Roundtable Discussion: Osimertinib Is Chosen as Best Option for Frontline Therapy for EGFR+ NSCLC

Miguel Albino, MD

During a Targeted Oncology Case-Based Roundtable event, Miguel Albino, MD, a medical oncologist/hematologist at Texas Oncology in Austin, Texas, discussed the case of a 73-year-old patient with EGFR-mutant non–small cell lung cancer (NSCLC).

ALBINO: We have a pretty competitive poll here, good to see. I have 3 votes for initiating therapy. I’d like to hear from those folks who would initiate chemotherapy in this situation, what their specific thought process is there if anybody would like to share that.

ARJUNAN: I voted for chemotherapy. Given the symptomatic nature of the disease, it doesn’t hurt to give 1 or 2 cycles of chemotherapy for cytoreduction. I can always make the decision to transition to targeted treatments or, just based off of this, if he has a high PD-L1, the CheckMate 9LA [regimen (NCT03215706) of nivolumab (Opdivo) and ipilimumab (Yervoy) with 2 cycles of chemotherapy] would be a perfect thing to use here if he didn’t have any driver mutations.

ALBINO: So, you would use an immunotherapy combination with this patient?

ARJUNAN: Yes, if there were no driver mutations.

ALBINO: We still don’t have the molecular panel available. Would that influence your decision?

ARJUNAN: I would do the chemotherapy alone. I wouldn’t do immunotherapy, I don’t think you get much benefit from that up front to get some symptomatic relief, so I would just do some chemotherapy.

ALBINO: Would anybody do immunotherapy either alone or in combination with chemotherapy? I do have 2 votes for chemoimmunotherapy and 3 votes for immunotherapy alone.

SAEZ: I wanted to comment that I had a patient like that recently that the insurance would not approve asymptomatic immunotherapy until I got the results, because it was easier for the patient to benefit from [chemotherapy]. So, they would not approve the immunotherapy portion of the regimen. They do approve the chemotherapy but not the other one.

ALBINO: I think that’s a very important point when we talk about patients that we treat with upfront immunotherapy and then we try to transition them to TKI [tyrosine kinase inhibitor] therapy.

Anybody care to share their experience in terms of complications and toxicities with these kinds of patients when they’re shifted over to TKI therapy if we start them on immunotherapy?

ARJUNAN: I don’t know about complications, but I just feel like immunotherapy, if you target that access, it doesn’t work very well in these driver mutation patients.

LUU: I think patients can have pretty bad pneumonitis as well after receiving immunotherapy and get switched to Tagrisso [osimertinib]. I’ve seen it once pretty bad.

ALBINO: There are some data out there in patients who are treated initially with IO therapy and then transition over to TKI who do tend to get pretty bad pneumonitis among other complications, that being the most important one, and other immune complications. They seem to be more enhanced in patients when we do TKI therapy after immunotherapy. So, that’s something that I always keep in mind when I am going to start a patient on treatment, especially when we obtain the molecular panel [results]. But excellent points in terms of cytoreduction in a highly symptomatic patient. That is definitely something that I practice. I think most of us consider that and have that in mind when we go to make the decision whether we start that before seeing the panel, which can sometimes take weeks. We know that, especially with a patient in the hospital, the delays can be even longer. So, all excellent points, very valid.

ALBINO: So, we’re talking about one of the sensitizing EGFR mutations, of course, mainly the most common one being exon 19 specifically. [Here] we’re talking about the second most common one and that was obtained when an NGS panel was done. EGFR mutation–positive NSCLC overall probably [presents in] about 15% of all patients, so we know it’s not the majority of all patients; it is going to be a lower amount, relatively speaking. I wanted to get into a discussion now of what everyone’s thoughts were of what to start this patient on in the first line. Does this patient’s PD-L1 expression influence your decision making at all?

Does anybody have any thoughts on the patient being 100% PD-L1 positive? Would there be anybody that would consider using that as the primary decision-making process here in considering immunotherapy despite the EGFR sensitizing mutation?

PHAM: No, I would target EGFR. I wouldn’t even consider immunotherapy at all.

SAES: I would go up front with Tagrisso. In a patient like this, immunotherapy doesn’t have that much benefit in this kind of patient in the EGFR or ALK group.

ALBINO: Absolutely. So you mentioned Tagrisso. I am assuming probably a lot of you would agree with starting Tagrisso as well. Is that the general feeling? Anyone else favor starting Tagrisso with this patient first line with an EGFR-sensitizing mutation despite the PD-L1– positive status?

ARJUNAN: I would also choose Tagrisso.

KOVOOR: I would also start Tagrisso as well, regardless of the PD-L1 status.

ARJUNAN: I would also do Tagrisso.

SHMERLIN: Another vote for Tagrisso.

