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. 2018 Sep 13:2:PO.18.00189.
doi: 10.1200/PO.18.00189. eCollection 2018.

Phase I Study of the BRAF Inhibitor Vemurafenib in Combination With the Mammalian Target of Rapamycin Inhibitor Everolimus in Patients With BRAF-Mutated Malignancies

Vivek Subbiah  1 , Shiraj Sen  1 , Kenneth R Hess  1 , Filip Janku  1 , David S Hong  1 , Soumen Khatua  1 , Daniel D Karp  1 , Javier Munoz  1 , Gerald S Falchook  1 , Roman Groisberg  1 , Apostolia M Tsimberidou  1 , Steven I Sherman  1 , Patrick Hwu  1 , Funda Meric-Bernstam  1
Affiliations

Phase I Study of the BRAF Inhibitor Vemurafenib in Combination With the Mammalian Target of Rapamycin Inhibitor Everolimus in Patients With BRAF-Mutated Malignancies

Vivek Subbiah et al. JCO Precis Oncol. .

Abstract

Purpose: Parallel activation of the phosphatidylinositol 3-kinase-mammalian 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.

Patients and methods: 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.

Results: 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.

Conclusion: 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-small-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.

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Conflict of interest statement

The funders had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the article; and the decision to submit the article for publication.The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Vivek SubbiahConsulting or Advisory Role: MedImmune Research Funding: Novartis (Inst), GlaxoSmithKline (Inst), NanoCarrier (Inst), Northwest Biotherapeutics (Inst), Genentech (Inst), Berg Pharma (Inst), Bayer (Inst), Incyte (Inst), Fujifilm (Inst), PharmaMar (Inst), D3 Oncology Solutions (Inst), Pfizer (Inst), Amgen (Inst), AbbVie (Inst), Multivir (Inst), Blueprint Medicines (Inst), Loxo (Inst), Vegenics (Inst), Takeda (Inst), Alfasigma (Inst), Agensys (Inst), Idera (Inst), Boston Biomedical (Inst) Travel, Accommodations, Expenses: PharmaMar, BayerShiraj SenNo relationship to discloseKenneth R. HessNo relationship to discloseFilip JankuStock and Other Ownership Interests: Trovagene Consulting or Advisory Role: Deciphera, Trovagene, Novartis, Sequenom, Foundation Medicine, Guardant Health, Immunome Research Funding: Novartis, BioMed Valley Discoveries, Roche, Agios, Astellas Pharma, Deciphera, Symphony Evolution, Plexxikon, Piqur, Fujifilm Other Relationship: Bio-RadDavid S. HongStock and Other Ownership Interests: MolecularMatch, Oncorena Honoraria: Adaptimmune, Baxter, Merrimack, Bayer Consulting or Advisory Role: Baxter, Bayer, Guidepoint Global, Janssen Speakers' Bureau: Genentech, Janssen Oncology Research Funding: Novartis, Genentech, Eisai, AstraZeneca, Pfizer, miRNA Therapeutics, Amgen, Daiichi Sankyo, Merck, Mirati Therapeutics, Eli Lilly, Adaptimmune, AbbVie, Bayer, Bristol-Myers Squibb, Genmab, Ignyta, Infinity Pharmaceuticals, Kite Pharma, Kyowa Hakko Kirin, Loxo, MedImmune, Molecular Templates, Takeda Travel, Accommodations, Expenses: Loxo, miRNA Therapeutics Other Relationship: Oncorena, EisaiSoumen KhatuaNo relationship to discloseDaniel D. KarpConsulting or Advisory Role: Black Beret Life Sciences Research Funding: Phosplatin Therapeutics Travel, Accommodations, Expenses: Phosplatin TherapeuticsJavier MunozConsulting or Advisory Role: Kite Pharma, Pfizer, Pharmacyclics, Bayer, Alexion