Progress in Targeted Cancer Drugs
This timeline of advances in targeted cancer drugs was developed by the American Society of Clinical Oncology
(ASCO), which represents nearly 30,000 physicians who treat people with cancer and research new cures. An
interactive version, which includes timelines of advances against a range of common cancers, is available online at
www.CancerProgress.Net.
Overview
Breakthroughs in our understanding of the biology of the cancer cell are driving development of a new generation
of drugs that are targeted to the unique genetics of each tumor and each patient. By blocking or switching off the
molecular defects that cause cancer to grow and spread, these agents attack cancer cells but leave healthy cells
largely untouched, resulting in better cancer control and better quality of life.
While targeted drugs are relatively new, some have already become staples of cancer treatment. For example,
trastuzumab (Herceptin) has transformed one of the most difficult forms of breast cancer into one that is often
curable if detected early, and imatinib (Gleevec) enables patients to live with a once-deadly form of leukemia as a
manageable, chronic disease. And recently, for the first time, targeted drugs have been shown to extend the lives
of people with advanced melanoma, long one of the most difficult cancers to treat.
Timeline
1960 Leukemia
Researchers link “Philadelphia chromosome” to leukemia
Investigators in Philadelphia identify a chromosomal abnormality linked to many leukemias. A decade
later, researchers discover that this abnormality results when parts of two chromosomes –
chromosomes 9 and 22 – switch places in a phenomenon called translocation. It later becomes the
target of one of the first-ever targeted cancer treatments, imatinib (Gleevec), which transforms
treatment of chronic myelogenous leukemia and other cancers.
1987 Lung Cancer
Scientists discover key genetic vulnerability in tumor cells – EGFR
Researchers first establish that a receptor on cancer cells called the epidermal growth factor receptor
(EGFR) plays an important role in the growth and spread of non-small cell lung cancer. The findings
present researchers with a new therapeutic target, and leads to the later development of targeted
drugs such as gefitinib (Iressa) and erlotinib (Tarceva).
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1997 Lymphoma
FDA approves first-ever targeted cancer drug, rituximab
The FDA approves the first molecularly targeted cancer drug, rituximab (Rituxan), to treat patients with
B-cell non-Hodgkin’s lymphoma who no longer respond to other treatments. Rituximab is in a new
class of drugs called monoclonal antibodies and targets a protein on the surface of immune cells
known as B cells, interfering with the development of cancer. It is later combined with other cancer
therapies to boost cure rates and increase survival.
1998 Breast Cancer
First targeted anti-breast cancer drug, trastuzumab (Herceptin), has major impact
on care
The FDA approves the groundbreaking drug trastuzumab (Herceptin) after research shows that adding
the monoclonal antibody to chemotherapy dramatically increases survival for women with advanced
breast cancer that over-produces a protein called HER2. In 2006, the drug is also approved as part of
adjuvant therapy (after surgery) for women with early-stage HER2-positive breast cancer, after two
major trials show that it reduces the risk of recurrence by more than 50 percent, an unprecedented
result.
About 25 percent of breast cancer patients have HER2-positive disease, and prior to the introduction of
trastuzumab, there were no effective treatments for these cancers, which were considered some of the
most aggressive, deadly forms of the disease.
2001 New targeted therapy transforms treatment for rare leukemia
The FDA approves imatinib (Gleevec) after just three months of review – the fastest approval in FDA
history – based on data showing the drug halted the growth of chronic myelogenous leukemia (CML)
in the majority of patients. Imatinib is the first drug proven to counteract a molecular defect on the socalled
“Philadelphia chromosome,” first discovered in 1960. It has since become the standard of care
for this disease, and its effectiveness and easily-administered pill form enables most patients to live
with CML as a manageable, chronic disease.
2001 Imatinib found highly effective against rare gastrointestinal tumor
Just weeks after being approved to treat chronic myelogenous leukemia, the targeted drug imatinib is
shown to be effective against a rare abdominal tumor called GIST (gastrointestinal stromal tumor).
