HER2/neu: Another Uncommon & Potentially Important Therapeut

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HER2/neu: Another Uncommon and Potentially Important Therapeutic Target in Lung Cancer

http://blog.lungevity.org/2012/01/02/he ... ng-cancer/

January 2nd, 2012 - by Dr. Jack West

Last year on the GRACE website, Dr. Mary Pinder from the Moffitt Cancer Center in Tampa, FL wrote a post about the potentially clinically relevant target of HER2/neu (HER2) mutations for lung cancer. In that introductory report, she relayed that Herceptin (trastuzumab), an antibody against the HER2 receptor (part of the human epidermal receptor family as EGFR, which is also known as HER1), though this agent hasn’t been especially impressive in NSCLC thus far. For example, an ECOG phase II study led by Dr. Corey Langer evaluated a target population of patients with advanced NSCLC and HER2 protein expression as measured by immunohistochemistry (IHC). This captures a large proportion of people with NSCLC, but it may be too broad a population, one that dilutes out the smaller subset whose cancer is especially driven by HER2. Instead, HER2 gene mutations, similar to mutations in EGFR that are far better studied in NSCLC, appear to be present in about 3-4% of patients with NSCLC. This population may be far more likely to benefit greatly from HER2-targeted therapy, though at this time this idea remains an essentially completely untested hypothesis.

This past month, an article by Li and colleagues out of Shanghai was published in the Journal of Thoracic Oncology that evaluates and attempts to better characterize this population of patients with a HER2 mutation a little more. They studied tissue from the lung cancers, adenocarcinoma only, of 224 consecutive patients in their institution’s tumor registry, looking for EGFR, KRAS, and HER2 mutations. Because this population was 62% never-smokers, only 5% stage IV, and entirely Chinese, is clearly a clinically distinct population from the more heterogeneous NSCLC populations seen in Europe or North America, but it’s notable that they saw a HER2 mutation in 3.6% of patients. This is in contrast with a startling 64.4% prevalence of an EGFR mutation and a 4.5% prevalence of a KRAS mutation — all mutually exclusive of each other:

(Click on the blog link above to view the image)

These HER2 mutations were only seen female never-smokers (Dr. Pinder ‘s post in the link above also noted that these are known associations with HER mutations in NSCLC). Looking at just patients who don’t have an EGFR mutation or KRAS mutation brought the prevalence up to 11% of this more limited group.

Another interesting point is that while there hasn’t been a completed study of HER2-inhibiting targeted therapy for NSCLC patients with a HER2 mutation, there is a report in the New England Journal of Medicine by my Italian friend and colleague Federico Cappuzzo that describes their group’s favorable experience giving a heavily pre-treated patient with a HER2 mutated advanced NSCLC a combination of Taxol (paclitaxel) and Herceptin; this was followed by an impressive result (and he also mentions the likely error of using Herceptin in too broad a population of patients with HER2 protein expression, rather than the much smaller population with a HER2 mutation).

We’re definitely coming to appreciate that the lung cancer populations in different locations vary in genetics along with their prevalence of smoking history, distribution of NSCLC histologic subtypes, and sex balance. Because of this, we can’t generalize from Shanghai to the rest of the world. But there is an emerging theme that HER2 may well be a small but important population who are present in sufficient numbers to do meaningful trials. Moreover, as testing for EGFR, KRAS, and ALK becomes more commonplace and we have tissue more readily available, it may be far more feasible to identify patients who could be very well served by being treated with HER2-targeted therapy that is already commercially available.

A decade ago, when Dr. Langer first presented his experience in treating lung cancer patients with Herceptin, he summarized that there could be a small population who did especially well with it but noted that the proportion of patients appeared to be so small that we would need to do an “intergalactic” trial to conduct a trial of that smaller population most likely to benefit. Today, however, in a world in which we’ve just seen the successful study and commercial approval of XALKORI (crizotinib) for an “ALK-positive” population that amounts to around 4% of the NSCLC population, these 2-5% populations are seen as a challenge but very worthy of study. It may require patients traveling to a small number of centers running their needed trial, rather than having that trial for them available nearby, but I hope and expect that we’ll see HER2-mutated lung cancer studied far more in the next few years. And with that we may find another limited population for whom we have a very effective therapy. And importantly, this research may lead to advances in treatment of the much broader NSCLC population as well.