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.)

BACKGROUND-Cetuximab, a chimeric mouse-human IgG1 monoclonal antibody against the epidermal growth factor receptor, is approved for use in colorectal cancer and squamous-cell carcinoma of the head and neck. A high prevalence of hypersensitivity reactions to cetuximab has been reported in some areas of the United States.

Mutationally activated kinases define a clinically validated class of targets for cancer drug therapy1. However, the efficacy of kinase inhibitors in patients whose tumours harbour such alleles is invariably limited by innate or acquired drug resistance2,3. The identification of resistance mechanisms has revealed a recurrent theme—the engagement of survival signals redundant to those transduced by the targeted kinase4. Cancer cells typically express multiple receptor tyrosine kinases (RTKs) that mediate signals that converge on common critical downstream cell-survival effectors—most notably, phosphatidylinositol-3-OH kinase (PI(3)K) and mitogen-activated protein kinase (MAPK)5. Consequently, an increase in RTK-ligand levels, through autocrine tumour-cell production, paracrine contribution from tumour stroma6 or systemic production, could confer resistance to inhibitors of an oncogenic kinase with a similar signalling output. Here, using a panel of kinase-‘addicted’ human cancer cell lines, we found that most cells can be rescued from drug sensitivity by simply exposing them to one or more RTK ligands. Among the findings with clinical implications was the observation that hepatocyte growth factor (HGF) confers resistance to the BRAF inhibitor PLX4032 (vemurafenib) in BRAF-mutant melanoma cells. These observations highlight the extensive redundancy of RTK-transduced signalling in cancer cells and the potentially broad role of widely expressed RTK ligands in innate and acquired resistance to drugs targeting oncogenic kinases.

Panitumumab plus FOLFIRI significantly improved PFS and is well-tolerated as second-line treatment in patients with WT KRAS mCRC.

SummaryBackgroundThere are few effective treatments for advanced urothelial carcinoma after progression following platinum-based chemotherapy. We assessed the activity and safety of nivolumab in patients with locally advanced or metastatic urothelial carcinoma who progressed after prior platinum-based therapy.MethodsThis phase 1/2 multicentre open-label study enrolled patients aged ≥18 years with urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra unselected by programmed death ligand-1 (PD-L1). Tumour PD-L1 membrane expression was assessed. Patients received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression or study treatment discontinuation, whichever occurred later. The primary endpoint was objective response rate by investigator assessment. All patients who received at least one dose of any study medication were analysed. Here we report an interim analysis of this ongoing trial. CheckMate 032 is registered with ClinicalTrials.gov, NCT01928394.FindingsBetween June 2014 and April 2015, 86 patients with metastatic urothelial carcinoma were enrolled and 78 were treated with nivolumab monotherapy. At data cutoff (March 24, 2016), minimum follow-up was 9 months. A confirmed investigator-assessed objective response was achieved in 19 (24·4%) of 78 patients (95% CI 15·3–35·4). Grade 3/4 treatment-related adverse events occurred in 17 (21·8%) of 78 patients, the most common being laboratory abnormalities: asymptomatic elevated lipase in four (5·1%) and asymptomatic elevated amylase three (3·8%) patients. Serious adverse events were reported in 36 (46·2%) of 78 patients. Two (2·6%) of 78 patients discontinued due to treatment-related adverse events (pneumonitis and thrombocytopenia) and subsequently died.InterpretationNivolumab monotherapy was associated with significant and durable clinical responses and a manageable safety profile in previously treated patients with locally advanced or metastatic urothelial carcinoma. These data indicate a favourable benefit:risk profile for nivolumab and support further investigation of nivolumab monotherapy in advanced urothelial carcinoma.