Vemurafenib (Zelboraf®) in Nonmelanoma Cancers with BRAF V600 Mutations

Ahroom Youk, Mercer University College of Pharmacy

In 2011, the United States Food and Drug Administration approved Vemurafenib (Zelboraf®), a kinase inhibitor indicated in BRAF V600E-positive patients with metastatic or unresectable melanoma.1  BRAF mutations most commonly occur at codon 600.  The BRAF V600E mutation consists of glutamic acid in place of valine, which increases serine kinase activity, thus causing the proliferation of cancer cells.  This mutation is seen in approximately half of all melanomas.2

Currently, researchers are investigating the use of vemurafenib in BRAF V600E-positive nonmelanoma cancers.  The study below depicts preliminary results of vemurafenib therapy in patients with Non-Small-Cell Lung Cancer (NSCLC), cholangiocarcinoma, Erdheim-Chester disease or Langerhans’ cell histiocytosis (ECD/LCH), anaplastic thyroid cancer, and colorectal cancer.  The goal of this study was to identify any potential signals of activity in each of these cancer types.3

Title Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations3
Design Multinational, histology-independent, early phase 2 cohort study; N = 122
Objective To determine the efficacy of vemurafenib in nonmelanoma cancer patients with BRAF V600 mutations
Study Groups Cohorts: NSCLC, cholangiocarcinoma, ECD/LCH, anaplastic thyroid cancer, multiple myeloma, colorectal cancer, breast cancer, ovarian cancer, all others
Methods Patients identified with the BRAF V600 mutation received vemurafenib 960 mg orally twice daily, and one cohort of colorectal cancer patients additionally received cetuximab.  Tumor assessments were completed at baseline and every eight weeks until study withdrawal, disease progression, or death.  A response rate of 15% was considered to be low, 35% was also considered low but indicative of efficacy, and 45% was considered to be high.
Duration Enrollment occurred from April 11, 2012 through June 10, 2014.
Primary Outcome Measure Response rate on the eighth week of treatment
Baseline Characteristics Characteristic NSCLC
(n = 20)
Colorectal Cancer Multiple Myeloma
(n = 5)
Cholangio-
carcinoma
(n = 8)
ECD/LCH
(n = 18)
Anaplastic Thyroid Cancer
(n = 7)
Other*
(n = 27)
Received Vemurafenib
(n = 10)
Received Vemurafenib + Cetuximab
(n = 27)
Sex, number (%)
     Male 14 (70) 5 (50) 10 (37) 4 (80) 3 (38) 7 (39) 4 (57) 9 (33)
     Female 6 (30) 5 (50) 17 (63) 1 (20) 5 (62) 11 (61) 3 (43) 18 (67)
Age, median (range) 61 (48-83) 59 (49-64) 63 (45-81) 64 (58-68) 53 (37-66) 64 (35-83) 65 (55-81) 55 (18-77)
ECOG performance status
     0 or 1 16 (80) 10 (100) 25 (93) 4 (80) 7 (88) 15 (83) 4 (57) 22 (81)
     ≥ 2 4 (20) 0 2 (7) 1 (2) 1 (12) 3 (17) 3 (43) 5 (19)
Prior systemic therapies, number (%)
     Any 19 (95) 10 (100) 27 (100) 5 (100) 8 (100) 11 (61) 7 (100) 21 (78)
     None 1 (5) 0 0 0 0 7 (39) 0 6 (22)
Prior radiation, number (%) 4 (20) 4 (40) 6 (22) 2 (40) 3 (38) 0 6 (86) 18 (67)
BRAF V600E mutation, number (%) 18 (90) 8 (80) 24 (89) 5 (100) 7 (88) 17 (94) 7 (100) 25 (93)
ECOG = Eastern Cooperative Oncology Group

*Brain tumors, head and neck cancer, esophageal and gastric cancers, breast cancer, pancreatic cancer, sarcoma, cervical cancer, ovarian cancer, unknown

Results Variable NSCLC
(n = 19)
Colorectal Cancer Cholangio-
carcinoma
(n = 8)
ECD/LCH
(n = 14)
Anaplastic Thyroid Cancer
(n = 7)
Vemurafenib
(n = 10)
Vemurafenib + Cetuximab
(n = 26)
Complete response, number (%) 0 0 0 0 1 (7) 1 (14)
Partial response, number (%) 8 (42) 0 1 (4) 1 (12) 5 (36) 1 (14)
Overall response, number (%) [95% CI] 8 (42) [20–67] 0 1 (4)

[< 1–20]

1 (12)

[< 1–53]

6 (43)

[18–71]

2 (29)

[4–71]

CI = Confidence Interval
Adverse Events Common Adverse Events: rash (68%), fatigue (56%), arthralgia (40%)
Serious Adverse Events: no grade 4 or 5 adverse events were reported
Percentage that Discontinued due to Adverse Events: ECD/LCH group (28.6%)
Study Author Conclusions The BRAF V600 mutation is a targetable oncogene in some cancer types such as NSCLC and ECD/LCH.

Although this study shows promising activity in NSCLC and ECD/LCH, it is difficult to determine the true efficacy and safety of vemurafenib in nonmelanoma cancers.  This study derives its findings from small subsets of patients, so the researchers advise to interpret these results with caution.3  Serious consequences of vemurafenib therapy in melanoma patients have been observed.  Vemurafenib increases the risk for cutaneous squamous cell carcinoma.2  Additionally, cancer cells may upregulate alternative pathways to reactivate raf signaling, causing tumor resistance to vemurafenib.4

References

  1. Zelboraf [package insert]. South San Francisco, CA: Genentech Inc.; 2011
  2. Shord SS, Medina PJ. Chapter 104. Cancer Treatment and Chemotherapy. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014. http://accesspharmacy.mhmedical.com/content.aspx?bookid=689&Sectionid=48811497. Accessed August 28, 2015.
  3. Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. N Engl J Med. 2015;373(8):726-36.
  4. Sausville EA, Longo DL. Principles of Cancer Treatment. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison’s Principles of Internal Medicine, 19e. New York, NY: McGraw-Hill; 2015. http://accesspharmacy.mhmedical.com/content.aspx?bookid=1130&Sectionid=71748332. Accessed August 30, 2015.
Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s