{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T21:57:48Z","timestamp":1778795868988,"version":"3.51.4"},"reference-count":31,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"2","content-domain":{"domain":["ascopubs.org"],"crossmark-restriction":true},"short-container-title":["JCO Precision Oncology"],"published-print":{"date-parts":[[2018,11]]},"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p> Parallel activation of the phosphatidylinositol 3-kinase\u2013mammalian target of rapamycin pathway represents a mechanism of primary and acquired resistance to BRAF-targeted therapy, but the two pathways have yet to be cotargeted in humans. We performed a phase I study to evaluate the safety and activity of the BRAF inhibitor vemurafenib in combination with the mammalian target of rapamycin inhibitor everolimus in BRAF-mutated advanced solid tumors. <\/jats:p><\/jats:sec><jats:sec><jats:title>Patients and Methods<\/jats:title><jats:p> We performed a 3+3 dose-escalation study with escalating doses of both oral (PO) vemurafenib administered twice a day and PO everolimus administered daily. <\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p> Twenty patients with advanced cancers were enrolled. The median adult age was 64 years (range, 17 to 85 years); two pediatric patients were 10 and 13 years old. Patients were heavily pretreated with prior BRAF or MEK inhibitors (n = 11), phase I clinical trial therapy (n = 10), surgery (n = 18), radiation therapy (n = 11), and chemotherapy (n=13). One of the two pediatric patients initially experienced grade 3 rash, but after dermatologic intervention, the patient remains on trial with partial response and no dose reduction at time of analysis. Four dose-limiting toxicities (rash, n = 1; fatigue, n = 3) were observed at dose level 2. Therefore, dose level 1 (vemurafenib 720 mg PO twice a day and everolimus 5 mg PO daily) was the maximum-tolerated dose. Overall, four patients (22%) had a partial response and nine patients (50%) had stable disease as best response. One pediatric patient with pleomorphic xanthroastrocytoma remains on protocol with continued clinical response after 38 cycles. <\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p> The combination of vemurafenib 720 mg PO twice a day and everolimus 5 mg PO daily is safe and well tolerated and has activity across histologies, with partial responses noted in advanced non\u2013small-cell lung cancer, melanoma, optic nerve glioma, and xanthroastrocytoma, including patients who previously experienced progression on BRAF and\/or MEK inhibitor therapy. Further investigation in a larger cohort of molecularly matched patients is warranted. <\/jats:p><\/jats:sec>","DOI":"10.1200\/po.18.00189","type":"journal-article","created":{"date-parts":[[2018,9,13]],"date-time":"2018-09-13T19:57:24Z","timestamp":1536868644000},"page":"1-12","update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":17,"title":["Phase I Study of the BRAF Inhibitor Vemurafenib in Combination With the Mammalian Target of Rapamycin Inhibitor Everolimus in Patients With <i>BRAF<\/i>-Mutated Malignancies"],"prefix":"10.1200","author":[{"given":"Vivek","family":"Subbiah","sequence":"first","affiliation":[{"name":"Vivek Subbiah, Shiraj Sen, Kenneth R. Hess, Filip Janku, David S. Hong, Soumen Khatua, Daniel D. Karp, Javier Munoz, Roman Groisberg, Apostolia M. Tsimberidou, Steven I. Sherman, Patrick Hwu, and Funda Meric-Bernstam, The University of Texas MD Anderson Cancer Center, Houston, TX; and Gerald S. Falchook, Sarah Cannon Research Institute at HealthONE, Denver, CO."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiraj","family":"Sen","sequence":"additional","affiliation":[{"name":"Vivek Subbiah, Shiraj Sen, Kenneth R. Hess, Filip Janku, David S. Hong, Soumen Khatua, Daniel D. Karp, Javier Munoz, Roman Groisberg, Apostolia M. Tsimberidou, Steven I. Sherman, Patrick Hwu, and Funda Meric-Bernstam, The University of Texas MD Anderson Cancer Center, Houston, TX; and Gerald S. Falchook, Sarah Cannon Research Institute at HealthONE, Denver, CO."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth R.","family":"Hess","sequence":"additional","affiliation":[{"name":"Vivek Subbiah, Shiraj Sen, Kenneth R. Hess, Filip Janku, David S. Hong, Soumen Khatua, Daniel D. Karp, Javier Munoz, Roman Groisberg, Apostolia M. Tsimberidou, Steven I. Sherman, Patrick Hwu, and Funda Meric-Bernstam, The University of Texas MD Anderson Cancer Center, Houston, TX; and Gerald S. Falchook, Sarah Cannon Research Institute at HealthONE, Denver, CO."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Filip","family":"Janku","sequence":"additional","affiliation":[{"name":"Vivek Subbiah, Shiraj Sen, Kenneth R. Hess, Filip Janku, David S. Hong, Soumen Khatua, Daniel D. Karp, Javier Munoz, Roman Groisberg, Apostolia M. Tsimberidou, Steven I. Sherman, Patrick Hwu, and Funda Meric-Bernstam, The University of Texas MD Anderson Cancer Center, Houston, TX; and Gerald S. Falchook, Sarah Cannon Research Institute at HealthONE, Denver, CO."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David S.","family":"Hong","sequence":"additional","affiliation":[{"name":"Vivek Subbiah, Shiraj Sen, Kenneth R. Hess, Filip Janku, David S. Hong, Soumen Khatua, Daniel D. Karp, Javier Munoz, Roman Groisberg, Apostolia M. 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