Prior to imatinib, available drug treatments had little effect on GIST tumors. Imatinib works like a
“circuit breaker” to block enzymes that can send faulty signals to trigger tumor cell growth. In GIST, it
blocks the growth signal of a gene called c-Kit.
2002 Lymphoma
Adding rituximab to “CHOP” chemotherapy boosts survival
The targeted drug rituximab (Rituxan), when added to standard CHOP chemotherapy
(cyclophosphamide, doxorubicin, vincristine and prednisone), is shown to boost survival for older
patients with diffuse B-cell lymphoma. Subsequent trials confirm the results in patients of all ages, and
the “R-CHOP” combination soon becomes standard treatment for this type of non-Hodgkin lymphoma.
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2002 Lymphoma
Radioimmunotherapy introduced to treat lymphoma
This new therapeutic approach becomes available to patients with the FDA approval of the drug
ibritumomab tiuxetan (Zevalin). The drug acts as a “smart bomb” against the tumor by combining a
radioactive material with a protein that locates and binds to a select receptor on cancer cells called CD-
20. The radioactive material kills the cells with which it comes in contact, while sparing the healthy
surrounding tissue. In 2003, a similar drug called tositumomab (Bexxar) is approved for the same use.
2003 Scientists decode the human genome
Scientists announce that they have successfully mapped the 3 billion DNA letters in the human
genome. This marks the completion of the Human Genome Project, an unprecedented international
collaboration between researchers in the U.S. in and six other countries, funded primarily by the U.S.
government. Results of the 13-year effort are made freely available to scientists around the world,
paving the way for research to identify the genetic defects that fuel cancer, and for new ways of
screening for and treating the disease.
2003 Lung Cancer
First targeted drug approved for non-small cell lung cancer
The FDA approves the first targeted therapy for non-small cell lung cancer, gefitinib (Iressa), following
studies showing it shrinks tumors in some patients with advanced cancer that progresses despite other
therapies. Gefitinib targets the epidermal growth factor receptor (EGFR), a protein on cell surfaces that
drives lung cancer growth and spread. Use of gefitinib is restricted by the FDA in 2005 to patients who
had already benefited from the drug or were receiving it through a clinical trial, after data from larger
trials show gefitinib therapy did not extend patients’ lives. However, later research suggests that
gefitinib has value as a first-line treatment, and is more effective than chemotherapy in patients whose
tumors carry an EGFR mutation.
2004 FDA approves first “anti-angiogenic” drug, bevacizumab
Bevacizumab (Avastin) is the first of a new generation of targeted drugs, called anti-angiogenics, that
attack cancer by blocking the growth of blood vessels that tumors needs to grow. First approved to
treat colorectal cancer, in 2004, the drug has since become an important treatment for patients with
advanced lung, ovarian and kidney cancers, and for certain brain tumors, who have few other effective
options.
2004, 2006 Leukemia
Epigenetic drugs approved to prevent cancer in patients with myelodysplastic
syndromes
The FDA approves azacytidine (Vidaza) in 2004 and decitabine (Dacogen) in 2006 for treatment of
myelodysplastic syndromes (MDS), a group of serious blood disorders that predispose a person to
acute myelogenous leukemia. These targeted drugs interfere with the control of genetic processes that
enable cancer cells to develop and multiply. Both drugs are shown to reduce or eliminate the need for
blood transfusions – a common MDS treatment that can impair patients’ quality of life.
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2004 Lung Cancer
Studies show that specific EGFR mutations are associated with response to
gefitinib
A series of major studies shows that lung cancer tumors with specific mutations of the EGFR
(epidermal growth factor receptor) protein are highly responsive to EGFR-targeted drugs. EGFR is an
important signaling pathway that stimulates cancer cell division, and these findings provide critical
information for identifying a subset of patients most likely to respond to gefitinib (Iressa) and erlotinib
(Tarceva). The relevant mutations are found most commonly in lung cancer patients without a
significant smoking history.
