Part 1: Highlights–Importance of Biomarker Testing

Four distinguished oncologists – Drs Corey Langer, Aaron Lisberg, Lyudmila Bazhenova, and Misako Nagasaka – describe biomarker testing in patients with advanced/metastatic NSCLC treated at their institutions. Topics include their use of internal vs external panels, the need for liquid biopsy in different settings, and the challenges of slow turnaround times in patients who don’t have time to wait for treatment.

This roundtable discussion is sponsored by Daiichi-Sankyo.

Click here to return to the entire video series 

Read the full Transcript:

Spoken by Corey Langer, Aaron Lisberg, Lyudmila Bazhenova, and Misako Nagasaka

Corey Langer, MD:

Welcome to our round table discussion today, hosted by Oncology Learning Network. I'm Corey Langer, the director of thoracic oncology at the Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine. I'm also the co-chair of the medical oncology committee in the, energy cooperative group. And today, we've gathered some of the leading minds in lung cancer oncology to discuss some of the key breakthroughs in the management of non small cell lung cancer, including advances in biomarker testing and novel therapeutics, particularly ADCs or antibody drug conjugates. Let's begin by meeting the panel.

Aaron Lisberg, MD:
My name's Aaron Lisberg. I'm a thoracic medical oncologist here at UCLA.

Lyudmila Bazhenova, MD:
I'm Lyudmila Bazhenov. I'm a thoracic medical oncologist and a lung cancer unit leader from University of California, San Diego.

Misako Nagasaka, MD:
Hi, my name is Misako Nagasaka. I am a thoracic medical oncologist at University of California Irvine School of Medicine.

Section Header: Biomarker Testing in Advanced/Metastatic Non-Small Cell Lung Cancer: Experience at 4 Respected Institutions

Corey Langer, MD:

So, we're going to discuss a number of different topics. Start off with basic clinical, practice guidelines for biomarker testing, what the current guideline recommendations are. We’ll go into the role of liquid biopsy as well as tissue biopsy and review actionable versus non-actionable genomic alterations. Also, for the benefit of our audience, briefly touch upon the difference between sematic and germline mutations, which I know our patients can’t get their heads around – they immediately assume, many of them, that their molecular abnormalities may be hereditary. How to differentiate the genomic alterations from what our molecular pathologists called the “VUS”s, or the variance of uncertain or unknown significance, and the current challenges. So, we'll start off with you, Aaron.

What's your current practice in the institution? Do you have an internal panel? Do you send it out? What’s included and do you consider crucial or a priority?

Aaron Lisberg, MD:

Sure, so as we’ve discussed many times over the past several years, I think the importance of biomarker testing in non-small cell lung cancer has never been higher. I really think that it's critical to be doing in all of our patients and kind of taking you through our workflow here at UCLA, briefly. So in all patients that have advanced or main non-small cell lung cancer, specifically those that have adenocarcinoma, we do have an internal panel that does a targeted EGFR analysis. We also go PDL1 by HC and ALK by HC, but that is by no means comprehensive, so allof our tissue is sent out at time of diagnosis to a third-party vendor.

Aaron Lisberg, MD:

That's at diagnosis at time of iterative progression, I always like to reassess my patients’ status, because you never know what may have emerged or what may have gone away.

Aaron Lisberg, MD:

I typically use liquid in that setting unless I have a high level of concern for potential like small-cell transformation in a patient with EGFR disease.

Lyudmila Bazhenova, MD:

Slight variation, so, we don't have an internal test. We only have PDL1 as a reflex internal test. The rest,  it's a send out.  I do believe in RNA-based next-generation sequencing, so as a  group, the companies that we’re using the most is Tempuss andCaris,and very similar to Aaron I do liquid biopsy at the same time for two reasons. Number one is faster turnaround time. If I find something in a liquid, I can start treating without waiting for the tissue. And number two, I do believe that those tests are complimentary rather than exclusionary, and we might be able to find something in the liquid that wasn't seen in the tissue. I do test squamous patients at the time of the diagnosis as well. I used to just test them if they're non-smokers, but as the guidelines evolved, I'm testing them all. As to post-progression biopsy, I do believe in it, but only for patients who have oncogenic alterations where I'm looking for quiet resistant mechanisms. If I had a full NGS and RNA at the patient at the time of the diagnosis and I didn't see any oncogenic alteration, then I would give patients let's say chemotherapy immunotherapy or immunotherapy by itself. Upon progression, I generally do not read biopsy because at this point, it doesn't change my practice, what I do, unless I have a clinical trial that requires to read biopsy, then I go ahead and do that.

