Retreating with an EGFR TKI after Acquired Resistance?

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Retreating with an EGFR TKI after Acquired Resistance?

http://blog.lungevity.org/2012/07/02/re ... esistance/

July 2nd, 2012 - by Dr. Jack West

I recently wrote about the concept of treating beyond progression with an EGFR tyrosine kinase inhibitor (TKI) or another targeted therapy, such as an ALK inhibitor, at the time of first progression in patients with a driver mutation (“acquired resistance”). My key takeaway was that such patients can have a cancer that develops a partial rather than complete resistance. Here, a subgroup of the cancer cells might still be quite sensitive to the targeted therapy, which leads to the idea that the optimal strategy might be a combination of a new treatment (typically chemo-based) to address the targeted therapy-resistant subset of cancer cells, along with ongoing targeted therapy for the cancer cells that remain sensitive to it. One other factor, however, is that if a patient has an interval without the targeted therapy, will this lead to a change in the relative proportion of cancer cells sensitive to the agent again? Is it beneficial to “re-challenge” patients with the same targeted therapy on which a person demonstrated progression?

There are definitely cases of responses with an EGFR TKI after someone has progressed after time off of it, though we really haven’t had any systematic studies of the question. We didn’t get any definitive answers from this year’s ASCO, but we did at least get a couple of reports that looked retrospectively at populations that could help us think about the question with a little more insight.

One of these was presented by Dr. Stephanie Heon from the Dana Farber Cancer Institute and pooled patient results from the other Harvard hospitals Brigham & Women’s Hospital, & Massachusetts General Hospital as well. They looked at a cohort of 24 patients collected from a period extending back nearly a whole decade (9.5 yrs) who had an activating EGFR mutation and who had been retreated with an EGFR TKI after a break from it. In this group, the investigators saw a response rate of 4% (1 patient of the 24), though 2/3 demonstrated at least stable disease initially. They saw a progression-free survival (PFS) of 3.3 months for the retreatment, which is the same PFS seen with afatinib in the LUX-Lung1 trial in patients previously treated with an EGFR TKI. As we might expect, the patients off of an EGFR TKI for a longer interval, in this case longer than the median of 5 months, had a longer PFS (4.4 vs. 1.9 months) than those off of an EGFR TKI for just a very brief interval.

Investigators from Kobe, Japan also reviewed the benefit of retreatment with an EGFR TKI, studying 73 patients with an EGFR mutation who had developed progression. They compared the overall survival (OS) for the 56 retreated with an EGFR TKI with the outcomes of the 17 who did not. These investigators noted that the patients who went back onto EGFR TKI therapy had a significantly longer OSl (with a more than doubling of the median OS, from 10.4 mo to 22.6 months). Moreover, this variable was among the most significant ones in a multivariate analysis of factors that could potentially be associated with OS. Unlike the Boston series, their population didn’t demonstrate a significant association of greater benefit with the length of the interval off of EGFR TKI; however, the median interval here was only 34 days. Several patients were actually off treatment for only a few weeks as they received radiation for new brain metastases. So with such a short interval for many of these patients off of an EGFR TKI, I’m not sure this really addresses the question of the value of retreatment after potential resensitization to the EGFR TKI; instead, if a patient goes back after just 2-3 weeks off, this may just underscore that there is still value in the targeted therapy after the first signs of progression (i.e., not really very different from the “treat beyond progression” concept that I described in my last post).

In the end of that last post, I also described a trial being led by Dr. Leora Horn that will include retreating patients with acquired resistance with an EGFR TKI after progression on chemo alone. Therefore, this trial will directly and prospectively test “ongoing treatment beyond progression” with “retreatment after a break”. But whichever of these strategies might be best, I think it’s telling that they both include continuing the targeted therapy in some way after initial progression, highlighting the growing consensus among the experts that you often don’t exhaust the benefit of a targeted therapy at that early point of first progression. For now, my personal strategy in this kind of setting is to recommend continuing the targeted therapy if the progression is relatively slow and the disease burden is less than the person started with, but to discontinue it and consider trying retreatment later if we’re seeing more rapid progression.

But that perspective can be modified by actual data to address this question, and we’re starting to do those trials now.