2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

APPROVAL OF NEW AGENTS
IDH mutations show hypermethylation of both DNA and
histone marks. Human tumors that display mutations in
IDH 1 or 2 include a subset of human leukemias (AML),
thyroid cancers, gliomas, chondrosarcomas, and intrahepatic
cholangiocarcinomas. 12
Two kinds of drugs might be effective in tumors driven by
IDH 1 or 2 mutation. Analogs of AKG/2HG that inhibit
mutant IDH enzymatic activity are an obvious choice, and
are under development by Agios and other pharmaceutical
companies. 13 A second strategy would be to develop inhibitors
of H3K27 methylation, and such drugs are also nearing
the clinic from Epizyme and others. 14 A third strategy would
be to use inhibitors of DNA methylation, although it is not
clear whether the primary transforming event is methylation
of DNA or histones. A tightly focused phase I strategy
aimed at relapsed or refractory IDH mutant AML, grade 4
gliomas, chondrosarcomas, or cholangiocarcinoma might
produce convincing early results with these agents. None of
these settings are curable with standard therapy (with the
possible exception of high dose chemotherapy/stem cell
transplant for relapsed AML). Such a trial will require the
Author’s Disclosures of Potential Conflicts of Interest
Author
Bruce Chabner*
*No relevant relationships to disclose.
Employment or
Leadership
Positions
Consultant or
Advisory Role
1. United States Food And Drug Administration. Significant Dates in U.S.
Food and Drug Law History. http://www.fda.gov/AboutFDA/WhatWeDo/
History/Milestones/ucm128305.htm. Last accessed 3/7/12. Accessed October
14, 2010.
2. Broder S. The development of antiretroviral therapy and its impact on
the HIV-1/AIDS pandemic. Antiviral Res. 2010;85:1-18.
3. Johnson JR, Ning YM, Farrell A, et al.Accelerated approval of oncology
products: The food and drug administration experience. J Natl Cancer Inst.
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4. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic Lymphoma Kinase
Inhibition in Non-Small-Cell Lung Cancer. N Engl J Med. 2010;363:1693-
1703.
5. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated
BRAF in metastic melanoma. N Engl J Med. 2010;26:809-19.
6. FDA approves Xalkori with companion diagnostic for type of late-stage
cancer. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/
ucm269856.htm. Last Accessed March 7, 2012.
7. Chapman PB, Hauschild A, Robert C, , et al. Improved survival with
vemurafenim in melanoma with BRAF V600E mutation. N Engl J Med.
2011;364:2507-2516.
participation of multiple institutions to identify the relatively
uncommon subjects for these studies. Mutational
analysis has been developed to identify candidates for accrual
to these trials. Confirmation of target engagement will
require evaluation of 2HG levels in tumor cells, serum or
urine, or by imaging, and analysis of DNA and histone
methylation before and after treatment. If response rates
and TTP reach impressive levels in any of these subject
tumor subsets, and provided that the safety profile of the
drug is acceptable, there would be an obvious path to
accelerated approval.
Despite the early success of targeted therapies in various
settings, it is apparent that single agent treatment will not
cure metastatic disease. Combination therapies aimed at
mechanisms of resistance will be required to derive longterm
benefit. Proving the value of combination trials will
likely require randomized phase III studies to achieve marketing
approval. The phase III trial is not antiquated or
obsolete. It simply needs to be adapted to the new paradigm
of rapid, single agent approval. Its continued place in the
sun is assured.
Stock
Ownership Honoraria
REFERENCES
Research
Funding
Expert
Testimony
Other
Remuneration
8. Chabner BA. Early accelerated approval for highly targeted cancer
drugs. N Engl J Med. 2011;364:1087-1089.
9. Chao Lu, Ward PS, Kapoor GS, et al. IDH Mutation impairs histone
demethylation and results in a block to cell differentiation. Nature. Epub 2012
Feb 12.
10. Turcan S, Rohle D, Goenka A, , et al. IDH1 mutation is sufficient to
establish the glioma hypermethylator phenotype. Nature. Epub 2012 Feb. 15.
11. Koivunen P, Lee S, Duncan CG, Lopez G, Lu G, et al. Transformation
by the (R)-enantiomer of 2-hudroxyglutarate linked EGLN activation. Nature.
Epub 2012 Mar 22.
12. Borger DR, Tanabe KK, Fran KC, et al. Frequent mutation of isocitrate
dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through
broad-based tumor genotyping. Oncologist. 2012;17:72-79.
13. Yen KE, Schenkein DP. Cancer-associated isocitrate dehydrogenase
mutations. Oncologist. 2012;17:72-79.
14. Copeland RA, Solomon ME, Richon VM. Protein methyltransferases as
a target class for drug discovery. Nat Rev Drug Discov. 2009;8:724-732.
15. Von Hoff DD, LoRusso PM, Rudin CM, et al. Inhibition of the hedgehog
pathway in advanced basal-cell carcinoma. N Engl J Med. 2009;361:1164-
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