EGFR inhibitors: Iressa, Tarceva, and Erbitux (gefitinib, erlotinib, and

Property	Information
Drug Name	EGFR Inhibitors (Tarceva, Erbitux) in combination with Stupp Protocol
FDA Approval	Yes, for other cancer types; off-label for GBM
Used for	Glioblastoma Multiforme (GBM), particularly with EGF receptor overexpression or mutation
Clinical Trial Phase	Varied; includes studies with mixed outcomes
Clinical Trial Explanation	Not specified
Common Side Effects	Specifics depend on individual drugs; can include rash, diarrhea, and potential infusion reactions
OS without	Median survival with standard Temodar protocol: approximately 14.1 months
OS with	Median survival with Tarceva addition: ranges from 15.3 to 19.3 months in studies, though one study showed only 8.6 months
PFS without	Not specified
PFS with	Improvement noted when EGFR inhibitors used in combination treatments, though highly variable
Usefulness Rating	3
Usefulness Explanation	EGFR inhibitors show potential when combined with standard treatments, suggesting a tailored approach based on genetic profiling of tumors may enhance efficacy. However, variability in outcomes indicates a need for further research and careful patient selection.Property "Has Usefulness Explanation" (as page type) with input value "EGFR inhibitors show potential when combined with standard treatments, suggesting a tailored approach based on genetic profiling of tumors may enhance efficacy. However, variability in outcomes indicates a need for further research and careful patient selection." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.
Toxicity Level	2
Toxicity Explanation	While generally well-tolerated, EGFR inhibitors can cause specific side effects, their severity depending on the drug and individual patient factors.

From Ben Williams Book: The effectiveness of EGFR inhibitors like Tarceva and Erbitux for GBM treatment appears contingent on a combination approach and the genetic characteristics of the tumor, specifically EGFR overexpression and mutations in PTEN and PKB/AKT. Initial results suggest a moderate improvement in survival rates compared to standard protocols alone, but outcomes vary significantly. This underscores the importance of personalized medicine in GBM treatment, potentially enhancing effectiveness through the strategic combination of targeted therapies with established protocols. Further study is needed to refine these approaches and better predict patient response based on tumor genetics.Property "Has original text" (as page type) with input value "The effectiveness of EGFR inhibitors like Tarceva and Erbitux for GBM treatment appears contingent on a combination approach and the genetic characteristics of the tumor, specifically EGFR overexpression and mutations in PTEN and PKB/AKT. Initial results suggest a moderate improvement in survival rates compared to standard protocols alone, but outcomes vary significantly. This underscores the importance of personalized medicine in GBM treatment, potentially enhancing effectiveness through the strategic combination of targeted therapies with established protocols. Further study is needed to refine these approaches and better predict patient response based on tumor genetics." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.

Loading comments...

These three drugs, which have FDA approval for several different types of cancer, have the common feature that they target a growth-signaling channel known as the epidermal growth factor. Overexpression or mutation of EGF receptors is involved in the growth many different kinds of cancer, including more than half of glioblastomas. In general, use of these drugs as single agents has produced disappointing results, although occasional long-term survivors have occurred. More promising results have occurred when EGFR inhibitors have been used in combination with the Stupp protocol.

When Tarceva has been added to the standard Temodar protocol for newly diagnosed patients, median survival was 15.3 months (N=97) in one study (72) and 19.3 months (N=65) in a second study (73). The results of the second study were compared to two previous phase II trials involving a similar patient population, in which Temodar was combined with either thalidomide or accutane. Median survival for those trials was 14.1 months.

The moderately positive results of the just described trial are in conflict with a very similar trial (N=27) conducted at the Cleveland Clinic (74). In that trial median survival was only 8.6 months, notably worse than the outcomes obtained when temodar has been used without tarceva. How the conflicting results can be reconciled is unclear.

Erbitux (also known as cetuximab) is a monoclonal antibody, which differs from Iressa and Tarceva, which are small molecules, Because monoclonal antibodies are not believed to cross the blood-brain barrier, the natural expectation is that Erbitux would be ineffective against brain tumors. As a single agent, this seems to be true, as PFS-6 was only 10% for patients with recurrent high-grade gliomas (75). But when Erbitux was added during the radiation phase of the standard temozolomide protocol for 17 newly diagnosed patients (76), 87% of patients were alive at the end of one year and 37% were progression free. The median survival time had not been reached at the time of the report (an abstract at a meeting). It is possibly important to note that some investigators believe that radiation temporarily disrupts the blood-brain-barrier, which would allow a monoclonal antibody such as erbitux to reach the tumor.

An important development for identifying patients likely to respond to Tarceva has come from a study (77) of glioma patients whose tumor pathologies were also assessed for their levels of a second protein called PKB/AKT. This is a signaling channel that results from inactivation of the PTEN gene, a tumor suppressor gene commonly mutated in glioblastomas. None of the tumors with high levels of PKB/AKT responded to treatment with Tarceva, whereas 8 of 18 tumors with low levels did respond to the treatment. A refinement of this approach tested for three different proteins: expression of PTEN, expression of EGFR, and of a mutation of the EGFR protein known as EGFR variant III (78). The level of EGFR was not related to clinical outcome, whereas the co-expression

of EGFR variant III and PTEN strongly predicted clinical outcome.

Because the inhibition of PKB/AKT should plausibly increase the effectiveness of EGFR inhibitors, a treatment strategy now being tested is the combination of EGFR inhibitors with rapamycin (trade name rapamune, generic name sirolimus), an existing drug used for organ transplants to suppress the immune system and prevent organ rejection, but which also inhibits mTOR complex 1, a tumor growth promoter downstream of AKT. A phase I trial (79) combined Iressa with rapamycin for 34 patients (25 GBM) with recurrent tumors; two patients had a partial tumor regression and 13 patients achieved stable disease. PFS-6 was 24%. A second clinical trial (80) with 28 heavily pretreated patients with low performance status (median Karnofsky score of 60) received either Iressa or Tarceva in combination with rapamycin, with the result that 19% of patients had tumor regression while 50% had stable disease, with a PFS-6 value of 25%. Yet a third clinical trial (81) that combined tarceva and sirolimus for recurrent GBM had much worse results, with PFS-6 value of only 3%.

The foregoing results of the use of EGFR inhibitors for GBM treatment range from moderately positive to minimal efficacy. The reasons for this variability are not obvious, although treatment efficacy is likely dependent on numerous genetic markers. Thus, without a genetic analysis of individual tumors, it is hard to see a basis for recommending their use.

One recent paper (83) of potential major importance has noted that tumors may not respond to anti-EGFR drugs because of activation of the gene for a second growth factor known as the insulin-like growth factor receptor I (IGF1R). IGF1R has also been implicated as a source of resistance to tamoxifen and various other treatment agents. It is noteworthy, therefore, that two of the supplements to be discussed, silibinin and lycopene, are known to inhibit IGF-I. This suggests that silibinin and lycopene might substantially increase the effectiveness of any treatment that relies on EGFR inhibition. Metformin, a widely used diabetes drug, is also known to reduce the level of IGF-1, currently is under investigation as a treatment for several different kinds of cancer.

An important issue is how the effectiveness of EGFR inhibitors are related to the findings discussed earlier that metronomic schedules of Temodar produce a large survival improvement for GBMs that have EGFR overexpression. All of the clinical trials discussed in this section used the standard Temodar schedule, so it is unclear whether a metronomic schedule might produce different outcomes. }}