This post, on FDA-approved small-molecule targeted therapies for cancer, seems like a homework assignment of sorts. But really I found it a useful exercise and hope some readers might find it so, too. In searching the Web, I found remarkably little on this that’s public-domain, comprehensive and organized. In fact, there seems to be a lot of confusion about what these drugs are and how these differ from conventional, cytotoxic chemotherapies.

Some historical perspective:

Before 1970, few people received chemotherapy. Even with a cancer diagnosis, most treatments were surgical and radiation-based. A few older agents, chemotherapy pills such as chlorambucil and melphalan were given by mouth. From 1970 until 2000 (more or less), the thrust of most new cancer treatments involved stronger and sometimes more effective combination chemotherapy regimens. Almost all of those new treatments were given by intravenous (IV).

One point here that’s relevant to health care reform and the current debate on physician payments is that as things stand, oncologists and medical centers make money by giving IV infusions. Each treatment is billed as a procedure, apart from the cost of the medication in itself. So if patients can take a drug without a catheter, it might be less costly – there’s no nurse to hire, no catheter to purchase and insert and there’s no billing for an infusion per se.

And there’s less cost to the patient in terms of hassle and some untoward effects of IV treatment. With oral drugs (capsules, pills or tablets – anything taken by mouth) there’s no need to go to the doctor’s office or medical center every week or every other week, or even daily as is prescribed for some chemo regimens. There’s no need to have one’s arms shot up or a permanent, dangling catheter inserted. There’s no attendant risk for infection from an IV or semi-permanent catheter.

Reality check: most effective cancer drugs are not available in pill form, and for the most part these targeted treatments are in their infancy. But their number is expanding, so much so that most of the cancer pills I’m about to list have been approved only in the past five years.

Take further note: these are toxic drugs. Targeted therapies are designed, in principle, to kill malignant cells while leaving normal, healthy cells alone. Unfortunately, the effects of the medications listed below are broader than would be ideal. In general, these pills take aim at molecules that are over-active in cancer cells. But most of the affected enzymes are present in regular, healthy cells, too.

Here’s a list of small-molecule, oral drugs that target cancer cell enzymes and have received Food and Drug Administration approval prior to March 9, 2010, in order of approval:

1. Gleevec (imatinib, STI-571) was the first drug in this class to receive FDA approval. It counteracts an abnormal enzyme, a tyrosine kinase, that’s active in chronic myelogenous leukemia (CML) cells. The malignant tyrosine kinase, bcr-abl, arises in most cases from a chromosomal switch, called the Philadelphia Chromosome.

It turns out this drug works, also, against another tyrosine kinase, one related to a cell surface receptor protein called c-kit that’s mutated and activated in many Gastrointestinal Stromal Tumors (GIST). In 2002 the FDA approved use of Gleevec for GIST tumors in “c-kit+” tumors, meaning GIST cancers in which the c-kit receptor is mutated.

Since then the drug’s been approved for additional uses, only in some and quite specific circumstances, for adults with acute lymphoblastic leukemia (ALL) in which the malignant cells harbor the Philadelphia Chromosome (Ph+) and for some patients with other, mainly rare blood disorders in which particular genetic changes are established. (Novartis, May 2001)

2. Tarceva (erlotinib). This drug is also a tyrosine kinase inhibitor and is thought to act primarily by blocking growth signals of the Epidermal Growth Factor Receptor (EGFR). The drug was initially approved for use in some patients with non-small cell lung cancer and, more recently, for patients with pancreatic cancer. (Genentech, November 2004)

(Here I should mention Iressa (gefitinib) that was approved by the FDA early on for treatment of patients with advanced non-small lung cancer. Like Tarceva, Iressa has activity against EGFR-linked kinase activity and growth signals. The drug is no longer approved for most patients. AstraZeneca, 2003)

3. Sprycel (dasatinib). Like Gleevec, this targeted therapy blocks the bcr-abl tyrosine kinase activity in CML. The FDA approved this medication for CML patients whose disease progressed while on Gleevec (Gleevec-refractory CML) and for some adults with ALL in whom the malignant cells are Ph+. (Bristol-Myers Squibb, June 2006)

4. Sutent (sunitinib). Sutent is approved for use in metastatic kidney cancer and in GIST tumors that have progressed during treatment with Gleevec. It’s a fairly broad-acting tyrosine kinase inhibitor. (Pfizer, January 2006)

5. Tykerb (lapatinib). Tykerb is the only small-molecule drug that’s FDA-approved for use in some breast cancer cases. It blocks growth signals through Her2 (Her2/neu), a receptor tyrosine kinase that’s present on the surface of some breast cancer cells. The drug is approved for patients with metastatic breast cancer that’s Her2+ (meaning that the malignant cells display this molecule) and when it’s given in combination with Xeloda (capecitabine, an oral version of an otherwise conventional chemotherapy).

In January of 2010, the FDA granted accelerated approval of Tykerb in conjunction with Femara (letrozole, a hormonal therapy) in some patients with metastatic, Her2+ breast cancer in which the cells also express estrogen and/or progesterone receptors. (GlaxoSmithKline, March 2007)

6. Tasigna (nilotinib). This is the latest drug to tackle the bcr-abl tyrosine kinase activity in CML. It’s approved for adults with CML who have failed at least one regimen containing Gleevec. (Novartis, October 2007).

7. Nexavar (sorafenib). This therapy may not be targeted in the truest sense because its activity is so broad. It blocks receptor-linked tyrosine kinases such as those associated with Vascular Endothelial Growth Factor Receptor (VEGF-R) and Platelet Derived Growth Factor Receptor (PDGF-R). It inhibits other types of signaling enzymes inside cells, such as Raf-associated serine-threonine kinases.

The FDA has approved this drug for two groups of patients: those with advanced renal cell (kidney) cancer and those with liver tumors that can’t be removed by surgery.  (Bayer, November 2007)

8. Afinitor (everolimus) is in a slightly different class of drugs, in that it blocks mTOR (mammalian target of rapamycin, another sort of cellular enzyme). This drug is approved for use in patients with metastatic kidney cancer whose disease has progressed after Sutent and Nexavar. (Novartis, March 2009)

9. Votrient (pazopanib) blocks numerous tyrosine kinases and is the latest FDA-approved drug in this class. It’s approved for patients with advanced renal cell (kidney) cancer. (GlaxoSmithKline, October 2009)

Note to readers: other, oral targeted therapies are available that act by different sorts of mechanisms. I will cover those separately.

Several websites provide more information on so-called targeted therapies for cancer, including new intravenous treatments, monoclonal antibodies and some drugs that act by distinct mechanisms. Some of the sites I recommend for this topic include the National Cancer Institute and the American Society of Clinical Oncology’s Cancer.Net.

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