Misako Nagasaka, MD:

I agree to what has already been said by Aaron and Lyudmila. At the time of diagnosis for metastatic disease, I do both tissue and liquid-based molecular testing.  The vendors that I use are Caris for tissue and Foundation Liquid for the liquid biopsy. I agree in a sense that liquid biopsy at this point in time should be complimentary because often times the tissue biopsy specimens come from a EUS-FNA sample, and sometimes you can't run the whole panel. And also I've had times where liquid biopsy was able to detect a targetable mutation, but not from tissue because the tissue was necrotic, or what was supposed to be a soft tissue biopsy ended up being a bone biopsy and the tissue molecular testing failed. At the time of progression, I agree with Aaron, these patients are usually not feeling well. The disease is not under control, and it's hard to just apply a tissue biopsy unless you're really suspecting small cells. So, I try to do liquid biopsy at the time of progression to see if there's any resistance mechanisms that I can target.

Corey Langer, MD:

I think our practices differ a little bit from yours. You're all pretty consistent in testing both squamous and non-squamous; we're still not quite fully on board with squamous. Certainly if they're never smokers or remote former smokers, we'll test those individuals, but uniformly across the board, not necessarily. We do have theoretically reflex testing. So anyone with a diagnosis of non-small cell non-squamous according to our internal pathways will get automatically tested.

Corey Langer, MD:

I think the big issue that we're all contending with, obviously, is turnaround time, and I want to get into that momentarily. The quicker we can cut that down, the better off we are. So patient satisfaction goes up, and I would have to argue that physician satisfaction and quality of life also goes up. We don’t have to go through that same song and dance that I’m sure you’ve all done where we've got the diagnosis, but we don't know how to treat you yet. You’re PDL1-positive, but starting immunotherapy, if you have an EGFR mutation, you know this best of all Aaron, is ill advised at the very least and potentially quite dangerous. So, getting all the data in quickly, I think, is our biggest challenge.

Aaron Lisberg, MD:

I think in the last year or so, we've gotten a lot better at having pathology reflexively send the specimen out for NGS to our third-party vendor prior to the patient seeing the oncologist, which helps a lot. It doesn't work every time, but as you alluded to, turnaround time is a big issue. And typically it's probably 10 to 14 business days for our third-party vendor. So if that time can be cut by a week or so, sometimes, between the time that the diagnosis is made and the time that the patient sees me, that's very helpful. So that's one step that I think has gotten better in our institution more recently.

Lyudmila Bazhenova, MD:

Similar to Aaron, we are not sending reflexive next-generation sequencing, so it has to be seen by an oncologist first. We are getting our patients in pretty much within 7 days after the diagnosis is made and the referral has been made. So, I think we are trying to cut up on that time. Otherwise, it is a challenge, as you stated, to be able to confidently tell to our patients that we have to wait until we have a molecular testing, which is hard to do, because we usually just told the patient that they have a metastatic disease, and this is not curable, and eventually this disease is going to take their life. And then at the same visit, trying to explain why I can't start you on therapy, right, or why do we have to wait? It is challenging, but I think if, as an oncologist, we believe in the fact that we need to wait, then I think we will convince our patients that it needs to wait. And based on AR and data for EGFR study, I think we have plenty of evidence that we need to wait for those patients before giving them immunotherapies in the setting of a potentially antigenically driven tumor.

Corey Langer, MD :

What's the average time from initial diagnosis to full molecular profiling at your institution?

Lyudmila Bazhenova, MD:

About 3 weeks if you use tissue. If you use liquid, that's going to be a week and a half.

Corey Langer, MD:

But of course, the liquid might be negative and they might still have a tissue positive for potential oncogenic driver in that setting. When you're in this situation where a patient's quite ill, you want to wait, but you feel the patient cannot wait. What do you typically do?

Lyudmila Bazhenova, MD:

Platinum doublet, hold off immunotherapy until I know molecular testing. If there is no antigenic drivers, add immunotherapy to cycle two, but initially start this platinum doublet.

Corey Langer, MD:

So, but await the results of both liquid and tissue before you add the immunotherapy, before you add presumably pembro or go with a combinatorial regimen. Do you use bevacizumab in that setting or strictly pem platinum?

Lyudmila Bazhenova, MD:

Have not. So, I usually just do platinum doublet and then just decide on adding on that immunotherapy later. I have not used pep bevacizumab in addition to platinum doublet while I wait.

Corey Langer, MD:

Misako the same questions: how to improve turnaround time? How do you sort of expedite the process and what do you do when you're confronted with a very ill patient who really can't wait?

Misako Nagasaka, MD:

At our institution, the medical oncologist has to send for molecular testing, whether it be tissue or from blood. So, they have to be seen. I believe UCI is trying to do an initiative where from the time of request, the patients are seen within one or two days. And sometimes we can fulfill their requests, sometimes we can't, but we always try to expedite the turnaround time for testing. In a scenario that I do not have the results of the molecular testing but the patient is quite ill, there is significant tumor burden, I start off with doublet chemotherapy, as Lyudmila has mentioned, and we'll add on immunotherapy if molecular targets are all negative.