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Insights on “Acquired Resistance” to Oral EGFR Inhibitors

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Insights on “Acquired Resistance” to Oral EGFR Inhibitors: A Place for Local Therapy?

June 14th, 2012 - by Dr. Jack West

http://blog.lungevity.org/2012/06/14/in ... l-therapy/

At the huge ASCO conference that just ended, I reviewed and provided some commentary on several notable poster presentations on the theme of managing acquired resistance to EGFR inhibitors, the progression that develops after months or sometimes years of effective treatment with an oral EGFR tyrosine kinase inhibitor (TKI) in patients with a EGFR mutation that appears to be a key driver for their non-small cell lung cancer (NSCLC). Although the numbers of people in these reports are relatively small and not enough to provide a clear path to definitive treatment strategies, they at least offer a starting point for how to approach these issues, and perhaps some early insights.

Here, I’m going to focus on two questions:

1) Is a ”local therapy” such as surgery or radiation that is directed to a specific spot potentially valuable in patients with acquired resistance on an EGFR TKI or an ALK inhibitor like XALKOR (crizotinib)?

2) Is there reason to think that progression isolated to the brain repesents a “special case”?

I would make the point that there are really a few different subsets of patients who might all fit under the category of acquired resistance but are clinically distinct and should probably be treated differently:

-some people have good control of their cancer except for just a single area of progression or one new nodule

-others might have several areas of rather indolent progression, but they still have quite a bit less disease than they had prior to the start of the EGFR or ALK inhibitor

-still others have many areas of progression of cancer that is growing at a more significant pace

To try to address the first question, work from oncologists from Memorial Sloan-Kettering Cancer Center (MSKCC) assessed results from a small subset of the 184 with an EGFR mutation and developed acquired resistance there who were felt to be very good candidates for local therapy. Specifically, 18 of those 184 were treated with radiation or surgery, presumably because they demonstrated only a very limited extent of progression. The investigators from MSKCC excluded patients with brain metastases, noting that this is a group of people for whom local therapy (most commonly radiation) is already the standard approach. They found that this small subset of patients went a median of 10 months before they demonstrated further progression, a median of 22 months before showing enough progression to be felt to need further systemic therapy, and they had a rather excellent median overall survival from progression of 34 months.

(click on link above to view image)

What is most notable to me is that there are people with prolonged good results over a course of many years, even without further intervention beyond a local treatment for a limited area of progression, along with continuation of the same EGFR inhibitor therapy.

The results from University of Colorado were presented by Weickardt and colleagues, who reported on results from patients with either an activating EGFR mutation or ALK rearrangement. From their institutional review, 51 of 65 patients with an EGFR mutation or ALK rearrangement had demonstrated acquired resistance, and of these, 25 (49%) were treated with local therapy. The criteria for pursuing that approach was more liberal than in New York. At the University of Colorado, patients were felt to be appropriate for local treatment if they demonstrated progression in the brain (though excluding patients with leptomeningeal carcinomatosis) or progression in 4 or fewer sites outside of the brain. Patients in their local therapy group went a median of 4 months on ongoing targeted therapy before further progression if the initial progression was outside of the brain, while those with initial progression in the brain demonstrated a median duration before further progression of 7 months after local therapy.

The authors hypothesized that the better results for ongoing treatment with targeted therapy after “brain first” or “brain only” progression is because this situation might not represent a case of the cancer there actually being resistant to the current therapy, but rather that the drug levels of the targeted therapy at a standard schedule doesn’t penetrate into the central nervous system (CNS) well enough to fight cancer effective. In fact, limited evidence supports that idea that drug levels in the cerebrospinal fluid are too low to be effective. In fact, some data rfom researchers in Kobe, Japan that was also presented at ASCO also supports this hypothesis: they found that in patients with an activating EGFR mutation who underwent rebiopsy after progression in the setting of acquired resistance, the rate of secondary resistance T790M mutations was just 10% for CNS relapses vs. 60% rate of T790M mutations for progression in the rest of the body. In other words, progression outside of the brain is most often from real resistance, while CNS progression is much more likely to be not from selective pressure leading to resistance, but rather that the brain is a “sanctuary site” for cancer to grow without the treatment getting there.

The implication is that the EGFR TKI therapy can still be very effective against the disease it IS able to reach, while local therapy to the brain — generally radiation — can be used to treat the sanctuary site. This is why I do believe that it makes sense to approach progression in the brain first/brain only as a “special case” of acquired resistance that doesn’t necessarily suggest a patient should discontinue their targeted therapy.

I noted in my discussion that that it was notable with this strategy of continued targeted therapy and local treatment for progression was far better in the Memorial Sloan-Kettering experience, which I believe is because it was used in a much more limited group of patients – just 10% of those with acquired resistance, versus half of the patients in the Colorado experience. If there is a real benefit to local therapy, it’s probably for a rather selected group: applying it far more broadly will really dilute our ability to see a real benefit. Alternatively, these patients with very limited could just happen be the patients destined to do the best no matter what treatment they receive, so it may be selection bias more than anything else. In other words, the patients who are the best candidates for local therapy are the very ones who would do just as well if we did nothing other than ignore the slight progression until much later, and being a candidate for local therapy is the reason people do well, rather than actually getting the local therapy.

We’ll soon turn to the question of how to approach multifocal progression, and specifically what to do when it’s time to start chemotherapy: should the targeted therapy be continued concurrent with the chemo, or should patients take a break from targeted therapy and potentially benefit from re-starting it after an interval off of it.

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