1c: metastases to other visceral sites or distant metastases to any site with elevated LDH
·   Approximately 50% of cutaneous melanomas contain a mutation in the BRAF gene (of which 90% are the V600E mutation)
·   Currently FDA approved therapies for metastatic melanoma: dacarbazine and ipilimumab
·   Other commonly used agents for metastatic melanoma include temozolomide, high-dose interleukin-2
·   The response rate is typically less than 20% in 1st and 2nd line settings and there is little consensus regarding standard
·   NCCN Recommendation for Stage III2
o    Single or small # of in-transit metastases- surgical resection with negative margins if feasible
o    Limited # of in-transit unresectable metastases- local injections of BCG or interferon alfa or topical imiquimod
o    Multiple, regional in-transit metastases- regional chemotherapy and systemic therapy after failure.
·   NCCN Recommendation for Stage IV without brain metastases2
o    Resection if feasible
o    Clinical trial (recommended)
o    Ipilimumab (category 1)
o    Vemurafenib (category 1)
o    Dacarbazine, temozolomide, or high dose IL-2
·   Opinions vary regarding optimal duration and schedule of follow-up. Most patients who relapse do so in first 5 years2
·   Dacarbazine is an alkylating agent approved for the treatment of various cancers including malignant melanoma.[4]
o    It is administered intravenously.
o    Typical dosing for malignant melanoma: 850 mg/m2 every 3 weeks or 150-250 mg/m2 days 1-5 every 3-4 weeks infused over 30-60 min.
o    Onset of action- 18-24 days
o    Renal adjustment necessary based on study (not on FDA approved labeling)
o    Common ADRs: prominent nausea and vomiting (can be dose limiting); myelosuppression; and hepatotoxicity
·   Ipilimumab is a monoclonal antibody directed to cytotoxic T lymphocyte antigen-4 (CTLA-4) receptor. It binds to CTLA-4 and prevents interaction of CTLA-4 and ligands, CD80/86 resulting in augmentation of T cell activation and proliferation.2,[5],[6]
o    56% of Grade 3 and 4 adverse events when ipilimumab + dacarbazine was studied. Most events were immune related: diarrhea; rash; pruritus; hepatic enzyme elevations
o    3 year survival: 20.8% ipilimumab + dacarbazine
o    OS: ipilimumab alone 10.2 months
·   Vemurafenib is a small molecule inhibitor of mutated BRAF kinase, specifically BRAF V600E, which is constitutively active in absence of growth factors.[7]
o    It is FDA approved for unresectable or metastatic melanoma with V600E mutation.
o    Patients must be tested for V600E using the cobas ® 4800 BRAF V600E Mutation Test
o    It is available as 240 mg oral tablets, which simplifies dose adjustments
o    Phase 1 study: recommended Phase 2 dose of 960 mg twice daily, with increases limited due to Grade 2 or 3 rash, fatigue, and arthalgia.[8]
o    Most common ADRs include arthalgia, rash, alopecia, fatigue, photosensitivity reaction, nauseas, pruritus, and skin papilloma.
o    Package insert contains warnings for SJS/TEN, QT prolongation, liver lab abnormalities, and new primary malignant melanomas.
Relevant Trials
·   Joseph EW, Pratilas CA, Poulikakos PI, et al. The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in V600E BRAF-selective manner. Proc Natl Acad Sci USA 2010;107:14903-8.
·   Ribas A, Kim KB, Schucter LM, et al. BRIM-2: An open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAF V600E mutation-positive melanoma. J Clin Oncol 2011;29:Suppl:8509. 
Why this study?
·   Prognosis for malignant melanoma remains poor and current approved therapies provide marginal benefits. Resistance due to the BRAF V600E mutation hampers optimal therapy. Vemurafenib can prolong overall survival (OS) and progression free survival (PFS) in patients with the BRAF V600E mutation.


