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Clinical Trial
. 2015 Aug 20;373(8):726-36.
doi: 10.1056/NEJMoa1502309.

Vemurafenib in Multiple Nonmelanoma Cancers With BRAF V600 Mutations

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Free PMC article
Clinical Trial

Vemurafenib in Multiple Nonmelanoma Cancers With BRAF V600 Mutations

David M Hyman et al. N Engl J Med. .
Free PMC article

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Abstract

Background: BRAF V600 mutations occur in various nonmelanoma cancers. We undertook a histology-independent phase 2 "basket" study of vemurafenib in BRAF V600 mutation-positive nonmelanoma cancers.

Methods: We enrolled patients in six prespecified cancer cohorts; patients with all other tumor types were enrolled in a seventh cohort. A total of 122 patients with BRAF V600 mutation-positive cancer were treated, including 27 patients with colorectal cancer who received vemurafenib and cetuximab. The primary end point was the response rate; secondary end points included progression-free and overall survival.

Results: In the cohort with non-small-cell lung cancer, the response rate was 42% (95% confidence interval [CI], 20 to 67) and median progression-free survival was 7.3 months (95% CI, 3.5 to 10.8). In the cohort with Erdheim-Chester disease or Langerhans'-cell histiocytosis, the response rate was 43% (95% CI, 18 to 71); the median treatment duration was 5.9 months (range, 0.6 to 18.6), and no patients had disease progression during therapy. There were anecdotal responses among patients with pleomorphic xanthoastrocytoma, anaplastic thyroid cancer, cholangiocarcinoma, salivary-duct cancer, ovarian cancer, and clear-cell sarcoma and among patients with colorectal cancer who received vemurafenib and cetuximab. Safety was similar to that in prior studies of vemurafenib for melanoma.

Conclusions: BRAF V600 appears to be a targetable oncogene in some, but not all, nonmelanoma cancers. Preliminary vemurafenib activity was observed in non-small-cell lung cancer and in Erdheim-Chester disease and Langerhans'-cell histiocytosis. The histologic context is an important determinant of response in BRAF V600-mutated cancers. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT01524978.).

Figures

Figure 1
Figure 1. Study Design and Cohorts
The all-others cohort included cervical cancer, brain tumors, head and neck cancer, esophageal and gastric cancers, pancreatic cancer, sarcoma, and carcinoma of unknown primary type. The breast cancer cohort was closed because of insufficient accrual; the single patient with breast cancer was included in the all-others cohort for the purposes of this report. The ovarian cancer and multiple myeloma cohorts did not have sufficient numbers of patients for a stage 1 analysis and therefore did not undergo formal analysis. Preliminary efficacy results for these cohorts are included with the results for the all-others cohort for the purposes of this report. ECD/LCH denotes Erdheim–Chester disease or Langerhans’-cell histiocytosis, and NSCLC non–small-cell lung cancer.
Figure 2
Figure 2. Maximum Percent Change from Baseline in the Sum of the Diameters of Target Lesions
The change from baseline in the target lesion diameter is shown for patients who had measurable disease at baseline according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and who underwent at least one post-treatment evaluation; dashed lines indicate −30% change, the minimum necessary to qualify for partial response according to RECIST. Data are shown for 18 patients in the NSCLC cohort (Panel A), 26 patients in the colorectal cancer cohort who were treated with vemurafenib plus cetuximab (Panel B), and patients in the all-others cohort (i.e., patients with tumor types that were not prespecified) plus 1 patient with low-grade serous ovarian cancer (Panel C). The tumor types in the all-others cohort included gliomas, head and neck cancer, pancreatic cancer, pleomorphic xantho-astrocytoma, esophageal and gastric cancers, sarcoma, and carcinoma of unknown primary type. Five patients (1 in the NSCLC cohort and 4 in the all-others cohort) died before evaluation. Asterisks indicate patients in the dose-escalation stage (dose levels 1 and 2).
Figure 3
Figure 3. Time to Events in Individual Patients and According to the Best Overall Response
The time to events is shown for patients who had measurable disease at baseline according to RECIST. Results are shown for 20 patients in the NSCLC cohort (Panel A), 27 patients in the colorectal cancer cohort who received vemurafenib plus cetuximab (Panel B), and patients in the all-others cohort plus 1 patient with low-grade serous ovarian cancer and 5 patients with multiple myeloma (Panel C). The bar length represents the duration of progression-free survival. Arrows indicate patients who were still receiving the study drug, and asterisks patients in the dose-escalation stage (dose levels 1 and 2). AE denotes anaplastic ependymoma, CR complete response, EGC esophageal and gastric cancer, HNC head and neck cancer, OC low-grade serous ovarian cancer, PR partial response, PXA pleomorphic xanthoastrocytoma, SD stable disease, SGC salivary-gland carcinoma, TCC thoracic clear-cell, V600G BRAF V600G mutation, and V600Unk unknown BRAF V600 mutation.

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