Alita - modest improval in survival in some lung cancer patients

Alita - modest improval in survival in some lung cancer patients

Tarceva is a "targeted" therapy, in that it halts the growth of certain
cancers by zeroing in on a signaling molecule critical to the survival of
those cancer cells. The drug is effective in about 10-15% of patients with
non-small cell lung cancer. The drug works specifically in patients whose
cancers contain mutations in a gene that encodes the epidermal growth
factor receptor (EGFR). Lung cancer patients with these mutations are
often people who have never smoked.

Although this targeted therapy is initially effective in this subset of
patients, the drug eventually stops working, and the tumor begins to grow
again. This is called acquired or secondary resistance. This is different
from primary resistance, which means that the drugs never work at all. The
change of a single base in DNA that encodes the mutant EGFR protein has
been shown to cause drug resistance. The story is the same as for Erbitux
and Iressa. Drug resistance evolves by multiple mechanisms.

Initially, tumors have the kinds of mutations in the EGFR gene that were
previously associated with responsiveness to these drugs. But, sometime
tumors grow despite continued therapy because an additional mutation in
the EGFR gene, strongly implies that the second mutation was the cause of
drug resistance. Biochemical studies have shown that this second EGFR
mutation, which was the same as before, could confer resistance to the
EGFR mutants normally sensitive to these drugs.

It is especially interesting to note that the mutation is strictly
analogous to a mutation that can make it tumor resistant. Non-small cell
lung cancer makes up about 80 percent of all lung cancers. Mutations in a
gene called KRAS, which encodes a signaling protein activated by EGFR, are
found in 15 to 30 percent of these cancers. The presence of a mutated KRAS
gene in a biopsy sample is associated with primary resistance to these
drugs.

Tumor cells from patients in a study who developed secondary resistance to
Tarceva after an initial response on therapy did not have mutations in
KRAS. Rather, these tumor cells had new mutations in EGFR. This further
indicates that secondary resistance is very different from primary
resistance.

All the EGFR mutation or amplification studies can tell us is whether or
not the cells are potentially susceptible to this mechanism of attack.
They don't tell you if Tarceva is better or worse than some other drug
which may target this. There are differences. The drug has to get inside
the cells in order to target anything.

EGF-targeted drugs like Tarceva are poorly-predicted by measuring the
ostansible target EGFR, but can be well-predicted by measuring the effect
of the drug on the "function" of live cells. An EGFRx targeted therapy
profile includes analysis of the following targeted drugs: Tarceva,
Iressa, Nexavar, and Sutent.

Literature Citation:
PLoS Medicine, February 22, 2005
Eur J Clin Invest 37 (suppl. 1):60, 2007

Alimta (pemetrexed) is a very promising drug. It is considered to be a
significant advance than other available treatments. Toxicity is
relatively low. It is not a "me too" drug, but is actually a third
generation drug of its kind.

Studies have shown that Alimta improves survival, albeit modestly,
compared with supportive care only.

Expense is horrendous though. If you fit into the subset of patients that
this drug works well with, I'm sure it will work well.
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From a lung cancer forum.
J