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.)

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Macrophage infiltration has been identified as an independent poor prognostic factor in several cancer types. The major survival factor for these macrophages is macrophage colony-stimulating factor 1 (CSF-1). We generated a monoclonal antibody (RG7155) that inhibits CSF-1 receptor (CSF-1R) activation. In vitro RG7155 treatment results in cell death of CSF-1-differentiated macrophages. In animal models, CSF-1R inhibition strongly reduces F4/80(+) tumor-associated macrophages accompanied by an increase of the CD8(+)/CD4(+) T cell ratio. Administration of RG7155 to patients led to striking reductions of CSF-1R(+)CD163(+) macrophages in tumor tissues, which translated into clinical objective responses in diffuse-type giant cell tumor (Dt-GCT) patients.

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Eisai.

PURPOSE KEYNOTE-158 ( ClinicalTrials.gov identifier: NCT02628067) is a phase II basket study investigating the antitumor activity and safety of pembrolizumab in multiple cancer types. We present interim results from patients with previously treated advanced cervical cancer. PATIENTS AND METHODS Patients received pembrolizumab 200 mg every 3 weeks for 2 years or until progression, intolerable toxicity, or physician or patient decision. Tumor imaging was performed every 9 weeks for the first 12 months and every 12 weeks thereafter. The primary end point was objective response rate (ORR), assessed per Response Evaluation Criteria in Solid Tumors (version 1.1) by independent central radiologic review. Safety was a secondary end point. RESULTS Ninety-eight patients were treated. Median age was 46.0 years (range, 24 to 75 years), and 65.3% of patients had Eastern Cooperative Oncology Group performance status of 1. Eighty-two patients (83.7%) had programmed death-ligand 1 (PD-L1)–positive tumors (combined positive score ≥ 1), 77 having previously received one or more lines of chemotherapy for recurrent or metastatic disease. Median follow-up was 10.2 months (range, 0.6 to 22.7 months). ORR was 12.2% (95% CI, 6.5% to 20.4%), with three complete and nine partial responses. All 12 responses were in patients with PD-L1–positive tumors, for an ORR of 14.6% (95% CI, 7.8% to 24.2%); 14.3% (95% CI, 7.4% to 24.1%) of these responses were in those who had received one or more lines of chemotherapy for recurrent or metastatic disease. Median duration of response was not reached (range, ≥ 3.7 to ≥ 18.6 months). Treatment-related adverse events occurred in 65.3% of patients, and the most common were hypothyroidism (10.2%), decreased appetite (9.2%), and fatigue (9.2%). Treatment-related grade 3 to 4 adverse events occurred in 12.2% of patients. CONCLUSION Pembrolizumab monotherapy demonstrated durable antitumor activity and manageable safety in patients with advanced cervical cancer. On the basis of these results, the US Food and Drug Administration granted accelerated approval of pembrolizumab for patients with advanced PD-L1–positive cervical cancer who experienced progression during or after chemotherapy.

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