2004 Lung Cancer
FDA approves second targeted drug, erlotinib, for non-small cell lung cancer
Erlotinib (Tarceva) is approved for patients with advanced non-small cell lung cancer that has
worsened after at least one regimen of chemotherapy. The approval is backed by data showing that
erlotinib improves survival by two months, compared to placebo. A follow-up analysis shows that
erlotinib also improves patients’ quality of life, reducing pain and allowing better physical function.
Erlotinib is administered in pill form – a convenient alternative to traditional chemotherapy, which is
generally administered intravenously in a doctor’s office or hospital.
2005 U.S. launches effort to map cancer genomes
The National Cancer Institute and the National Human Genome Research Institute team up to launch
The Cancer Genome Atlas project. In its initial phase, the project aims to develop a comprehensive atlas
of the genomes of three common cancers – lung, ovarian, and glioblastoma, a form of brain cancer. By
gaining a deeper understanding of the genetic pathways involved in the development and growth of
these cancers, researchers hope to identify molecular targets that can guide development of effective
new treatment.
2005 Kidney Cancer
First FDA approval of a targeted drug for kidney cancer
FDA approves the new treatment sorafenib in December 2005, based on studies showing it delays
tumor progression in patients with advanced renal cell carcinoma whose cancer recurs or persists
despite previous immunotherapy. It is the first treatment found to benefit patients with this advanced,
pre-treated form of the disease.
2005 Lung Cancer
Anti-angiogenic drug bevacizumab extends survival for advanced lung cancer
A major study shows that adding the targeted drug bevacizumab (Avastin) to standard chemotherapy
extends survival compared to chemotherapy alone for select patients with advanced lung cancer. In
2006, the FDA approves bevacizumab in combination with standard chemotherapy as an initial therapy
for inoperable, non-squamous non-small cell lung cancer that has spread within or outside the lungs,
or that has recurred. Bevacizumab is the first of a new generation of targeted drugs called “antiangiogenics,”
which attack cancer by blocking the tumor’s ability to develop the blood vessels it needs
to grow.
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2005 Lymphoma
Bortezomib shrinks tumors in mantle cell lymphoma
Two studies show that the drug bortezomib (Velcade) shrinks tumors in nearly half of patients with
mantle cell lymphoma, one of the rarest forms of non-Hodgkin lymphoma. The drug is approved the
next year for patients who have relapsed after prior treatment. Bortezomib targets a key pathway in a
cancer cell called the proteasome. This pathway is similar to a recycling process whereby key cancer cell
proteins are broken up and destroyed so that their parts can be re-used by new cancer cells. A
proteosome inhibitor, like bortezomib, stops this process in order to rob the cancer cell of proteins
that would otherwise help fuel its growth. Researchers continue to explore other drugs that inhibit this
pathway.
2004-2008 Colorectal Cancer
Two targeted drugs approved for advanced colon cancer
The drugs cetuximab (Erbitux) and panitumumab (Vectibix) are approved to treat colon cancer that has
spread to other parts of the body (metastatic disease). These drugs attack tumors that express the
epidermal growth factor receptor (EGFR) protein, which is involved in cancer cell growth. Later, a
coordinated analysis of multiple studies shows that cetuximab and panitumumab are effective only in
patients with the normal form of a gene known as KRAS. This discovery helps physicians ensure that
the drugs are used only for patients who stand to benefit, while eliminating unnecessary treatment
and costs for patients who will not.
2005 Pancreatic Cancer
First targeted drug approved for pancreatic cancer
A major clinical trial finds that adding the targeted drug erlotinib (Tarceva) to standard gemcitabine
(Gemzar) chemotherapy extends the lives of patients with inoperable pancreatic cancer, compared to
gemcitabine alone. This is the first trial to identify a survival benefit with a new drug for patients with
advanced pancreatic cancer since gemcitabine was introduced nearly a decade earlier. The FDA
approves erlotinib for pancreatic cancer later the same year. The new drug targets a protein called the
epidermal growth factor receptor (EGFR), which fuels the growth of some types of cancer cells.