ALBINO: Anybody prefer using Tagrisso as a second line in case a patient develops an EGFR T790M mutation on a first-generation TKI? So would anybody advocate for using a first- or second-generation TKI for that matter, in case a patient develops an actionable mutation? Being able to use osimertinib in a second line may have, perhaps, an additive effect as well is what I am trying to say here. Would anybody consider that at all—an earlier-generation TKI and then reserve Tagrisso for second line in this particular situation?

PHAM: I think that you have to look at more than just systemic therapy, like the tendency for brain metastasis and all that. Tagrisso is clearly superior.

ALBINO: I absolutely agree with that. Also, I think it’s maybe over simplifying things to think we’ll get that same first-line benefit we see in the data with osimertinib in the second line in the biology of patients that have already been treated with an earlier-generation tumor is probably not going to be the same benefit that you are going to get once you get that T790M mutation to use osimertinib. So, to assume that we are going to get that benefit that we see with FLAURA [NCT02296125] will maybe be a mistake because of that.¹

ALBINO: The concern for toxicity is going to be higher when you’re talking about a combination treatment.

What about the mutational status? Does having a mutation [in exon] 21 or 19 make a difference in your decision making at all or that doesn’t affect?

PHAM: That doesn’t really affect me because I think those are sensitive mutations that it will respond to Tagrisso.

ALBINO: Yes, fair enough. So, anybody who might consider it and why would you consider it?

AGARWAL: I had a question. Why are they not doing a head-to-head trial with this research now? The combination vs [osimertinib]. Is there any trial in process [for] head to head?

ALBINO: Not that I am aware of. So, would you say specifically in any EGFR sensitizing or in a particular mutation?

AGARWAL: Not any 1 I would not. For example, [exon] 20 doesn’t work. This is very compelling data because you can start with this combination and, if they progress, in the side-to-side trials you can see, even with Tagrisso, that the overall survival is very close to each other, and the patients who are positive for this mutation will go on Tagrisso later on.

So, it’s very compelling, but I think now they need to do a head-to-head trial with Tagrisso to prove that this combination may be better and the sequencing may be better also. I am not using it; I would love to use it, but it’s not an option yet.

ALBINO: So you would definitely be interested in finding out if there might be a way to sequence these drugs together or compare them head to head to Tagrisso to see if it can answer those questions; would it be better with a head-to-head option or would sequencing them make sense? That’s an excellent point; thank you for sharing that. Anybody else that might or might not consider or would definitely consider?

STRAIN: Yes, you might consider it if you have a patient who is super aggressive and wants every ounce of benefit, but there’s not going to be many who need this. Yes, I would consider it, but I probably wouldn’t use it in the average patient.

ALBINO: Any specific patient that would move the needle for you and you would say, “Yes, this patient may be a better candidate?” Any specific factor that would make you say, “Oh, this is definitely something I would consider in this patient?”

STRAIN: The younger they are, the more fit they are— if they’re young and fit, where we are trying to get every ounce of benefit.

PHAM: I think the better study would be Tagrisso plus Cyramza. Cause it’s like you’re choosing to combine it with something we already know is inferior.

ALBINO: Great, so you’re referring to the fact that the trial was done comparing a combination with a first-generation TKI, correct?

PHAM: Right, right.

STRAIN: That also begs the question when that study was designed.

ALBINO: It was pretty clearly designed and started approval before Tagrisso and that is a point well taken that the comparison here is to Tarceva and I don’t know who is using it at that point in the first-line setting, and [while it] is still technically in the guidelines, it is not something that is being widely used and is not practical since we are not really using that anymore.

The FLAURA trial did allow patients also with erlotinib, if you look at the trial scheme, the control arm is patients that received either erlotinib or gefitinib [Iressa] for just the second generation, but that is an excellent point that the comparison to the drug is basically only towards erlotinib in this case, which is a drug that I don’t know who is using it at this point in the first line. Anybody else who might or might not consider it or any thoughts on this subject?

STRAIN: It seems like the question they’re really asking is who would consider the use of combination treatment.

ALBINO: So, in this case, the patient received frontline osimertinib, which goes in line with what most of us are practicing right now in the first line for our EGFR-sensitizing mutation patients with stage IV disease.

When we’re talking about resistance for osimertinib in the first line, we are going to have some of these patients that are going to transform and have a lot of targeted mutations.2 So our options are going to be more limited in the patients that develop these off-target mutations and transformations.

So, that’s also something to keep in mind with some patients having these off-target mutations that are not as sensitive. Just something to take home and think about more when making decisions for our first-line patients with EGFR-mutated cancer.

_REFERENCES

_{1. Soria JC, Ohe Y, Vansteenkiste J, et al; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137}

_{2. Schoenfeld AJ, Chan JM, Kubota D, et al. Tumor analyses reveal squamous transformation and off-target alterations as early resistance mechanisms to first-line osimertinib in EGFR-mutant lung cancer. Clin Cancer Res. 2020;26(11):2654-2663. doi:10.1158/1078-0432.CCR-19-3563}