EGFR Inhibitors for Brain Metastases

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May 6, 2007 - 8:09 pm email to a friend printer friendly view / write comments

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Dr. West

  Inhibitors of the epidermal growth factor receptor (EGFR), such as Iressa (gefitinib) and Tarceva (erlotinib) are generally known for being often minimally toxic, oral, targeted therapies that can occasionally produce dramatic and long-lasting responses in a minority of patients and more modest, minor responses or prolonged disease stabilization in a larger proportion of patients.  They are not widely considered as a treatment for brain metastases, but there are many reports that describe responses, including prolonged ones, of brain metastases to Iressa or Tarceva.

  One of the earlier reports (abstract here) came from an Italian friend of mine from the global lung cancer community, Dr. Federico Cappuzzo, who described four patients who received Iressa alone, two having had prior whole brain radiation therapy (WBRT) and had partial responses in the brain, with one lasting up to 15 months, and another ongoing at 11+ months at the time of publication.  All of these patients also experienced improvement in their neurologic symptoms.  Since then, multiple case reports and small series have described responses of brain lesions in one or a couple of patients who received Iressa or Tarceva, including some patients heavily pretreated with chemo and brain radiation.  However, these don’t give a sense of how commonly those responses occur among patients who receive EGFR inhibitors.

    There have been a few studies that gave an EGFR inhibitor to several patients with brain metastases and reported their success rate.  One was from Ceresoli and colleagues in Italy (pdf of the full article free here), who described their experience of giving Iressa 250 mg by mouth daily as a phase II study to 41 patients as a second or third line therapy to patients with brain metastases from NSCLC.  Of these, 33 patients had received a prior platinum-based chemo doublet, and 18 had received WBRT.  They saw 4 patients (10%) achieve a partial response, and 7 more (17%) at least had stable disease in the brain, for a total disease control rate of 27%. One very good response is shown here:

 (click to enlarge)

While a response rate of 10% in the brain is about what you’d expect as a response rate in Europe or the US (that was the general response rate for Iressa in the US-based IDEAL-2 trial (abstract here), we’ve seen higher response rates in Asia.  In fact, the work from Asian on EGFR inhibitors for brain metastases has demonstrated greater benefits there.  Hotta and colleagues from Japan reported on a retrospective review of 57 patients who received Iressa for NSCLC (abstract here), of whom 14 had brain metastases.  Of those 14, one had a complete response, 5 had a partial response, and the other 8 showed stable disease in the brain.  Interestingly, 7 of those 14 patients also responded outside of the brain, including all six who responded in the brain (86% concordance).  Another trial from Taiwan (abstract here) gave Iressa to 76 patients with brain metastases, of whom 57 had measurable disease; they saw a response rate in the brain of 33%, and 63% with stable disease, with a median progression-free survival of 5 months and median survival of 10 months.  Finally, in a group of patients particularly selected to do well with an EGFR inhibitor, Lee and colleagues from Korea studied Iressa in 37 never-smokers there (abstract here) produced a response rate of 69% overall, but it also produced responses in the brain for 7 of 10 patients with metastases there.  This impressed me enough that I made note of it in a slide I made last year to discuss the potentially very striking benefits of EGFR inhbitors in selected populations like never-smokers or those with EGFR mutations:

All seven of these responses in the brain were in patients who also responded outside of the brain.  Another of those 10 patients with brain metastases had stable disease in the brain and a partial response outside of the brain, while the last two progressed both inside and brain and elsewhere.

  You’ll note that these reports are with Iressa, but similar case reports have come out with Tarceva as well.  However, Iressa came into wide use first, so the work on brain mets has also emerged with Iressa first, and Iressa is still the standard EGFR inhibitor in Asia, where some of the most impressive results with EGFR inhibitors has originated.

  Finally, there has been a little bit of study that has shown that the levels of EGFR inhibitor (Tarceva in this case, along with its active metabolite) in the cerebrospinal fluid surrounding the brain is only in the range of 10% of the levels in the blood (abstract here).  However, it’s not clear how to interpret this.  As shown above, patients seem to show response rates in the brain that are similar to the response rates outside of the brain with EGFR inhibitors, and it is generally in the same patients who respond outside of the brain.  So without more information to support it, it’s hard for me to see the appeal of escalating the dose of Iressa or Tarceva in an effort to generate responses in the brain, especially since these agents reach a dose-limiting toxicity of not far above where they are routinely used.  But taken together, the small studies do suggest that in some patients, EGFR inhibitors can be an effective treatment for brain metastases, including patients who have already received WBRT.

Posted in: Epidermal growth factor receptor (EGFR)-based therapies, First-line treatment, Lung Cancer, Management of Brain Metastases, Non-Small Cell Lung Cancer (NSCLC), Second-line treatment, Stage IV/Advanced/Metastatic NSCLC, Targeted therapies, Third-line therapy and beyond, Treatment                     email to a friend printer friendly