ONCAlert | Upfront Therapy for mRCC

Case 2: Frontline Therapy in EGFR-Mutated Lung Cancer

Targeted Oncology
Published Online:1:10 PM, Thu June 20, 2019


EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Benjamin P. Levy, MD: As Isabel mentioned, it’s important to wait. Let’s go back to the case. This is a patient where we decided not to manage their oligometastatic disease aggressively. We’re going to treat with either a TKI [tyrosine kinase inhibitor] or with immunotherapy because they have both markers. What we’ve learned in the past 2 years is essentially that EGFR-mutant lung cancer is not the right cancer for immunotherapy, at least not for single-agent immunotherapy.

We had a meta-analysis of 5 trials comparing immunotherapy with chemotherapy. We know immunotherapy is better than chemotherapy in the second line, and the meta-analysis basically showed that overall trend—immunotherapy is better than chemotherapy in second-line non–small cell lung cancer. But if you look at the patients who were in those trials who were EGFR mutant, and in looking at those patients, the meta-analysis would suggest there’s no benefit in those who are EGFR mutant. That was the first signal we got that we may need to pump the brakes on immunotherapy with EGFR-mutant lung cancer.

The second, perhaps more convincing and compelling data, was presented at the ASCO [American Society of Clinical Oncology] Annual Meeting as an oral session in 2018, and then subsequently published in the Journal of Thoracic Oncology’s fascinating study. Basically, it took patients who were treatment-naïve and stage IV, roughly 20 patients, and all EGFR mutated, and most of them were high PD-L1 [programmed death-ligand 1]. They basically wanted to ask the question, “Let’s not give these patients a TKI. Let’s just give them immunotherapy, and let’s see how they do. Let’s give them single-agent pembrolizumab.” They’re all EGFR mutated, and 75% of them had high PD-L1 status as well.

You would think that you would achieve some responses in these patients who got single-agent immunotherapy given that 75% of them also had PD-L1 greater than 50%. The response rate was 0. There was no response in these patients to a single-agent immunotherapy. In fact, there were some toxicity concerns with sequencing the immunotherapy followed by a TKI. There is a running joke from this trial, not that this trial was a joke, but it certainly did solidify the lack of evidence for immunotherapy. There was 1 patient in this study who did have a response to immunotherapy. But in hindsight they found out this patient wasn’t EGFR mutated.

It really does alter our perceptions of immunotherapy in EGFR-mutated lung cancer. Also, as Isabel said, the problem that Sam mentioned is that the PD-L1 comes back right away. It’s ready, but the EGFR may take 2 or 3 weeks. We have that coupled with patient enthusiasm saying, “Hey, my PD-L1 is 50%. I want pembrolizumab. I’ve seen that drug on TV; it’s immunotherapy.” I wish I could tell you I’m making this up, but this is what we see in our clinics. I think there is a role of the medical oncologist to temper the enthusiasm on immunotherapy to say, “Wait, we’ve got to wait for some of these mutations to come back.” I don’t know. Isabel, have you struggled with patients really wanting it, and you have to push back? Or do they usually come on board and say, “OK, I’m with you, doctor. I can wait a little bit longer”?

Isabel Preeshagul, DO, MBS: I have definitely had patients coming strong with the desire to get frontline pembrolizumab, or they mention Opdivo [nivolumab] or any immunotherapy that they see on the television. But fortunately, in my practice I have not had patients who have been defiant to me educating them. But I do anticipate that happening 1 day, and I think that having the opportunity to discuss liquid biopsy, to maybe use that to further temper them, may be a nice way to interweave that into my practice.

Benjamin P. Levy, MD: I’m selfish. I want to defend myself, so I’ll just order this liquid biopsy really quickly and get the results, so we’ll have it within 5 days. There are limitations—Sam, you highlighted them eloquently—with liquid biopsies that we still need to iron out.

Anshu K. Jain, MD: Ben, I would add, I think this is a great case that also demonstrates some of the value that radiation plays in these patients, especially patients that are receiving some targeted agents like this. We’ve seen good data that have demonstrated that in patients who were either rendered into or remained in an oligometastatic state that they’re on targeted therapies. You’re essentially putting a selection pressure on these patients, and they may develop or stay on stable disease. You can treat those sites of disease with stereotactic radiation therapy or some type of local therapy, and they can stay on their targeted agent and actually derive at a significant progression-free interval even and not have to change into a second-line or third-line therapy.