Inclusion criteria
·   Unresectable, previously untreated stage IIIC or IV melanoma positive for BRAF V600E mutation
·   Age > 18 years
·   Life expectancy > 3 months
·   ECOG performance status of 0 or 1
·   Adequate hematologic, hepatic, and renal function
Exclusion criteria
·   History of cancer within past 5 years (except basal- or squamous- cell carcinoma of the skin or carcinoma of the cervix) or metastases to central nervous system, unless metastases were definitely treated  3 months previously with no progression and no required glucocorticoid therapy
·   Concomitant treatment with other anticancer therapy
·   Vemurafenib 960 mg twice a day
o    Intolerable Grade 2 toxic effect or worse: administration interrupted until resolution to Grade 1 and restarted at 720 mg twice daily (480 mg twice daily for Grade 4 events).
o    Dose reduction to 480 mg twice daily if toxic effects recurred. Permanent discontinuation of toxic effect did not improve or recurred at 480 mg twice daily dose
·   Dacarbazine 1000 mg/m2 by IV infusion every 3 weeks
o    Administration interrupted for Grade 3 and 4 toxic effects and restarted on recovery within 1 week to Grade 1 (full dose) or Grade 2(75% dose) or 75% dose for Grade 4 neutropenia or febrile neutropenia
Outcome measures
·   Primary outcomes:
o    Rate of overall survival (OS): time from randomization to death  
o    Progression-free survival (PFS): time from randomization to documented progression or death
·   Secondary outcomes:
o    Confirmed response
o    Duration of response
o    Time to response
·   Tumor assessments performed at baseline, weeks 6 and 12, and every 9 weeks afterwards
·   Tumor response determined by Response Evaluation Criteria in Solid Tumors (RECIST)
Statistical analyses
·   Designed for 680 patients to be randomly assigned
·   Final analysis after 196 deaths (Log-rank test, P< 0.0247) and interim analysis after 50% of projected deaths (Pocock boundary, P< 0.028) 
·   Final analysis of PFS performed at time of interim analysis of OS
·   Power of 80% to detect hazard ratio of 0.65 for OS with alpha of 0.045 ( increase in median survival from 8 months for dacarbazine to 12.3 months for vemurafenib)
·   Power of 90% to detect hazard ratio of 0.55 for PFS with alpha of 0.005 (increase in median survival from 2.5 months for dacarbazine to 4.5 months for vemurafenib)
·   Survival- time from randomization to death from any cause
·   PFS- time from randomization to documented disease progression or death
·   Two-sided unstratified log-rank test to compare survival
·   Hazard ratios estimated using unstratified Cox regression
·   Event-time distributions estimated using Kaplan-Meier
·   P values are two-sided
·   Confidence intervals are at 95% level
·   Efficacy analyses performed in intention-to-treat population
·   2107 patients screened from January 2010 through December 2010 at 104 centers in 12 countries
·   675 patients randomly assigned in 1:1 ratio to receive vemurafenib or dacarbazine
·   Negative test for BRAF mutation was most common reason for screening failure
·   20 patients with non-V600E mutation enrolled (19 with V600K and 1 with V600D)
Baseline characteristics
Vemurafenib (N = 337)
Dacarbazine (N = 338)
Median age (range)- years
56 (21-86)
52 (17-86)
Male sex- no. (%)
200 (59)
181 (54)
White race- no. (%)
333 (99)
338 (100)
ECOG performance status- no. (%)

229 (68)
108 (32)

230 (68)
108 (32)
Extent of metastatic melanoma- no. (%)
Unresectable IIIC

221 (66)
62 (18)
34 (10)
20 (6)

220 (56)
65 (19)
40 (12)
13 (4)
Lactate dehydrogenase- no. (%)

142 (42)
195 (58)

142 (42)
196 (58)
·     Total of 118 deaths at time of interim analysis
·     Median follow-up for interim analysis: 3.8 months for vemurafenib group and 2.3 months for dacarbazine group
·     Data and safety monitoring board determined that OS and PFS reached statistical significance in favor of vemurafenib and recommended that patients be allowed to cross over from dacarbazine to vemurafenib
·     672 patients evaluated for OS; HR for death in vemurafenib group was 0.37 (95% CI: 0.26-0.55; P<0.001)
  • Inadequate number of patients at interim analysis with follow-up beyond 7 months to provide reliable Kaplan-Meier estimate of survival curve 
  • OS at 6 months: 84% (95% CI: 78-89) in vemurafenib group and 64% (95% CI: 56-73) in dacarbazine group. Further follow-up needed.

Subgroup Analysis
Hazard Ratio (95% CI)
Disease stage (n)
   IIIC (33)
   M1a (74)
   M1b (126)
   M1c (439)

0.53 (0.07-3.76)
0.31 (0.07-1.47)
0.91 (0.33-2.52)
0.32 (0.21-0.50)

·     PFS evaluated in 549 patients.
  • HR for tumor progression in vemurafenib group was 0.26 (95% CI: 0.20-0.33; P<0.001)
  • Estimated median PFS was 5.3 months in vemurafenib group and 1.6 months in dacarbazine group. Superior PFS in all subgroups except for patients > 75 years of age.
·     439 (65%) patients evaluated for tumor response:
  • 106 of 219 patients (48%; 95% CI: 42-55) assigned to vemurafenib had a confirmed objective response including 2 CR and 104 PR with median time to response of 1.45 months
  • 10 patients in vemurafenib group had BRAF V600K mutation: of these 4 (40%) patients had PR
  • 12 of 220 (5%; 95% CI: 3-9) patients in the dacarbazine group had an objective response (all PR) and the median time to response of 2.7 months
  • Difference in response was statistically significant (P<0.001 by chi-square test)
Adverse events
·   618 (92%) patients underwent at least one assessment and were evaluated for toxic effects
·   Vemurafenib had higher incidences of the following Grade 2 adverse events compared with dacarbazine: arthalgia (18% vs. <1%); rash (10% vs. 0%); cutaneous squamous-cell carcinoma (12% vs. 0%); keratocanthoma (6% vs. 0%); and alopecia (8% vs. 0%).
·   Only 2 patients in the vemurafenib group experienced neutropenia (Grade 2 and 4) compared with 28 patients assigned to dacarbazine 
·   Results show a relative  reduction of 63% in the risk of death and 74% in risk of tumor progression in favor of vemurafenib as compared to dacarbazine
·   48% of patients treated with vemurafenib experienced a confirmed response. Most patients had some tumor shrinkage.
·   Partial response seen in 4 of 10 patients with BRAF V600K mutation
·   Confirmed response in dacarbazine group was 5%, which is lower than published trials. Results are reliable since patients in current study had BRAF V600E mutation, which is associated with a more aggressive and chemotherapy resistant tumor.
·   48 patients (14%) assigned to dacarbazine did not receive treatment; mostly because of withdrawn consent. (29 were available for evaluation)
·   Patients assigned to vemurafenib reported few Grade 3 adverse events (rash, arthalgias, photosensitivity, and fatigue).
·   Dose modification of vemurafenib was required for 38% patients due to adverse events
·   Squamous-cell carcinoma or keratocanthoma was reported in 18% of patient receiving vemurafenib

·   Introduction and Rationale
o The authors are studying a novel treatment for malignant melanoma, a disease state with poor prognosis. The agent, vemurafenib, is targeted to a common mutation found the patient population.

·   Methods
o Randomized, multicenter, intention-to-treat, active control study
o Study included patients from countries/ regions with high rates of melanoma (US, Australia, Western Europe)
o Baseline characteristics between groups were similar
o Primary and secondary outcomes were appropriate
o Use of RECIST criteria for tumor response is standard of care and objective measurement
o Adverse events graded according to NCI’s Common Terminology Criteria for Adverse Events
o Interim analysis was performed after 50% of projected deaths occurred
o Dosing of dacarbazine was higher than approved dosing.  V600E mutation is believed to be more aggressive and therefore a higher dose might be more beneficial.
o Mutation test was performed at 1 of 5 central laboratories ensuring consistent results
o Dose reductions due to Grade 2 adverse events or worse for patients receiving vemurafenib.
o Power and alpha levels were acceptable
o Statistical tests were appropriate for parameters
o Patients allowed to cross over from dacarbazine to vemurafenib due to statistically significant improvement of OS and PFS
o Authors considered effect of LDH levels on efficacy since elevated levels are correlated with poorer outcomes

·   Results
o Unstratified results were statistically significant for OS, PFS, and tumor response
o PFS results were statically significant for all sub-groups except patients > 75 years of age
o Statistically significant improvement of OS in M1c disease sub-group
o LDH levels had no effect on OS and PFS outcomes.
o Vemurafenib was relatively well-tolerated (only 1 patient with Grade 4 adverse event)

·   Introduction and Rationale
o Title is biased
o The introduction is brief and gives a superficial overview of disease state and current therapies.

