Genomic Test in Lung Cancer: Waiting Is the Hardest Part

Next-generation sequencing (NGS) is recommended by the National Comprehensive Cancer Network (NCCN) for all patients with non-small cell lung cancer (NSCLC). Several studies at the recent American Society of Clinical Oncology virtual annual meeting explored the application of biomarker testing in the U.S., as well as the turnaround time of the test results and the time it takes to go from diagnosis to first-line therapy. But how should you manage the patient while they wait?

In this third of four exclusive episodes, MedPage Today brought together three leaders in the field — moderator Vinay Prasad, MD, of the University of California San Francisco, is joined by Chul Kim, MD, of Georgetown University and MedStar Health in Washington, D.C., and Andrae Vandross, MD, of NEXT Oncology in San Antonio and Austin — for a roundtable discussion on this issue.

Episode one: What Did We Learn From IMpower010 in Resectable NSCLC?

Episode two: What the New KRAS Inhibitor Means for Lung Cancer

Following is a transcript of their remarks:

Prasad: I’m back, Dr. Vinay Prasad from MedPage Today. I’m joined by Dr. Chul Kim from Georgetown University and Dr. Andrae Vandross. We are talking about lung cancer.

One of the scenarios that happens a lot in lung cancer that we don’t talk about explicitly enough — that I am very curious what these two gentlemen think — is the situation of a newly diagnosed patient, where you’ve sent out genetic testing and you’re facing that treatment dilemma right now.

Here are the scenarios that so often happen: A patient gets admitted, or a patient comes to clinic, and they are diagnosed with non-small cell lung cancer. You have a clear sign on CT or PET scan they have metastatic non-small cell lung cancer. They may even have some small brain metastases.

You’ve sent the tissue for genomic testing. But you know what? This genomic testing, it needs to be like door-to-balloon time. It needs to be a quicker turnaround, but it isn’t always and sometimes it takes weeks to get it back — 3 weeks!

I think there is an interesting second-order effect that happens. If the patient in front of you is a young female nonsmoker, young male nonsmoker, you are hoping … your optimism that they have a druggable alteration goes really high. Your, perhaps, reluctance to give chemotherapy while you wait also increases. How do you navigate this space? You might do them some disservice actually by delaying treatment.

Dr. Kim, how do you think about this dilemma? The person in your clinic, this isn’t the 75-year-old smoker that you are not very optimistic about. Let’s say this is a 50-year-old nonsmoker, newly diagnosed with non-small cell lung cancer, they’ve got a lot of disease, and you sent out the genetic results. You don’t have them yet. How are you thinking about this patient?

Kim: Right. Lung cancer many times can progress quite quickly. Some are more indolent, some are really aggressive. I look at how symptomatic the patients are and what’s the burden of disease, as you mentioned, Dr. Prasad. Then in my practice, I send tissue NGS as well as circulating tumor DNA.

If I have a patient like you described, a young patient, no smoking history, likely to have a very high chance of having a mutation that is targetable, the benefit of doing circulating tumor DNA is that the turnaround time is pretty fast — about 7 to 10 days time period. Many patients can wait another 7 to 10 days before we make the final decision.

If the patient cannot wait and needs to get treatment right away, what I do is I give them chemotherapy without immunotherapy. Because the challenge if you start the patient on immunotherapy-based treatment and then the next-generation sequencing shows some targetable mutations, say EGFR [epidermal growth factor receptor], then you have a hard decision to make.

Because you can start, yes, TKI [tyrosine kinase inhibitor] osimertinib [Tagrisso] or other drugs, but then the rate of side effects goes quite high if the patient is receiving immunotherapy and they are starting the TKI. I tend to use chemotherapy alone in this kind of situation, if the patient needs chemotherapy and cannot wait for the results of NGS.

Prasad: Yeah, I agree with you and I tend to do that. I actually think my suspicion is we don’t do that enough actually, that we are … actually in equivocal cases, we are more likely to wait than we are to just give a cycle of Carbo/Taxol [carboplatin/paclitaxel] or something like that while you wait.

I wonder if this is actually like a ripe place to do a study, a study of what to do while you are waiting for the genomic results. It’s either that or find a way to get them done faster. I always say that time-to-pathology report should be a new metric because I want to see that metric.

Dr. Vandross, how do you think about these situations? They happen not infrequently, and they are more and more these days. You have that patient that you are worried about. When do you decide to pull the trigger on a cycle of chemotherapy while you are waiting for these NGS results?

Vandross: I’m telling you the anxiety that came up as soon as you mentioned this scenario, it just, goes through the roof. That’s just me. I mean, just consider the patient.

I don’t have much more to add based on what you guys just said, except to the fact, just to highlight this, like, yeah, it is a very serious issue.

I do think that a study would be very helpful in terms of strategies and being able to counsel patients appropriately to know that, “Okay, yeah, we are going to send NGS. We have a high likelihood, or a low likelihood, that it’s going to yield an actionable mutation such that you’ll get osimertinib or something similar.” But in the meantime, based on the clinical status and their level of comfort waiting, we are going to give a cycle of chemotherapy.”

Because one of the issues always for all of us is when we are assessing a patient, they look great. They can look great, but one thing that I’ve learned over time is that sometimes you don’t know how close to a clinical cliff someone is standing. That’s really distressing to me sometimes. Those are the things that you sort of wake up and stay awake at night about.

Prasad: That’s funny you say that, because that’s how I feel. Those are the cases that haunt me, are these choices. They really do haunt me and I regret, and I think about how I could have done better.

I think one of the challenges here that makes this really complicated is that the younger they are and the more they fit the phenotype of driver mutation, the more you are optimistic and willing to hold off a little bit.

Then as you get into the brain [metastasis] space, if somebody has some small brain mets and you think they are EGFR positive, you are going to think, “Oh, he has got a good blood-brain barrier penetration,” and you are not going to want to pursue radiation or something like that.

But there is not a 100% chance they are going to come back with an EGFR mutation. You are letting brain mets sit idly for potentially weeks while you are waiting for that.

Those are the cases I agonize about, and I think you’ve put it well. You don’t know how close to a cliff someone is. We’ve all had the experiences of you thought somebody could make it there and something unexpected happened, such as even DIC [disseminated intravascular coagulation] or even some really profound catastrophic brain bleed.

Dr. Kim, any more thoughts on this scenario? I really think it’s an under-discussed place, this anxiety.

Kim: Right. I think it is important to act, and if you have to give a dose of chemotherapy, that’s my approach for patients who are waiting for the molecular testing results and have a really high burden of disease and are really symptomatic. I think it’s important to give the timely treatment to patients, be it chemotherapy, be it TKI. I guess timing of treatment sometimes matters quite a bit.

Prasad: Yes, that’s well put. Well, my closing thoughts on this are we are very interested in oncology and looking for more genes and more cancers. But what I’m very interested in is the genes I want to know about, I want to know about faster. That is my interest in oncology.

Dr. Kim and Dr. Vandross, thank you so much for that.