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Combining Systemic Targeted Therapy with Old School Targeted

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Combining Systemic Targeted Therapy with Old School Targeted Therapy (Radiation) to Address Cancer Cell Resistance

http://blog.lungevity.org/2012/04/14/rt ... esistance/

April 14th, 2012 - by Dr. Jared Weiss


We’ve spoken at length about EGFR and related mutations such as EML4/ALK and ROS1 on GRACE. For those who are not familiar with these subjects, I will refer you to podcasts from my recent webinar for a summary on the most recent data on EGFR, EML4/ALK and ROS1:

(Click link above to view the data links below)

http://cancergrace.org/lung/2012/03/15/ ... egfr-axis/

http://cancergrace.org/lung/2012/03/18/ ... r-targets/

Following the webinar was a Q&A session in which there were several questions about the setting of acquired resistance, where patients become resistant to a targeted therapy after an initial very good response. When Dr. West asked if, in my opinion, there was one strategy that was particularly promising, I couldn’t resist the bait and mentioned a trial I’ve been developing based on a good deal of thought and research I’ve dedicated to the subject. Here, I’d like to review the rationale for the strategy for a setting like acquired resistance to EGFR inhibitor therapy and how amenable this approach will be to new mutations, such as ALK and ROS-1 rearrangements.

The Strategy:

(Click on link above to view image)

The basic idea is to take patient whose cancer has grown on an EGFR inhibitor like Tarceva (erlotinib), use focal radiation to treat the spots that have grown, in order to eliminate the resistant clones, then continue using Tarceva for the rest of the cancer that has shown evidence for ongoing sensitivity to this treatment.

Progression of patients with EGFR mutation on tarceva

When cancer progresses during chemotherapy, it typically grows in multiple spots and generates new areas of disease. In contrast, when EGFR-mutated lung cancer grows through Tarceva, it’s common to see it progress only in one or two spots. Recent research has demonstrated some of the mechanisms of this resistance, as discussed in Dr. Lecia Sequist’s webinar.

The key point is that progression is often limited, with a new resistance mechanism potentially in just one area. Often, most of the cancer cells remain sensitive to Tarceva while one or two spots acquire some change (with “some change” partially defined in the figure above and in Dr. Sequists’s webinar). So if you might eliminate those few spots of resistance, it’s easy to imagine that the cancer in the rest of the body can still be effectively controlled on Tarceva.

Why radiation for minimal progression?

There are actually several trials that have tried to cure patients with cancer spread to only a few sites (called oligometastatic spread, from the oligo root meaning “few”). Dr. Mary Pinder previously described the idea of treating with radiation possibly with curative intent in this setting, and it was actually her post that initially got me thinking about the strategy that led to this trial.

Dr. Pinder showed data from the University of Rochester, a report of the research on 49 patients with a total of 125 metastatic lesions were treated with radiation, resulting in a crude local control rate (control at the spots radiation was given) of 94%.

I explored the research on the question further and unearthed a trial specific for lung cancer, treating patients with only 1-2 sites of metastatic spread:

And I found research of a similar theme for other cancers. I don’t intend to generally address oligometastatic cancer here (though it’s an interesting topic that I leave for another day). These studies, however, along with others that I haven’t cited here, illustrate that it is feasible to pursue stereotactic radiosurgery like Cyberknife to a limited number of sites and expect to see high rates of controlling cancer at those sites, with minimal risk of serious complications.

Why focus on acquired resistance in patients with an EGFR mutation?

well, one practical reason was that at the time I was going over these ideas, the EGFR mutation was the only “druggable” molecular marker with an FDA approved therapy. But the rationale for starting with EGFR actually has justification beyond the merely practical. First, laboratory data actually demonstrate higher radiation sensitivity for EGFR mutated lung cancer cells compared to other lung cancer cells. Importantly, this includes EGFR mutated cells that have acquired the T790 resistance mutation, the most common known mechanism, seen in about half of all cases of acquired resistance:

But what really gave me new momentum was new research I saw human data at ASCO, 2010. Clinical researchers from Dana Farber Cancer Institute reviewed their outcomes after chest RT between EGFR mutant and wild-type (non-EGFR mutant) tumors in a retrospective cohort of patients with locally advanced NSCLC:

(Grey curve EGFR mutant, Black curve EGFR Wild-Type)

These findings suggest that radiation may be a particularly effective treatment for patients with EGFR-mutated lung cancer.

What about other mutations?

I am hoping that the trial for second line treatment of patients with an EGFR mutation that I briefly described above, which is being funded by Astellas (the makers of Tarceva), will become active at my own center (University of North Carolina at Chapel Hill) this coming week. But Dr. West also recently asked about the extension of this idea to other molecular markers, such as EML4/ALK and ROS-1, as patients with each of these can have dramatic and prolonged responses to these before developing acquired resistance (at least for an ALK rearrangement — it’s still too early to say anything definitive about ROS-1). I have also been thinking about this idea and think it sufficiently promising that I’ve brought the idea up with a very smart clinician scientist from Pfizer (the makers of the ALK inhibitor XALKORI (crizotinib)) and have sent him the protocol for the EGFR-mutated trial to suggest doing something similar with XALKORI. There are, however, a few important differences. First, we don’t have a large bulk of experience with progression of patients with EML4/ALK or ROS1 on XALKORI to know if their progression is frequently limited to a few sites the way it often is with Tarceva in patients with an EGFR mutation. Second, we know very little about the relative radiosensitivity of patients with these other genetic changes: do they share the apparent radiosensitivity of EGFR mutation-positive cells/patients, do they show actual radioresistance, or neither? Finally, a caveat to the last point: given the high rate of local success with a stereotactic radiation approach like Cyberknife, does radiosensitive really matter? In other words, even if a particular mutation renders cells radioresistant, might Cyberknife overcome it? Ultimately, we will need clinical trials to truly answer these questions — and I promise to keep working to provide those answers.

Disclosures: I hope that my conflicts of interest here are already plainly stated: 1) Astellashas funded my study for EGFR mutants, and I am proposing a similar study to Pfizer.

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