Pharmaceuticals, Bristol-Myers Squibb, Janssen, Seattle Genetics, Gilead Sciences, Kyowa Hakko Kirin Speakers' Bureau: Kite PharmaGerald S. FalchookEmployment: Sarah Cannon Research Institute, HealthONE Research Funding: Millennium, EMD Serono, Celgene, MedImmune, Genmab, Vegenics, Novartis, AstraZeneca, Incyte, ARMO BioSciences, Kolltan Pharmaceuticals, 3-V Biosciences, AbbVie, Aileron Therapeutics, DelMar Pharmaceuticals, eFFECTOR Therapeutics, Strategia Therapeutics, Fujifilm, Hutchison MediPharma, Regeneron, Biothera, Curegenix, Curis, Eli Lilly, Jounce Therapeutics, OncoMed, Precision Oncology, Syndax, Taiho Pharmaceutical, Tesaro, Takeda, BeiGene, Ignyta, Merck, Rgenix, Tarveda Therapeutics, Tocagen Patents, Royalties, Other Intellectual Property: Handbook of Targeted Cancer Therapy Travel, Accommodations, Expenses: Millennium, Sarah Cannon Research Institute, EMD Serono, Bristol-Myers SquibbRoman GroisbergNo relationship to discloseApostolia M. TsimberidouConsulting or Advisory Role: Roche Research Funding: EMD Serono (Inst), Baxter (Inst), Foundation Medicine (Inst), Onyx (Inst), Bayer (Inst), Boston Biomedical (Inst), Placon (Inst), IMMATICS (Inst), Karus Therapeutics (Inst), Stem Cells (Inst), OBI Pharma (Inst)Steven I. ShermanHonoraria: Genzyme, Eisai Consulting or Advisory Role: Eisai, Exelixis, Veracyte, Novo Nordisk, Bristol-Myers Squibb, Loxo, Genzyme, Ignyta, Novartis Research Funding: Genzyme Travel, Accommodations, Expenses: Eisai, Veracyte, IgnytaPatrick HwuStock and Other Ownership Interests: Immatics Consulting or Advisory Role: Dragonfly Therapeutics, GlaxoSmithKline, Immatics, Sanofi Research Funding: Genentech (Inst)Funda Meric-BernstamHonoraria: Sumitomo Group, Dialectica Consulting or Advisory Role: Genentech, Inflection Biosciences, Pieris Pharmaceuticals, Clearlight Diagnostics, Darwin Health, Samsung Bioepis, Spectrum Pharmaceuticals Research Funding: Novartis, AstraZeneca, Taiho Pharmaceutical, Genentech, Calithera Biosciences, Debiopharm Group, Bayer, Aileron Therapeutics, PUMA Biotechnology, CytomX Therapeutics, Jounce Therapeutics, Zymeworks, Curis, Pfizer, eFFECTOR Therapeutics, AbbVie

Figures

Fig 1.
Fig 1.
(A) Waterfall plot depicting best response as percent change in target lesions in all 18 evaluable patients with advanced cancer treated with vemurafenib and everolimus. Patients previously treated with a BRAF and/or MEK inhibitor are in blue. Stars indicate patients still on trial without disease progression at the time of analysis. (B) Representative restaging images of a patient with metastatic melanoma and a PTEN (P95S) mutation who had a partial response on vemurafenib and everolimus after disease progression on vemurafenib and PX866, an investigational PI3K inhibitor. Astro, anaplastic astrocytoma; AT, anaplastic thyroid; CRC, colorectal cancer; CUP, cancer of unknown primary; Glio, glioblastoma; Glioma, optic nerve glioma; Mel, melanoma; PT, papillary thyroid.
Fig 2.
Fig 2.
Graphical depiction of a patient’s circulating tumor DNA level of BRAFV600E (shown as copies per milliliter of plasma) while on treatment with vemurafenib plus everolimus with representative restaging scans and response to therapy, per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. PD, progression of disease; PR, partial response.
See this image and copyright information in PMC

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