The story of Erbitux: in medicine and outside medicine

While having lunch with Dr. Bruce Sheng-Dean Luo (羅盛典醫師, an ENT doctor who was leaving UPMC to go back to Taiwan then) yesterday [1/18/2014] he mentioned Erbitux, which is a very interesting biologic (or biological) that is worth talking about in many aspects, medicine or otherwise.

Soon [today is 3/27/17] another ENT doctor, Dr. Chun-Yi Chuang ( 莊俊義醫師), who was also about to go back to Taiwan, leaving UPMC.  The head and neck surgery is Dr. Chuang’s specialty.  Erbitux has been used for head and neck cancer, thus it is time to revise this writing, considering my current reading interest is monoclonal antibody.

Erbitux is a biological, not a conventional chemical drug

Unlike conventional drugs, such as chemotherapy agents for cancers, the biologicals are made by living cells. Erbitux (cetuximab) is a biological, a monoclonal antibody [more about this later] that binds to the epidermal growth factor receptor, thus inhibiting the binding of epidermal growth factor (EGF), resulting in inhibition of cell growth.  This is how Erbitux is used, in combination of conventional chemotherapy, to treat certain types of cancers: colorectal cancers and head and neck cancers, and the off-label use (not officially approved by FDA) in several types of cancers.

Martha Stewart

Erbitux was developed by ImClone, a biotech company. It was rejected by FDA in 2001, at which time the CEO and his friend, Martha Stewart, sold the shares the day before the news of FDA rejection was announced, for which they went to jail.  Martha Stewart was actually never prosecuted for insider trading, but for lying to the investigators; it is a crime to lie to the government officials.

Merck (“German Merck”, not to be confused with Merck, USA), a partner of ImClone, conducted another clinical trial and obtained FDA approval to treat colorectal cancer, metastatic, KRAS wild-type (without mutation) in 2004.  It was approved for the head and neck cancer in 2006, the first such medicine in 45 years.

There were 329 patients in the study, leading to 2004 FDA approval. Erbitux, when used in conjunction of standard chemotherapy, 23% of patients responded and tumor growth was delayed by 4.1 months.  When used alone, the response rate was only 10.8%, delaying tumor growth by 1.5 months only.

Biologicals, especially monoclonal antibodies, are where money is

This doesn’t sound very impressive, but enough to become a potential “blockbuster”, the stock price began to climb again, from below $20 a share, all the way up to $60s, and way passing the price Martha Stewart sold (in the $40s).  ImClone was bought by Eli Lilly at $70 a share in 2008. Bristol-Myers Squibb initially offered $60 a share; it was a bidding war then; all for the only product of the company—Erbitux.

Carl Icahn acquired a majority of stock and became the chairman of the board in 2006.  He paid $30 a share on average (he boasted saying he paid $20/share) and it was $70/share when the company was bought.  One cannot but respect this seasoned billionaire investor.

For a $200 million gift, Mount Sinai School of Medicine is now the Icahn School of Medicine at Mount Sinai.

Believe it or not, the era of personalized medicine (based on one’s genes) is upon us.  Erbitux is another example.  There was an important article at New England Journal of Medicine (4/2/2009), “Cetuximab (Erbitux) and chemotherapy as initial treatment for metastatic colorectal cancer”, in which it was reported that the benefit of Erbitux is only seen in the patients who have a “wild type” (i.e. normal with no mutation) KRAS gene.

This is a very important advance.  A genetic test will be done on the cancer tissue, the patients with a mutated KRAS gene (about 40% of the patients with colon cancers), Erbitux will not be given, thus are spared for the potential adverse effects.

This genetic test may give Erbitux an upper hand on the ongoing war between Erbitux and Avastin (bevacizumab—a vascular endothelial growth factor inhibitor, also a monoclonal antibody) for colorectal cancer.  Both products can command billion dollars sales a year.  Roche paid big bucks for Genentech, mainly because of Avastin and other biologicals blockbusters, the likes of Rituxan (rituximab) and Herceptin (trastuzumab), all of them monoclonal antibodies.

Omnipresent, omnipotent monoclonal antibodies

Monoclonal antibodies are tailor-made proteins that seek out and attach themselves to specific molecules, such as certain proteins on the cell surface.  Monoclonal antibody is produced through recombinant DNA technology.  One way to do it is first identify the gene that makes a specific antibody, then insert the genes into viruses, which infect bacteria.  The infected bacteria then produce antibodies faithfully. 

