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Acquired Resistance to Oral EGFR Inhibitor Therapy: Should t


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Acquired Resistance to Oral EGFR Inhibitor Therapy: Should the Targeted Therapy Continue Beyond Progression?

June 24th, 2012 - by Dr. Jack West

http://blog.lungevity.org/2012/06/24/ch ... tki-at-ar/

While we typically see a very good response in patients with an activating EGFR mutation who receive an EGFR tyrosine kinase inhibitor (TKI), unfortunately we pretty much invariably see progression months or sometimes years later. Often the pattern is that a CT shows that that a few existing lesions are progressing at an indolent pace, but patients often still have overall less disease than they started with before the EGFR TKI, even after some time with slow progression. At some point, the progression is enough that we feel we need to make a change and start a new treatment to counter the progression. The most common strategy at that point is to start chemo, most typically the same kind of treatment you’d give to someone with advanced NSCLC if they didn’t have an EGFR mutation. And we then face a central question: do we continue the EGFR TKI, combined with chemotherapy, or do you discontinue the EGFR TKI and say it’s just time to move on?

Classically, oncologists have been taught to discontinue anticancer therapy and not look back when someone progresses on a treatment. When your cancer becomes resistant to a treatment, we’ve presumed that there isn’t a benefit to returning to it. But we historically haven’t had treatments that work against a critical “driver mutation”: for these targeted therapies, we can envision a model of a mixed picture (as illustrated above in a figure from Oxnard et al., Clin Cancer Res, 2011) of some cancer cells still responsive to the targeted therapy, even as a subset of cancer cells are becoming resistant and multiplying. This leads to a mixed picture of progression alongside other areas of still controlled disease. When we add a new angle of treatment (typically chemotherapy) to treat the resistant disease, should we continue the targeted therapy to treat the portion of the cancer that is still sensitive?

It’s worth noting that a minority of EGFR mutation patients with acquired resistance can experience a sudden rapid progression of their disease (sometimes referred to as a “disease flare”) at the time of discontinuation of the EGFR inhibitor, even if they were progressing on it already. In fact, some work from Memorial Sloan-Ketting Cancer Center in NYC have seen that up to 20-25% of patients discontinuing an EGFR mutation after prior response can experience a tumor flare that leads to hospitalization or even death. Though I think that fraction is on the high side compared with what I and many other colleagues actually see in the clinic, it’s a real possibility that you can sometimes see. I think of this as the concept that “bad brakes are better than no brakes”.

At ASCO a few weeks ago, researchers from Massachusetts General Hospital, Dana Farber Cancer Institute, and Brigham & Women’s Hospital reviewed results from a retrospective analysis of 78 patients in Boston with an EGFR mutation and who received either chemo alone (44 patients) or chemo with ongoing EGFR TKI (34 patients) at the time of acquired resistance. They reported a significantly higher response rate in recipients of chemo/EGFR TKI compared with chemo alone (41% vs. 18%) but no real differences in either progression-free or overall survival. Overall, the findings are limited by being retrospective (there may have been significant differences for why some patients was recommended to receive one approach vs. another), but they at least suggest that at least there isn’t any detrimental effect from the combination of chemo with ongoing EGFR TKI therapy. There may, in fact be a beneficial effect, but that will need to be clarified by prospective studies.

Fortunately, there actually are a couple of prospective trials now that have been designed to answer this question directly. First, the IMPRESS trial, being conducted outside of the US, is enrolling patients with an activating EGFR mutation who demonstrate progression after prior treatment with the EGFR TKI Iressa (gefitinib). They are then randomized to cisplatin/Alimta (pemetrexed) chemo alone or with ongoing Iressa, so the schema as shown below: (click the link above to view image)

Dr. Leora Horn from Vanderbilt is running a similar trial with Tarceva (erlotinib), and with the chemotherapy being either cisplatin or carboplatin with Alimta. The key difference that I see with the US trial is that it incorporates mandated re-treatment with Tarceva in patients assigned to chemotherapy alone and then progress. Will switching away from an EGFR TKI and starting chemo, then going back to the EGFR TKI be as good, better, or worse than just continuing the EGFR TKI with the start of chemo?

This issue of the potential value of re-treatment with an EGFR TKI is another big one, and I’ll turn to it and a little new work from ASCO on this topic in my next post.

Look for that soon.

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