Targeting MET Exon 14 Skipping Mutations in NSCLC

Part 1: Practices for Molecular Testing to Determine Frontline Therapy in NSCLC

During a live virtual event, Ravi Salgia, MD, PhD, discussed a possible approach for biopsy and molecular testing of a patient diagnosed with lung adenocarcinoma.

CASE SUMMARY

A 71-year-old woman presented to her primary care physician with rib pain after a fall and reported increasing shortness of breath and fatigue​. She had no history of smoking. Imaging showed a right hilar mass as well as rib and adrenal metastases​. Her brain MRI was negative for brain metastases​. She had an ECOG performance status of 1 and was diagnosed with stage IV lung adenocarcinoma.

DISCUSSION QUESTIONS

  • What would be your approach toward molecular testing for this patient?​Next-generation sequencing (NGS)​, liquid biopsy​, polymerase chain reaction (PCR)​, immunohistochemistry​, other?​
  • Is PD-L1 testing a reflex test at your institution? How do you factor results into treatment planning? ​
  • What can medical oncologists do to help ensure that sufficient tissue quantity is collected, and that tissue is used efficiently? What needs to be communicated to the interventionalist conducting the biopsy? To the pathologist? ​
  • Do you use “liquid biopsy” in your practice? If so, how/in what scenarios? ​

RAVI SALGIA, MD, PHD: What would you do? We wanted your approach as to how you would think about this patient and go forward.

MAY CHO, MD: I’ll get the NGS and liquid biopsy at the same time.

SWARNA CHANDURI, MD: If the quantity is not sufficient, I’ll probably send them for liquid biopsy. We have started doing these.

SALGIA: What happens if you don’t get enough information? Do you order another biopsy?

CHANDURI: Yes, if we can get the biopsy easily. If the lesion is too small, or if they had a bad experience with the previous one, like pneumothorax, I may not. I will try to do it, but not always.

SALGIA: Suppose you get a liquid biopsy that’s negative. The way I always think of this is sometimes you can have these secretors and non-secretors; so you can have cell-free DNA that’s not being secreted into the bloodstream. If you don’t get a positive answer on liquid biopsy, it’s still important to get that true biopsy done—that will help you.

The true biopsy is also important for histology. For squamous histology, if you don’t find any actionable mutation versus adenocarcinoma, you treat them differently. I think we all practice that, and our colleagues in pathology and other multidisciplinary teams appreciate that, as well. So, our part is to educate on that at the same time.

DISCUSSION QUESTION

  • How often does PD-L1 come back before all remaining biomarkers? In that situation, what do you do? Do you start therapy before all results come back? ​

SALGIA: Suppose the PD-L1 test came back, let’s say, 70%. Would that help you in your decision, before any of the actionable mutations came back? How would you like to proceed?

MERIN STEPHEN, MD: In practice, they come back together. Before the whole NGS panel comes back, we get back PD-L1 plus some of the main mutations, maybe by PCR. Those all come back together. I’d probably wait for the whole panel because I think even if it was a high PD-L1 of 70%, I probably wouldn’t want to start immunotherapy and then switch to a targeted therapy. I’m thinking there might be some loss of efficacy. I’d probably wait for all the results.

SALGIA: Yes, I like that approach. We always say, is there an emotional emergency or a physical emergency? If you truly have an incredible amount of disease burden, and you need to start something, usually we say you could potentially do chemotherapy and not add the checkpoint inhibitor until you know what the molecular alterations are. Then, you can add in the immune checkpoint inhibitors [ICI], or you can then decide to continue with the chemotherapy and then think about the targeted therapy, as well. You’re exactly right, because in some of the cases, in patients with EGFR or ALK as an example, and even MET exon 14 skipping, it doesn’t help you as much.

The National Comprehensive Cancer Network recommendations [support these tests].1 We all routinely test for this, and more and more are coming through, as you can imagine. And then, there are a lot of molecular alterations that can help us in terms of clinical trials, as well, so that’s important. It’s very clear all of us are convinced that NGS is important. And even now, KRAS, especially in the context of G12C, with sotorasib [Lumakras] being approved, is an important therapeutic maneuver that we can do.2 It’s approved in the second line, but we’ll see what happens in the first-line setting.

REFERENCES:

1. NCCN. Clinical Practice Guidelines in Oncology. Non­–Small Cell Lung Cancer, version 7.2021. Accessed December 6, 2021. https://bit.ly/3Io3BSR

2. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. FDA. Published May 28, 2021. Accessed December 1, 2021. https://bit.ly/3ph9o42