Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-Mutated Colorectal Cancer

Scott Kopetz, Jayesh Desai, Emily Chan, Joel Randolph Hecht, Peter J O'Dwyer, Dipen Maru, Van Morris, Filip Janku, Arvind Dasari, Woonbook Chung, Jean-Pierre J Issa, Peter Gibbs, Brian James, Garth Powis, Keith B Nolop, Suman Bhattacharya, Leonard Saltz, Scott Kopetz, Jayesh Desai, Emily Chan, Joel Randolph Hecht, Peter J O'Dwyer, Dipen Maru, Van Morris, Filip Janku, Arvind Dasari, Woonbook Chung, Jean-Pierre J Issa, Peter Gibbs, Brian James, Garth Powis, Keith B Nolop, Suman Bhattacharya, Leonard Saltz

Abstract

Purpose: BRAF V600E mutation is seen in 5% to 8% of patients with metastatic colorectal cancer (CRC) and is associated with poor prognosis. Vemurafenib, an oral BRAF V600 inhibitor, has pronounced activity in patients with metastatic melanoma, but its activity in patients with BRAF V600E-positive metastatic CRC was unknown.

Patients and methods: In this multi-institutional, open-label study, patients with metastatic CRC with BRAF V600 mutations were recruited to an expansion cohort at the previously determined maximum-tolerated dose of 960 mg orally twice a day.

Results: Twenty-one patients were enrolled, of whom 20 had received at least one prior metastatic chemotherapy regimen. Grade 3 toxicities included keratoacanthomas, rash, fatigue, and arthralgia. Of the 21 patients treated, one patient had a confirmed partial response (5%; 95% CI, 1% to 24%) and seven other patients had stable disease by RECIST criteria. Median progression-free survival was 2.1 months. Patterns of concurrent mutations, microsatellite instability status, CpG island methylation status, PTEN loss, EGFR expression, and copy number alterations were not associated with clinical benefit. In contrast to prior expectations, concurrent KRAS and NRAS mutations were detected at low allele frequency in a subset of the patients' tumors (median, 0.21% allele frequency) and were apparent mechanisms of acquired resistance in vemurafenib-sensitive patient-derived xenograft models.

Conclusion: In marked contrast to the results seen in patients with BRAF V600E-mutant melanoma, single-agent vemurafenib did not show meaningful clinical activity in patients with BRAF V600E mutant CRC. Combination strategies are now under development and may be informed by the presence of intratumor heterogeneity of KRAS and NRAS mutations.

Trial registration: ClinicalTrials.gov NCT00405587.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

© 2015 by American Society of Clinical Oncology.

Figures

Fig 1.
Fig 1.
(A) Waterfall plot of best RECIST response to vemurafenib in evaluable patients. (*) Fifty-nine percent growth from baseline. (†) Patients with notable mixed responses. (B) Progression-free survival. (C) Overall survival.
Fig 2.
Fig 2.
Correlation of best overall response rate with molecular characterization. Gray boxes represent samples unable to be analyzed for the specified assay. Numbers in the copy number (CN) alteration boxes represent the number of unique segments with CN alterations. Percentages in the RAS clone box represent mutant allele frequency. (*) Not evaluable for response.
Fig 3.
Fig 3.
(A) Rare KRAS-mutant (mut) clones were detected in a validated cohort of BRAF V600E–mutant colorectal cancer tumors by droplet digital polymerase chain reaction (ddPCR). (*) Lower limit of detection for clinical sequencing is approximately 5% to 20% depending on assays used. (†) Lower limit of detection for ddPCR. (B) A patient-derived xenograft model developed resistance to vemurafenib analog PLX4720 provided through ad lib chow at a dose of 417 mg/kg. Gray represents control arm; blue and gold represent PLX4720 treatment arm with acquisition of KRAS G12R and G12D mutations, respectively.
Fig A1.
Fig A1.
Development of keratoacanthoma while on therapy. (A) Before initiation of therapy and (B) after 8 weeks of treatment. (C and D) Development of multiple keratoacanthomas requiring treatment discontinuation.
Fig A2.
Fig A2.
Mean steady-state concentration-time profile of patients with metastatic colorectal cancer (CRC) compared with patients with melanoma treated with vemurafenib 960 mg twice per day.
Fig A3.
Fig A3.
Response by positron emission tomography to vemurafenib. (Top) Baseline scan. (Bottom) After one cycle of vemurafenib.
Fig A4.
Fig A4.
(A) Progression-free survival (PFS) for patients with or without identified alterations resulting in PI3K pathway activation (as denoted in Fig 2). (B) PFS for patients with tumors with intact or absent EGFR expression by immunohistochemistry.