·   Methods
o Trial was designed for 680, but only 675 patients were enrolled
o Authors mention that the trial is intention-to-treat, but statistical analysis is a modified version.
o The trial was open-label
o Patients were evaluated for OS, PFS, and confirmed response if randomized at least 2, 9, and 14 weeks, respectively, before the cutoff date.
o No mention of time between diagnosis of malignant melanoma and study randomization.
o Majority of patients were Stage M1c.  Only 2-5% of patients present at this stage.  Applicability to most patients is weak.
o Higher dose of dacarbazine resulted in high percentage of patients suffering from Grade 2 or worse adverse effects associated with dacarbazine (13% had Grade 2 or 3 nausea and 10% experienced Grade 2-5 neutropenia).
o Lactate dehydrogenase ULN range were not standardized among centers
o The use of anti-emetics and G-CSF was not standard across study centers
o OS was evaluated in patients randomized at least 2 weeks before cutoff date. Based on 672 patients evaluated for OS and 549 evaluated for PFS, 123 patients evaluated for OS were randomized less than 9 weeks before analysis. This is a short time for clinically useful results.
o Onset of action for dacarbazine is 18-24 days and is administered every 3 weeks.   Based on these factors, OS estimation is likely to include patients who have not achieved full benefit of dacarbazine therapy. 
o Trial length was too short to assess longer term toxicities and efficacy and potential resistance to therapy

·   Results
o The data was collected by the sponsor and analyzed with senior authors
o Insufficient number of patients enrolled for reliable Kaplan-Meier estimates of survival curves
o Authors do not mention how they considered patients who crossed over from dacarbazine to vemurafenib into statistical analyses or conduct analysis of patients.
o The number of patients who crossed over is not mentioned
o Sub-group analysis for OS reveals that HR was not significant for melanoma subtypes with exception of M1c.  The greater number of patients with this sub-type contributed immensely to unstratified OS statistical significance. 
o Data used for OS estimation included patients who did not receive treatment (48 in dacarbazine group and 2 in vemurafenib group).  This is a wide discrepancy and may contribute to superior vemurafenib results.
o Authors do not address duration of response, which was a secondary outcome
o Reports of secondary cancers in patients who received vemurafenib.  The short trial length may underestimate the true carcinogenic potential.
o Authors do not mention follow-up of patients in study

·   Despite insufficient number of enrolled patients and short length, vemurafenib shows superior results compared dacarbazine in terms of OS, PFS, and tumor response.
·   The V600E is a common mutation in metastatic melanoma patients and vemurafenib offers a treatment for these patients.
·   It would be recommended to initiate vemurafenib in patients with the BRAF V600E mutation.  Due to a lack of knowledge regarding long term efficacy and safety, the use should be restricted to FDA approved indication of unresectable or metastatic melanoma with BRAF V600E mutation detected by FDA approved test.
·   Insufficient evidence exists regarding genetic testing of all melanoma patients.


[1] Kim KB, Davies MA, Rapini RP, et al. Chapter 39. Malignant Melanoma. In: Kantarjian HM, Wolff RA, Koller CA, eds. The MD Anderson Manual of Medical Oncology. 2nd ed. New York: McGraw-Hill; 2011. Accessed Jan 9, 2012.
[2] National Comprehensive Cancer Network. Melanoma. NCCN Clinical Practice Guidelin.e in Oncology. Version 3.2012
[3] American Joint Commission on Cancer. Melanoma of the skin Staging. Accessed Jan 8, 2012
[4] Dacarbazine [Drug]. In. Taketomo CK, Hodding JH, Kraus DM, editors. Pediatric Dosage Handbook. 16th ed. Hudson: Lexi-Comp; 2009. p. 388-9. 
[5] Yervoy [package insert] Bristol-Myers Squibb; 2011. Accessed Jan 10, 2012
[6] Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364: 2517-26.
[7] Zelboraf [package insert] Genentech; 2011. Accessed Jan 8, 2012
[8] Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010;363:809-19.