2006 Leukemia
New drug helps CML patients who become resistant to imatinib
Researchers identify a second targeted treatment, dasatinib (Sprycel), for patients with chronic
myelogenous leukemia who cannot tolerate or develop resistance to imatinib (Gleevec). The drug is
approved based on study results showing that more than 90 percent of these poor prognosis patients
had no evidence of their cancer following dasatinib treatment. Dasatinib targets the same mutated
protein as imatinib, but through a different mechanism.
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2006-2007 Kidney Cancer
Two new targeted drugs are proven effective in major trials; FDA approvals follow
Sunitinib (Sutent) is approved in January 2006 for advanced renal cell cancer in previously untreated
patients, based on studies showing it shrank more tumors and resulted in slower disease progression
compared to the previous standard treatment, interferon.
In May 2007, FDA approves another targeted drug, temsirolimus (Torisel), based on studies showing
that it prolonged median overall survival of patients with advanced renal carcinoma by more than 3
months (or about 50 percent), compared to standard interferon treatment. This drug targets the mTOR
protein, which regulates cancer cell growth and division.
2007 Breast Cancer
Lapatinib approved for patients whose HER2-positive breast cancer no longer
responds to trastuzumab
The targeted therapy lapatinib (Tykerb) is approved by the FDA for use in combination with the drug
capecitabine for patients with advanced breast cancer whose tumors overproduce the HER2 protein.
Lapatinib is used to slow disease progression in cancers that no longer respond to trastuzumab
(Herceptin). In 2010, the drug is also approved as an initial therapy in combination with the aromatase
inhibitor letrozole (Femara) for patients with HER2-positive cancer.
2007 Leukemia
Study supports expanded use of dasatinib for CML
Research shows that dasatinib (Sprycel) – initially approved for use only when treatment with imatinib
fails – should also be an option for initial treatment of early-stage chronic myelogenous leukemia. The
FDA approves the drug for this broader indication in 2010, giving patients with CML multiple options
for controlling their cancer.
2008 Brain Cancer
Bevacizumab (Avastin) receives FDA approval for glioblastoma
Two early-stage trials suggest that giving the targeted therapy bevacizumab (Avastin), alone or with
the chemotherapy drug irinotecan (Camptosar), may cause tumor shrinkage in patients with
glioblastoma whose disease progresses after previous therapy. Based on these findings, the FDA grants
accelerated (or early, conditional) approval for bevacizumab to treat glioblastoma. Bevacizumab is an
“anti-angiogenic” drug, meaning it works by interfering with the development of blood vessels that
tumors need to grow and spread. This marks the first new drug approved for treating brain tumors in
a decade, and studies are ongoing to determine if initial treatment with bevacizumab improves overall
survival.
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2008 Lung Cancer
Circulating tumor cells in the blood can help track treatment response in select
patients
Recent advances in lab technologies have made it possible to detect cancer cells that have broken free
of the tumor, called circulating tumor cells, using a simple blood sample. In a new study, researchers
show that tracking the number of these circulating tumor cells is useful for assessing how well a
patient with non-small cell lung cancer is responding to therapy.
2008 Lymphoma
First drug approved specifically for T-cell lymphoma treatment
A study shows that the new targeted anticancer drug pralatrexate (Folotyn) shrank tumors in nearly
one-third of patients with peripheral T-cell lymphoma that persisted or returned after conventional
therapy. Tumors disappeared completely in more than 10 percent of patients in the study. In 2009, the
FDA grants accelerated approval for pralatrexate for peripheral T-cell lymphoma that has relapsed or
has not responded well to other forms of chemotherapy. This is the first drug to be specifically
approved to treat T-cell lymphoma, and this accomplishment reflects a movement toward increased
clinical research coordination among lymphoma researchers in the U.S. and worldwide to identify new
therapies for this rare but often aggressive disease.