References

    1. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–954.
    1. Michaloglou C, Vredeveld LC, Mooi WJ, et al. BRAF(E600) in benign and malignant human tumours. Oncogene. 2008;27:877–895.
    1. Joneson T, Bar-Sagi D. Ras effectors and their role in mitogenesis and oncogenesis. J Mol Med (Berl) 1997;75:587–593.
    1. Sinicrope FA, Shi Q, Smyrk TC, et al. Molecular markers identify subtypes of stage III colon cancer associated with patient outcomes. Gastroenterology. 2015;148:88–99.
    1. Lochhead P, Kuchiba A, Imamura Y, et al. Microsatellite instability and BRAF mutation testing in colorectal cancer prognostication. J Natl Cancer Inst. 2013;105:1151–1156.
    1. Tran B, Kopetz S, Tie J, et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer. 2011;117:4623–4632.
    1. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809–819.
    1. Yang H, Higgins B, Kolinsky K, et al. Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer. Cancer Res. 2012;72:779–789.
    1. Abrams JS, Mooney MM, Zwiebel JA, et al. Implementation of timeline reforms speeds initiation of National Cancer Institute-sponsored trials. J Natl Cancer Inst. 2013;105:954–959.
    1. Morikawa T, Shima K, Kuchiba A, et al. No evidence for interference of H&E staining in DNA testing: Usefulness of DNA extraction from H&E-stained archival tissue sections. Am J Clin Pathol. 2012;138:122–129.
    1. Tang X, Varella-Garcia M, Xavier AC, et al. Epidermal growth factor receptor abnormalities in the pathogenesis and progression of lung adenocarcinomas. Cancer Prev Res (Phila) 2008;1:192–200.
    1. Shroff S, Overman MJ, Rashid A, et al. The expression of PTEN is associated with improved prognosis in patients with ampullary adenocarcinoma after pancreaticoduodenectomy. Arch Pathol Lab Med. 2013;137:1619–1626.
    1. Ahn JB, Chung WB, Maeda O, et al. DNA methylation predicts recurrence from resected stage III proximal colon cancer. Cancer. 2011;117:1847–1854.
    1. Colella S, Shen L, Baggerly KA, et al. Sensitive and quantitative universal pyrosequencing methylation analysis of CpG sites. Biotechniques. 2003;35:146–150.
    1. Dressman D, Yan H, Traverso G, et al. Transforming single DNA molecules into fluorescent magnetic particles for detection and enumeration of genetic variations. Proc Natl Acad Sci U S A. 2003;100:8817–8822.
    1. Morris V, Overman MJ, Jiang ZQ, et al. Progression-free survival remains poor over sequential lines of systemic therapy in patients with BRAF-mutated colorectal cancer. Clin Colorectal Cancer. 2014;13:164–171.
    1. Mao M, Tian F, Mariadason JM, et al. Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome with PI3K inhibition or demethylating agents. Clin Cancer Res. 2013;19:657–667.
    1. Shen L, Toyota M, Kondo Y, et al. Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer. Proc Natl Acad Sci U S A. 2007;104:18654–18659.
    1. Beach R, Chan AO, Wu TT, et al. BRAF mutations in aberrant crypt foci and hyperplastic polyposis. Am J Pathol. 2005;166:1069–1075.
    1. Coffee EM, Faber AC, Roper J, et al. Concomitant BRAF and PI3K/mTOR blockade is required for effective treatment of BRAF(V600E) colorectal cancer. Clin Cancer Res. 2013;19:2688–2698.
    1. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–2516.
    1. Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: A phase 1 dose-escalation trial. Lancet. 2012;379:1893–1901.
    1. Corcoran RB, Ebi H, Turke AB, et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2012;2:227–235.
    1. Prahallad A, Sun C, Huang S, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012;483:100–103.
    1. Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010;467:596–599.
    1. Yaeger R, Cercek A, O'Reilly EM, et al. Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients. Clin Cancer Res. 2015;21:1313–1320.
    1. Van Geel R, Elez E, Bendell JC, et al. Phase I study of the selective BRAFV600 inhibitor encorafenib (LGX818) combined with cetuximab and with or without the α-specific PI3K inhibitor BYL719 in patients with advanced BRAF-mutant colorectal cancer. J Clin Oncol. 2014;(suppl):32. abstr 3514.
    1. Rajagopalan H, Bardelli A, Lengauer C, et al. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature. 2002;418:934.
    1. Tie J, Gibbs P, Lipton L, et al. Optimizing targeted therapeutic development: Analysis of a colorectal cancer patient population with the BRAF(V600E) mutation. Int J Cancer. 2011;128:2075–2084.
    1. Fransen K, Klintenas M, Osterstrom A, et al. Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas. Carcinogenesis. 2004;25:527–533.
    1. Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468:973–977.
    1. Ahronian LG, Sennott EM, Van Allen EM, et al. Clinical acquired resistance to RAF inhibitor combinations in BRAF-mutant colorectal cancer through MAPK pathway alterations. Cancer Discov. 2015;5:358–367.
    1. Dadu R, Shah K, Busaidy NL, et al. Efficacy and tolerability of vemurafenib in patients with BRAF(V600E)-positive papillary thyroid cancer: M.D. Anderson Cancer Center off label experience. J Clin Endocrinol Metab. 2015;100:E77–E81.
    1. Peters S, Michielin O, Zimmermann S. Dramatic response induced by vemurafenib in a BRAF V600E-mutated lung adenocarcinoma. J Clin Oncol. 2013;31:e341–e344.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren