ADVANCES IN SQUAMOUS NSCLC

This is Mark Kris from Memorial Sloan Kettering. Today I would like to address a topic that we don't speak about too often, but its time has come, and that is squamous cell lung cancers.

Squamous cell lung cancers represent 20% of all lung cancers. Adenocarcinoma, with 60%, is the most frequent and squamous cell lung cancer is next with 20%. Small cell lung cancer is now down to 13%.

There have been innovations in the diagnosis of this illness. The World Health Organization categorization is based on a morphologic review. However, there is very specific staining (usually with P40 of the P63 stain) for squamous cell, and also the absence of other stains (such as napsin or TTF1) that would lead to the diagnosis of adenocarcinoma. When you use stains in addition to expert morphologic classification and you look at all lung cancers, these "not otherwise specified" or large cell lung cancers disappear. It is very important to work with your pathologist and to provide good-sized specimens so that you get all of the information you can.

The second factor that is growing in the treatment of squamous cell cancers is the use of multiplex molecular profiling. The current National Comprehensive Cancer Center guidelines recommend multiplex profiling for cases in which squamous cell cancers have been diagnosed in never-smokers, and also for those cases of squamous cell cancer in which there is insufficient material and the diagnosis of squamous cell cancer on morphologic grounds is somewhat less certain. The other emerging use of multiplex testing is for diagnosis. If you find something like a KRAS mutation, it would be almost certain that it is not a squamous cell cancer; rather, it would suggest that the cancer is in the adenocarcinoma category. Furthermore, there are increasingly more targets. A lot of research is going on with FTFR1, PI3K, and P10, and more drugs are entering the research space. MET amplification was highlighted in a recent article by Schildhaus,^[1] published in Clinical Cancer Research in February of this year. They found high-level MET amplification in 3% of squamous cancers. This has been associated with sensitivity to crizotinib, and that would be an additional option for a patient with high-level MET amplification with squamous cancer.

Within the past several months, two drugs have been approved in squamous cell cancer. The most recent drug is nivolumab, approved after a phase 3 trial comparing treatment with nivolumab to that of docetaxel after progression on cisplatin- or carboplatin-based therapy.^[2] Patients had improved outcomes with the use of nivolumab. No special tissue typing or testing was needed, and clearly there was benefit over docetaxel, so that becomes an option. The other agents that have been approved are the combination of docetaxel and ramucirumab, an anti-vascular endothelial growth factor (VEGF) agent approved just a few weeks ago.

Suddenly we have two regimens that we can recommend to patients after progression on cisplatin and combination therapy. My bias for initial therapy would be cisplatin with gemcitabine. However, other choices are available. Cisplatin and a taxane would be appropriate as well. However, in treatment after progression, nivolumab would be the obvious choice because it beat docetaxel in the recent head-to-head comparison. I would probably advocate cisplatin/gemcitabine first, nivolumab second, and the combination of docetaxel and ramucirumab third. It's an open question as to whether adding ramucirumab to docetaxel would be better than nivolumab alone, but because it appears that the benefit from nivolumab is present regardless of line of therapy, it would make the most sense to give that next and then to save docetaxel and ramucirumab for the next round, if that happens.

In summary, we have had a lot of developments in squamous cell cancer. Work with your pathologists and your molecular pathologists to get the best identification of squamous cancers and the best molecular characterization that you can get. Use these new drugs and develop your own pattern of how to recommend these drugs to patients first and in subsequent lines of therapy.