2008 Prostate Cancer
Advanced prostate cancers respond to new treatments in early studies
Two new targeted drugs appear promising in early studies among patients with advanced stages of
prostate cancer. In one study, a drug called abiraterone acetate (Zytiga) reduced levels of prostatespecific
antigen (PSA) by up to 90 percent in men who no longer responded to hormone therapy. A
second trial shows that adding the drug custirsen to standard chemotherapy significantly reduced PSA
and pain levels, compared to an alternative combination. (Custirsen is designed to make prostate
cancer cells more sensitive to chemotherapy.) In 2011, the FDA approves abiraterone acetate, in
combination with prednisone, for men whose advanced prostate cancer progresses despite other
therapies, including docetaxel (Taxotere) chemotherapy.
2008-2010 Breast Cancer
Bevacizumab (Avastin) approved for advanced breast cancer
In 2008, the FDA grants accelerated approval for bevacizumab (Avastin) in combination with paclitaxel
(Taxol) for women with newly diagnosed advanced breast cancers. Bevacizumab is an “antiangiogenic”
drug, meaning that it works by interfering with the growth of the blood vessels that
tumors need to grow and spread. The approval is based on studies showing this regimen delays cancer
growth. However, later, longer-term studies show that bevacizumab does not extend survival. Debate
continues about the use of this drug for breast cancer, although it has an established role in the
treatment of other common cancers, such as lung and colorectal cancers.
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2009 Breast Cancer
PARP inhibitors show promise for difficult-to-treat breast cancers
Researchers share the first encouraging findings on a new class of targeted drugs – PARP inhibitors –
for difficult-to-treat “triple-negative” breast cancers and those that involve BRCA1 and BRCA2 gene
mutations. PARP inhibitors are designed to disable key enzymes that cancer cells use to repair DNA
damage, including damage inflicted by chemotherapy, and to promote cancer cell death. They may
also make cancer cells more sensitive to other chemotherapy agents. Triple-negative breast cancers lack
receptors for estrogen, progesterone and HER2, and therefore do not respond to targeted drugs that
block these proteins.
Further long-term, randomized clinical trials are needed to determine whether PARP inhibitors truly
benefit patients with breast cancer, and if so, which specific types of breast tumors are most likely to
respond to the drugs.
2009 Kidney Cancer
Everolimus approved for renal cell carcinoma if other drugs fail
FDA approves everolimus (Afinitor) for treatment of renal cell carcinoma in patients whose disease
returned or progressed despite prior therapy with sunitinib (Sutent) and/or sorafenib (Nexavar).
Everolimus targets the mTOR protein, a pathway that is particularly active in renal cell carcinomas, and
was found to help patients live twice as long without their cancer progressing, compared to placebo
and standard supportive care.
2009 Kidney Cancer
Bevacizumab approved for renal cancer after multiple studies confirm benefit
Bevacizumab (Avastin) is approved to treat metastatic renal cell carcinoma when combined with
interferon. Approval is based on earlier studies showing this approach nearly doubled the time it took
for patients’ cancer to progress.
2009 Kidney Cancer
Pazopanib approved for advanced kidney cancer
FDA approves pazopanib (Votrient) for advanced renal cell carcinoma, based on data showing the drug
helped patients live twice as long without their disease progressing compared to placebo. Pazopanib is
an oral drug that blocks multiple cancer cell receptors associated with tumor growth and blood vessel
formation.
2009 Pediatric Cancer
Targeted drug helps children with hard-to-treat leukemia
Adding the targeted drug imatinib (Gleevec) to standard, intensive chemotherapy is found to
dramatically improve outcomes for patients with acute lymphoblastic leukemia (ALL) who have a
genetic mutation known as the Philadelphia chromosome. After three years, 80 percent of patients
who received both therapies in the study were alive, compared to 30 percent who received
chemotherapy alone. While further research is needed, the results offer hope to children with this
hard-to-treat form of cancer.