Dr. George Kohler and Dr Cesar Milstein produced the first monoclonal antibody, for which they’re awarded the Nobel Prizes in 1984.  “Theoretical work that would lead to the production of monoclonal antibody started in the early 1970s, but the New York Times would not mention the term until May 1, 1979.”  NY Times so reported in a regrettable tone in an 10 Oct. 2012 article.

Stanley Cohen: My American idol, my American hero
Another related story tells how great Stanley Cohen is.

Stanley Cohen

The discovery of restriction enzyme (so that DNA can be ‘cut’ open) by Stanley Cohen and Herbert Boyer paved the way for Paul Berg to develop recombinant DNA technology.  Genentech was founded on the knowledge of the discovery of restriction enzyme and recombinant DNA technology.  Herbert Boyer and Robert Swanson (the venture capitalist) were the cofounders.  Somehow Stanley Cohen didn’t participate, losing the chance to make a fortune when La Roche bought Genentech for 46.8 billion in 2009. 

Stanley Cohen went on to get his Nobel Prize for the discovery of the epidermal growth factor in 1986; he shared with Rita Levi-Montalcini, who died at age of 103 in 2012.  Cohen went to work with Rita Levi-Montalcini, who first discovered nerve growth factor.  Cohen subsequently discovered the epidermal growth factor; little did he, or anyone else, know that his discovery will one day make a huge impact on clinical medicine.  At age of 93 now, Stanley Cohen must be very gratifying in seeing his work bearing the fruits.

Seeing former President Jimmy Carter doing so well is the most gratifying moment of the Presidential inauguration

I cannot talk about the Presidential inauguration without mentioning science/medicine.  After talking about the most gracious moment of the day, seeing former President Jimmy Carter doing so well is the most gratifying moment.

In August 2015, 90 years old then, Carter announced he had metastatic melanoma that spread to the liver and brain.  It must have been detected (as far as the size of brain metastasis is concerned) as it said “four extremely small spots, about two millimeters in size.”

From my readings I never found out where was the primary melanoma, which can be tricky or even disappeared before the metastasis was detected.

Carter underwent surgery to remove the liver tumor in August 2015, followed by stereotactic radiation therapy, which delivers a strong beam of radiation with precision to the four tiny spots in his brain, thus avoiding the “collateral” damage to the nearby healthy brain.

One has to presume Carter might have other “micro-metastasis” in the brain or liver or other organs of the body that cannot be picked up by any image studies.  According to Dr. Keith Flaherty, Director of Termeer Center for Targeted Therapy at Massachusetts General Hospital (MGH), Carter received Pembrolizumab (or Keytrude marked by Merck).

Keytruda (Pembrolizumab) embodies the ingenious immunotherapy, expanding the powerful arsenal against cancer.

Keytruda is an anti-PD-1 monoclonal antibody (the concept of programmed death or PD-1 is beyond the scope of this writing).  Cancer activates brakes to the immune system; thus suppresses our immune system to attack cancer.  Keytrude inhibits the action of those brakes, reverses immune T-cell suppression and induce anti-tumor responses; this is the basic concept of cancer immunotherapy.

Normally activation of PD-1 receptor/pathway leads to programmed death, so it is negative regulation.  Keytrude binds to PD-1 receptor (thus PD-1 ligand cannot bind to it) on immune T cells, thus inhibits programmed cell death-1 (PD-1) activity.  Removing this suppression sets immune T cells free to do its job of attacking the cancer.

PD-1 (or PD-L1, PD-ligand 1) also has synergy with radiation therapy.

Keytrude (approved in Sept 2014) is the 6^th new anti-melanoma agent FDA approved since 2011.  A Wall Street Journal reported (5/19/16) 40% of 655 patients still alive 3 years after taking Keytrude; it used to be 10-20%.

The most famous Sunday School teacher (Carter never retired from this job) announced in his Bible lesson class at Maranatha Baptist Church in his hometown of Plains, Georgia on 12/7/15 that his latest scan showed no sign of cancer, he said, “When I went this week, they didn’t find any cancer at all, so I have good news.”  Glory to God!