Advances in Testing and Targeted Therapy for NSCLC: Translating Evidence to Clinical Practice - Episode 3

Use of Molecular Profiling in Early-Stage Non–Small Cell Lung Cancer

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A focused discussion on the use of molecular profiling in early-stage non–small cell lung cancer to inform decisions on adjuvant and neoadjuvant strategies.

Benjamin Levy, MD:
Molecular testing started in the stage IV setting because that's where all the drugs were, but as we will learn in our next segment, these drugs, fortunately, both targeted therapies and immunotherapies have moved up in the early stage, and it's really put the onus now to test in early-stage disease. Jessica, I'll come back to you. In early-stage lung cancer, the importance now of molecular testing, are you the one that's ordering this, or are you consulting with your medical oncologist? Now we do have data for adjuvant osimertinib. Maybe in a few years, we'll have data for neoadjuvant-targeted therapies. How does this fold out at the University of Chicago?

Jessica Donington, MD: We're lucky we have a multidisciplinary tumor board. We talk about every patient who would be possibly considered for adjuvant therapy. We have that discussion right away, and we're lucky that every patient who has some consideration for adjuvant therapy gets their molecular testing, but it is like we talked about earlier: that added step that has to happen, but we are also fortunate that anyone who gets a preoperative biopsy gets their molecular testing. I think that's the way to go. Just having that in your pocket before you go really guides your conversations with your patients. It's very helpful.

Benjamin Levy, MD: Is it just EGFR that you're ordering, or is it just the usual next-generation sequencing panel that you're doing?

Jessica Donington, MD: We order a whole panel on anybody who has a preoperative diagnosis.

Benjamin Levy, MD: Any other comments from institutions on how they leverage the ADAURA data and use that in everyday practice? Jonathan?

Jonathan Wesley Riess, MD: I would just like to amplify what Jessica said—that it's really important now with multimodality treatment, just for early-stage and for locally advanced disease [it] is more important than ever to adjudicate these patients at multidisciplinary tumor boards in terms of how to best sequence and what molecular testing to do because things have evolved much more and gotten more complicated. We have neoadjuvant chemo-IO [chemotherapy plus immunotherapy], we've got adjuvant targeted therapy, we've got adjuvant IO and chemotherapy, and how to best sequence those is really important to talk about in a multidisciplinary setting.

Heather Wakelee, MD: I think as we talk about this, it's really the full biomarker panel, and so it's that PD-L1 testing, of course, but that's not enough. I think you’ve brought this up a few times. I'm going to keep echoing it because I think it's so critical, that just because there's a high PD-L1 does not mean immunotherapy's going to work in the metastatic or the early-stage setting. We need to make sure there's not a driver mutation, which would kind of negate that PD-L1 result before we make that decision because we can cause real harm to people if you send them down the wrong path.

Benjamin Levy, MD: Increased toxicity, less efficacy, or no efficacy. It's a really great point. I'm going to ask everyone an unfair question. One of the only slippery slopes I think for next-generation sequencing and early-stage is you sometimes get an ALK [mutation], and the question is, “Gosh, osimertinib works really well in the adjuvant setting for patients that [have] an EGFR-sensitizing mutation.” Are we part of the slippery slope, where you would say, apply this to ALK or ROS? Is this something that you would do? We don't have any data on this yet. I want to say that.

Heather Wakelee, MD: There are open trials.

Benjamin Levy, MD: There are open trials, and I encourage everyone who finds these to enroll in these trials. It's a hard question. Is this something that you would use? Would you use a resected ALK if it was ALK and give alectinib?

Alexander Spira, MD: I think if you went around the table and asked everybody, I'm going to speak out loud and say that we all probably have done it. I mean a stage 3A that ends up being 3B resected—that looks really bad, and you know [it] has a 98% recurrence rate? We’ve done crazier things in oncology over the years than give somebody an ALK inhibitor. The other option is even off study. Since we're moving to a neoadjuvant world, neoadjuvant ALK sometimes might be helpful for patients for the resection or down staging as well.

Jessica Donington, MD: Don't get me so excited.

Jonathan Wesley Riess, MD: I think what everybody's saying brings up the broader question, which is how much can we extrapolate from ADAURA [trial]? We have the trials, and there are ongoing trials in RET, ALK, and others, but with the great data in ADAURA, and extrapolating from the metastatic setting, you've got great drugs: alectinib and ALK, selpercatinib and RET, as well as others. I think it's a reasonable extrapolation. I would say I would feel more confident giving adjuvant alectinib than, for example, adjuvant atezolizumab in a patient who is PD-L1–positive and ALK-positive.

Alexander Spira, MD: I think if you went around this table and asked us if it was, God forbid, any of us, and we had a reasonable stage lung cancer and it was ALK-positive, would you do this? And I would. Yes.

Benjamin Levy, MD: Yeah, on the record, I've never done it. Off the record, I've done it many times [laughter].

Alexander Spira, MD: Are we on the record or off the record here?

Heather Wakelee, MD: I think we need to be careful, though, because we do have examples of giving adjuvant EGFR TKIs [tyrosine kinase inhibitors] with gefitinib and erlotnib where the trials did show DFS [disease-free survival] benefit, but no overall survival [OS] benefit. So were those patients actually helped by being on that medication early? Now, we have that osimertinib data with ADAURA of course. That disease-free survival data is absolutely compelling—no question about it—and I very much hope that we see that OS benefit when the data comes through. But we have to be careful because not every TKI story is the same as osimertinib and the setting of EGFR mutation in metastatic. With ALK, yes: we have amazing progression-free and overall survival data in the metastatic setting, and so it's harder. But with some of the other drivers, that toxicity-to-benefit ratio, even in metastatic, it is a bit more questionable—the duration of response. So I think we do need to be careful on the slippery slope.

Jonathan Wesley Riess, MD: Absolutely.

Chaitali Nangia, MD: I would add 2 more points: toxicity and the quality of life have to be kept in mind because we really don't know at this point what those would mean. If you start someone out, early-stage resected, what would that mean 5 years later for that patient, and then definitely the economics of it? Who is going to pay for it?

Benjamin Levy, MD: Financial toxicity is real.

Alexander Spira, MD: The only thing I will say is: 100% you brought us back down to earth, Heather, because we've all been burned with, “Oh, this is going to work.” We have all seen some recent immunotherapy data where the phase 2 looked great and phase 3 was a bust. However, I think there's a clinical trial for almost any actionable mutation, and even if you don't have it, send them somewhere else. It'll take care of the patient and answer the question.

Jonathan Wesley Riess, MD: I think the other thing I would just bring up to Heather's point is where you draw the line? We all talk about ALK and alectinib, and you could say in the metastatic setting that the medium PFS [progression-free survival] is about 36 months, and then for osimertinib, they have 19 months, and you have the ADAURA data. Those are all reasonable extrapolations, but I think that is fundamentally different than, say, EGFR Exon 20 with mobocertinib and amivantamab and others, where the median PFS and the activity in the metastatic setting is much less. So where do you draw that line, again? It’s a slippery slope.

Benjamin Levy, MD: Where do you draw that line with the slippery slope? When does that slippery slope get too slippery, is the question?

Alexander Spira, MD: But you know what? If I were that patient, I know I'd at least like to have that discussion with my doctor, and I think all the more information helps. It's that shared decision-making we're talking about.

Transcript edited for clarity.