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Poster display session

3880 - Dose escalation study of vemurafenib with crizotinib or sorafenib in patient with BRAF-mutated advance cancers

Date

11 Sep 2017

Session

Poster display session

Topics

Cytotoxic Therapy

Presenters

Divya Sakamuri

Citation

Annals of Oncology (2017) 28 (suppl_5): v122-v141. 10.1093/annonc/mdx367

Authors

D. Sakamuri1, S. Kato2, H.J. Huang3, A. Naing3, V.R. Holley3, S. Patel4, S.A. Piha-Paul3, A.M. Tsimberidou5, D.S. Hong6, F. Meric-Bernstam7, F. Janku3

Author affiliations

  • 1 Gi Medical Oncology, MD Anderson Cancer Center, 77030-4095 - Houston/US
  • 2 Center Of Personalized Cancer Therapy And Division Of Hematology And Oncology, Department Of Medicine, UC San Diego Moores Cancer Center, 92093 - La Jolla/US
  • 3 Department Of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 77030 - Houston/US
  • 4 Department Of Melanoma Medical Oncology, MD Anderson Cancer Center, 77030-4095 - Houston/US
  • 5 Investigational Cancer Therapeutics, MD ANDERSON CANCER CENTER, TX77030 - Houston/US
  • 6 Phase I Unit, The University of Texas M. D. Anderson Cancer Center, 77035 - Houston/US
  • 7 Oncology, University of Texas MD Anderson Cancer Center, Houston/US
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Resources

Abstract 3880

Background

BRAF inhibitors are effective in melanoma and other cancers with BRAF mutations; however, patients ultimately develop therapeutic resistance through activation of alternative signaling pathways such as MET, PDGFR and CRAF. We hypothesized that combining the BRAF inhibitor vemurafenib and MET inhibitor crizotinib or PDGFR/CRAF inhibitor sorafenib can overcome resistance.

Methods

We designed a phase I study (3 + 3 design) to determine the safety of vemurafenib (240-960 mg PO BID q 28 days) with crizotinib (250 mg PO daily or BID q 28 days) in arm A or sorafenib (200 mg PO daily to 400mg PO BID q 28 days) in Arm B in patients with BRAF-mutant advanced cancers. Endpoints included maximum tolerated dose (MTD), dose limiting toxicities (DLT), safety, response (RECIST 1.1) and plasma cell-free DNA mutation analysis.

Results

Thirty-six patients (arm A, 13; arm B, 23), median number of 3 prior therapies (29 [81%] had prior BRAF/MEK inhibitors) were treated. Patients (melanoma 17/36, 47%; papillary thyroid cancer 5/36, 14%; colorectal cancer 3/36, 8%; lung adenocarcinoma 2/36, 6%; other 9/36, 25%) had BRAF V600E (30), V600K (3) or other BRAF mutations (3). Vemurafenib 720mg BID with crizotinib 250mg daily and vemurafenib 720 mg BID with sorafenib 400mg/200mg were identified as MTDs. DLTs included grade (G) 3 rash (2) in arm A and G3 rash and G3 hypertension in arm B. Other G3 treatment related toxicities were G3 fatigue (2), G3 anemia (1), G3 thrombocytopenia (1), G3 neutropenia (1), G3 thromboembolic event (1) in arm A and G3 hypertension (1), G3 headache (1), G3 diarrhea (2), G3 intraocular inflammation (1) in arm B. In Arm A, 3 of 13 (23%) patients (melanoma refractory to BRAF monotherapy [2] and lung adenocarcinoma) attained a partial response (PR). In Arm B, 4 of 23 (17%) patients (ovarian cancer refractory to MEK inhibitor, melanoma, lung adenocarcinoma, papillary thyroid cancer) attained a PR. Optional longitudinal collection of plasma cfDNA to assess clonal evolution was performed and will be presented at the meeting.

Conclusions

Vemurafenib in combination with crizotinib or sorafenib is well tolerated with encouraging activity including patients previously treated with BRAF/MEK inhibitors.

Clinical trial identification

NCT01531361

Legal entity responsible for the study

MD Anderson Cancer Center

Funding

National Center for Advancing Translational Sciences (grant no. UL1 TR000371); National Institutes of Health through MD Anderson’s Cancer Center Support Grant (P30 CA016672)

Disclosure

F. Janku: Research funding: Novartis, Genentech, BioMed Valley Discoveries. Scientific Advisory Board: Novartis. All other authors have declared no conflicts of interest.

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