Targeting NSCLC with Uncommon EGFR Mutations - Episode 6

Overview of Actionable Mutations and Molecular Profiling in NSCLC

Expert oncologist Roy Herbst, MD, PhD, provides a comprehensive overview of actionable mutations and molecular profiling in NSCLC.


Roy S. Herbst, MD, PhD: We have made so much progress in the last 20 years with targeted therapy [in non–small cell lung cancer], but it only makes a difference if you get those drugs to the patients. The guidelines, in my opinion, and what we do here at Yale [School of Medicine], is that anyone with advanced or even early lung cancer, based on data for adjuvant therapy with osimertinib from the ADAURA trial, should have next-generation sequencing, or at least some sort of profiling. This applies to everyone with metastatic disease, for sure the nonsquamous patients, and I even do this for the squamous patients because sometimes they are misdiagnosed, or you can see a mutation in the squamous tumors every once in a while. It’s important to profile for all the actionable mutations, which now are 8 or 9 in number: EGFR, ALK, ROS1, RET, and MET. Now we have NTRK, BRAF, and of course recently, KRAS. Almost all of the first group, except for KRAS, occur in the light or never smokers, but KRAS of course in the smokers. All of these mutations now have drugs. What we try to do, and what the national guidelines say, are to have this within 10 working days, and to have that back so that you can see the patient and treat them. It’s critical these days because if you have one of these driver mutations, the tumor will most likely shrink, not forever, but it will provide relief.

It’s still my preference to use an oral targeted agent, except for a few that are in the second line, like KRAS. This is still first before going to immunotherapy, which is much less likely to work in a driver mutation-positive patient. These data have to be available in real time, and that’s something that you can do internally. At Yale, we do our own internal testing, but many places send it out. Either is fine as long as you get it done. Another thing I want to bring up quickly is we have a trial called the Lung Master Protocol or Lung-MAP, which is a public-private partnership that is run through the national and clinical trials network. That provides free testing using the Foundation Medicine platform, which allows even more patients, especially those underserved and those in different parts of the country, to get profiling. Profiling is critical. You need the right drug for the right patient at the right time, and you can only do that if you profile and find it. You must get the results in time so that you can use them before you have to make your first treatment decision, which in many cases will be the distinction between targeted therapy or immunotherapy, or immunotherapy/chemotherapy combinations.

The US guidelines usually lead the world, and right now the US guidelines are to have all the actionable mutations checked. The CAP, College of American Pathologists, would say that you would have to have all those molecular markers done prior to treatment if possible. Is that available in all places? No. The other thing that I haven’t mentioned but is of course important is that PD-L1 testing is also critical. Is it 100% necessary? No, because you can give chemotherapy and immunotherapy to someone regardless of PD-L1 status, but still, we find it’s very important to have. In the United States, we try to get this profiling done. The last numbers I saw were that about 80% or so of people get it. That leaves 20% who don’t have it, and I’d hate to miss someone who has an EGFR, ALK, or RET mutation. This is because when you give the pill, the oral agent to those patients, as you know they do quite well. They may have to deal with resistance at some point in the future, but it allows you to get the patient to a better place in a very quick way.

Transcript edited for clarity.