‘Real World’ Safety Study of Vemurafenib in BRAF V600–Mutated Metastatic Melanoma Shows Similar Safety Profile as Pivotal Trials
As reported in The Lancet Oncology by Larkin et al, interim results of a safety study designed to reflect the spectrum of patients encountered in routine practice suggest that vemurafenib (Zelboraf) has a safety profile in patients with BRAF V600–mutated metastatic melanoma similar to that observed in the more select patient population included in registration trials. The study included patients with limited treatment options and sizable proportions with brain metastases, elevated lactate dehydrogenase (LDH), poor performance status, and age ≥ 75 years.
Study Details
In this open-label multicenter, single-arm study, patients with untreated or previously treated metastatic melanoma with BRAF V600 mutation received oral vemurafenib at 960 mg twice a day. The primary endpoint was safety. The current report is the third interim analysis of the study.
Between March 2011 and January 2013, 3,226 patients were enrolled in 44 countries, with 3,222 receiving at least one dose of vemurafenib. Patients had a median age of 55 years, with 8% aged ≥ 75 years. Fifty-seven percent of patients were male; median time since metastatic melanoma diagnosis was 5.7 months; metastatic stages were M1a in 12%, M1b in 14%, M1c in 71%, and unresectable stage IIIC in 2%; 23% had brain metastases; 50% had elevated LDH; 10% had Eastern Cooperative Oncology Group (ECOG) performance status of ≥ 2; and previous therapy included radiotherapy in 35%, surgery in 98%, and systemic therapy in 50%.
Adverse Events
At data cutoff, 27% of patients remained on study treatment and 73% had withdrawn, mainly due to disease progression. The most common adverse events of any grade were rash (49%), arthralgia (39%), fatigue (34%), photosensitivity reaction (31%), alopecia (26%), and nausea (19%). Overall, 46% of patients had grade 3 or 4 adverse events; the most common were cutaneous squamous cell carcinoma (12%), rash (5%), liver function abnormalities (5%), arthralgia (3%), and fatigue (3%). Grade 3 (59% vs 43%) and 4 (4% vs 3%) adverse events were more common in patients aged ≥ 75 years.
New Malignancies
Basal cell carcinomas and new primary melanomas were observed in 1% of patients each. There were 10 new primary malignancies, consisting of two cases of noncutaneous squamous cell carcinoma, three cases of cutaneous T-cell lymphomas, and one case each of progression of preexisting chronic lymphocytic leukemia, adenocarcinoma of the colon, Kaposi’s sarcoma, transitional cell carcinoma, and urinary tract tumor. The investigators noted, “Investigations to characterize the new primary malignancies and to understand the relation with vemurafenib are in progress.”
Corrected QT interval prolongation to > 500 msec occurred in 2% of patients. Median times to first incidence were 2.6 months for cutaneous squamous cell carcinoma, 3.7 months for new primary melanoma, and 1.9 months for corrected QT interval prolongation. Seven patients had pancreatitis, which was considered related to vemurafenib in three.
Adverse events led to death in 87 patients (3%) and were considered related to vemurafenib in 20 patients. The most common adverse events leading to death were general physical health deterioration in five patients, cerebral hemorrhage in five (four with brain metastases), cerebrovascular accident in four, and pulmonary embolism in four.
Response and Survival
Among 2,708 patients who could be assessed for efficacy, best overall response was complete response in 3% of patients, partial response in 31%, and stable disease in 55%. Median duration of response was 7.3 months. Response rates were higher in patients with no brain metastases (complete response and partial response in 4% and 33% vs 1% and 23%), normal vs elevated LDH level (6% and 37% vs 1% and 25%), and ECOG performance status of 0 to 1 vs ≥ 2 (4% and 32% vs 1% and 19%) at baseline. Complete response and partial response rates were 3% and 31% in patients aged < 75 years and 4% and 27% in older patients.
Median progression-free survival for the entire population was 5.6 months, with estimated progression-free survival of 47%, 19%, and 8% at 6, 12, and 18 months. Median overall survival was 12.0 months, with estimated overall survival of 75%, 52%, and 36% at 6, 12, and 18 months. Factors significantly associated with longer median progression-free and overall survival were normal LDH (7.6 and 21.6 months), ECOG performance status of 0 or 1 (6.0 and 14.2 months), absence of brain metastases (6.2 and 15.5 months), and lower M stage (9.0 months and median not estimable for stage M1a).
The investigators concluded, “Vemurafenib safety in this diverse population of patients with BRAFV600 mutated metastatic melanoma, who are more representative of routine clinical practice, was consistent with the safety profile shown in the pivotal trials of this drug.”
James Larkin, FRCP, of the Royal Marsden Hospital NHS Foundation Trust, London, and Christian U. Blank, MD, of Netherlands Cancer Institute, Amsterdam, are the corresponding authors for The Lancet Oncology article.
The study was funded by F. Hoffmann-La Roche. For full disclosures of the study authors, visit www.thelancet.com.
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