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2 Very Different Recommendations, Molecular Testing in NSCLC


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Two Cancer Leadership Groups, Two Very Different Recommendations for Molecular Testing in Advanced NSCLC

http://blog.lungevity.org/2011/09/22/as ... c-testing/

September 22nd, 2011 - by Dr. Jack West

The American Society of Clinical Oncology (ASCO) released a set of revised guidelines for stage IV NSCLC just a few weeks ago that are notable for several reasons including the rather striking contrast they offer with the guidelines from the National Comprehensive Cancer Network (NCCN) for this population. Specifically, looking at molecular testing and subsequent individualized treatment options, they provide very different approaches to who to test and what to test for, which is among the most timely questions in lung cancer management today. This question is particularly timely in light of the approval of the ALK inhibitor XALKORI (crizotinib) by the FDA just a few weeks ago, since this agent will only be commercially available to the 4-5% of patients with NSCLC who test positive for an ALK rearrangement at the designated central lab approved along by the FDA. In this case, and for the first time in lung cancer, a drug’s approval is actually predicated on molecular testing for patients.

The NCCN guidelines, which were released earlier this year, suggest EGFR mutation testing for all patients with advanced/metastatic non-squamous NSCLC, with EGFR tyrosine kinase inhibitor (TKI) Tarceva (erlotinib) recommended as first line therapy for patients who are shown to have an EGFR mutation. Though ALK testing and crizotinib are not mentioned, this is not surprising, as the drug wasn’t approved at that time. My personal view of these guidelines is that they are slightly ahead of where the evidence lies, such as calling for anyone with non-squamous NSCLC to be tested, when people with a very significant smoking history would have a quite low, even if non-zero, chance of having an EGFR mutation (somewhere in the low single digits % range). Moreover, while many studies have now shown that people with an EGFR mutation have a consistently longer progression-free survival and response rate with first line EGFR TKI compared with first line chemo, there isn’t clear evidence that survival is worse if people with an EGFR mutation receive an EGFR TKI after first line (in other words, A + B = B + A). Because EGFR inhibitors are readily available regardless of smoking status or NSCLC subtype (in the US, at least), it’s actually not clear that it’s critical to test everyone immediately after diagnosis. They key may just be that everyone who could possibly have an EGFR mutation gets their opportunity with an EGFR TKI, sooner or later. Of course, the ALK story adds a level of complexity now, since XALKORI isn’t an option if you aren’t tested. But that’s not yet addressed in any formal guidelines.

In contrast, ASCO guidelines are remarkably different. They note that collecting tumor tissue can be a practical challenge, and that without a proven survival benefit from it, molecular testing is currently considered as investigational rather than the standard of care. Moreover, even patients who are found to have an activating EGFR mutation, an EGFR TKI is considered an acceptable alternative to standard chemotherapy but not a definite superior choice. (And again, not surprisingly, no mention of ALK testing or XALKORI.)

My interpretation of these two sets of guidelines, with their very different, rather polarized views, is that most oncologists will (and probably should) fall within the spectrum between these extremes. I personally believe that the NCCN decree for testing in all non-squamous patients, without evidence that an EGFR mutation is present in more than a vanishingly small proportion of longtime smokers with large cell NSCLC, for instance, and without evidence that testing delivers a survival benefit, is on the heavy handed side. I see the guidelines as a reflection of the bias by many academic oncologists who don’t have much of a concept of the practical limitations of obtaining tissue in clinics outside of academic centers, or the frustrations and delays of ordering mutation testing in labs in another state rather than in the same building where you work.

On the other hand, I would definitely say that the data supporting treating patients with an EGFR mutation with an EGFR TKI relatively early, including in the first line setting most of the time, is solid enough that it truly supports the value of testing patients with a reasonable probability of having an EGFR mutation (many patients with an adenocarcinoma, many patients who are ex-smokers or never-smokers, regardless of tumor histology), and of favoring an EGFR TKI over chemo in EGFR mutation patients. Even if the data don’t support a declaration that EGFR mutation or other molecular testing is a mandate, calling all such testing “investigational” is, in my mind, an oversimplification in the other direction. As with the NCCN guidelines, the ASCO guidelines are a reflection of the group that developed them: ASCO represents the broad range of rank and file oncologists, most of whom see patients in the community setting who may have little tissue available from an initial biopsy and who may be more resistant to another invasive procedure, especially if molecular testing entails a delay of several weeks before results are available and treatment can be initiated.

This controversy will most definitely continue, as new evidence seems to come into the picture every few months. Whatever conclusions we might have will shift over time, and I suspect that it will only become more compelling to do molecular testing on more patients over time. However, I don’t think we’re at a point where we can demonstrate a clear tangible benefit to broadly test everyone, especially people who would be expected to have a low probability of having one of these molecular testing, so we need to be cautious about trying to define this as a new, clear standard of care or a mandate for the workup of a new advanced NSCLC. Still, I do honestly believe it will come to revolutionize how we see, categorize, and treat lung cancer (and other cancers) over the next decade.

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