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2010 Breast Cancer
Targeted drug denosumumab helps prevent common bone-related complications
in advanced breast cancer
About 80 percent of women with metastatic breast cancer experience cancer spread to the bone, a
complication that causes pain, bone weakening and other side effects that affect quality of life. In
2010, a large study shows that the targeted drug called denosumumab (Xgeva) can prevent or
significantly delay bone metastases. Other drugs, such as zoledronic acid (Zometa), have previously
been used to prevent and treat these bone-related complications, but this study suggests
denosumumab may be more effective.
2010 Leukemia
Tyrosine kinase inhibitors provide additional options for CML
Two studies show that dasatinib (Sprycel) and nilotinib (Tasigna) may be more effective than the
current standard drug, imatinib (Gleevec), for the initial treatment of chronic myeloid leukemia.
Though all three drugs target the same active genetic pathway on the “Philadelphia chromosome,”
studies suggest the newer drugs possibly elicit faster, stronger responses and cause fewer side effects
than imatinib.
2010 Lung Cancer
Drug aimed at a newly identified target causes dramatic tumor shrinkages
The drug crizotinib, which targets the anaplastic lymphoma kinase (ALK) pathway, is shown to cause
tumor shrinkage in a high percentage of patients whose tumors had an abnormality in the ALK gene.
This ALK gene mutation only occurs in about 4 percent of lung cancers, and is more common in
patients who never smoked. The development of crizotinib exemplifies the future of lung cancer
therapy, in which tumors will be analyzed for their molecular make-up and then treated based on
those findings.
2010 Melanoma
First drug shown to improve survival for patients with advanced melanoma
The targeted drug ipilimumab (Yervoy) is found to improve survival and delay disease progression in
patients whose advanced melanoma progresses despite other therapies. In a pivotal trial that leads to
the drug’s approval in 2011, researchers compared ipilimumab to a placebo and an experimental
vaccine. Ipilimumab is a monoclonal antibody, and works by targeting key molecular pathways to
enhance the immune system’s ability to fight cancer. However, the drug does not benefit all patients
and researchers continue to study how best to identify which patients will benefit and how to ease the
drug’s side effects, which may include skin problems and gastrointestinal inflammation.
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2010 Second targeted drug extends survival for advanced melanoma
Researchers release initial data showing that the targeted drug PLX4032 (Vemurafenib) shrinks tumors
in many advanced melanoma patients whose tumors have a specific mutation in the BRAF gene. In
many cases, patients experience dramatic reductions in pain and tumor shrinkage within days of
starting this therapy. The following year, researchers confirm the drug also substantially improves
survival. However, trials are ongoing to determine why the cancer eventually stops responding to this
novel drug after several months.
2010 Bevacizumab significantly delays progression of advanced ovarian cancer
A large study finds that adding the targeted drug bevacizumab (Avastin) to initial chemotherapy
treatment, and then using it as longer term “maintenance” therapy, significantly slows the spread of
the disease in women with cancer in their ovaries and surrounding tissue. Bevacizumab is designed to
interfere with the growth of blood vessels needed to fuel a tumor’s growth – a process called
angiogenesis. The drug continues to be studied to determine its optimal use and whether it actually
extends the lives of women with ovarian cancer.
2011 Leukemia
Adding rituximab extends survival for chronic lymphocytic leukemia
A large, long-term trial establishes that adding the targeted drug rituximab (Rituxan) to initial
treatment with the standard drug fludarabine (Fludara) slows the progression of chronic lymphocytic
leukemia, and improves survival. This is the first drug regimen ever found to significantly extend the
lives of patients with the disease. The trial found that more than 10 percent of patients treated with
this regimen had no disease progression after ten years.
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