Benjamin P. Levy, MD: That’s a great point. The selected pressure that happens and then addressing the selected pressure sites with radiation is critical. Maybe this would be the way that I would manage this patient, to start them out on a TKI and see how they did. If they’re doing well, maybe layer in the radiation, at 3 months or when they progression at the sites. I don’t think we’ve clearly ironed that out yet. But I agree. I think there’s a role in oligometastatic disease for each of our mutated lung cancer cases where you can continue the TKI while you’re delivering the radiation, which is important.

Transcript edited for clarity.


EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Benjamin P. Levy, MD: As Isabel mentioned, it’s important to wait. Let’s go back to the case. This is a patient where we decided not to manage their oligometastatic disease aggressively. We’re going to treat with either a TKI [tyrosine kinase inhibitor] or with immunotherapy because they have both markers. What we’ve learned in the past 2 years is essentially that EGFR-mutant lung cancer is not the right cancer for immunotherapy, at least not for single-agent immunotherapy.

We had a meta-analysis of 5 trials comparing immunotherapy with chemotherapy. We know immunotherapy is better than chemotherapy in the second line, and the meta-analysis basically showed that overall trend—immunotherapy is better than chemotherapy in second-line non–small cell lung cancer. But if you look at the patients who were in those trials who were EGFR mutant, and in looking at those patients, the meta-analysis would suggest there’s no benefit in those who are EGFR mutant. That was the first signal we got that we may need to pump the brakes on immunotherapy with EGFR-mutant lung cancer.

The second, perhaps more convincing and compelling data, was presented at the ASCO [American Society of Clinical Oncology] Annual Meeting as an oral session in 2018, and then subsequently published in the Journal of Thoracic Oncology’s fascinating study. Basically, it took patients who were treatment-naïve and stage IV, roughly 20 patients, and all EGFR mutated, and most of them were high PD-L1 [programmed death-ligand 1]. They basically wanted to ask the question, “Let’s not give these patients a TKI. Let’s just give them immunotherapy, and let’s see how they do. Let’s give them single-agent pembrolizumab.” They’re all EGFR mutated, and 75% of them had high PD-L1 status as well.

You would think that you would achieve some responses in these patients who got single-agent immunotherapy given that 75% of them also had PD-L1 greater than 50%. The response rate was 0. There was no response in these patients to a single-agent immunotherapy. In fact, there were some toxicity concerns with sequencing the immunotherapy followed by a TKI. There is a running joke from this trial, not that this trial was a joke, but it certainly did solidify the lack of evidence for immunotherapy. There was 1 patient in this study who did have a response to immunotherapy. But in hindsight they found out this patient wasn’t EGFR mutated.

It really does alter our perceptions of immunotherapy in EGFR-mutated lung cancer. Also, as Isabel said, the problem that Sam mentioned is that the PD-L1 comes back right away. It’s ready, but the EGFR may take 2 or 3 weeks. We have that coupled with patient enthusiasm saying, “Hey, my PD-L1 is 50%. I want pembrolizumab. I’ve seen that drug on TV; it’s immunotherapy.” I wish I could tell you I’m making this up, but this is what we see in our clinics. I think there is a role of the medical oncologist to temper the enthusiasm on immunotherapy to say, “Wait, we’ve got to wait for some of these mutations to come back.” I don’t know. Isabel, have you struggled with patients really wanting it, and you have to push back? Or do they usually come on board and say, “OK, I’m with you, doctor. I can wait a little bit longer”?

Isabel Preeshagul, DO, MBS: I have definitely had patients coming strong with the desire to get frontline pembrolizumab, or they mention Opdivo [nivolumab] or any immunotherapy that they see on the television. But fortunately, in my practice I have not had patients who have been defiant to me educating them. But I do anticipate that happening 1 day, and I think that having the opportunity to discuss liquid biopsy, to maybe use that to further temper them, may be a nice way to interweave that into my practice.

Benjamin P. Levy, MD: I’m selfish. I want to defend myself, so I’ll just order this liquid biopsy really quickly and get the results, so we’ll have it within 5 days. There are limitations—Sam, you highlighted them eloquently—with liquid biopsies that we still need to iron out.

Anshu K. Jain, MD: Ben, I would add, I think this is a great case that also demonstrates some of the value that radiation plays in these patients, especially patients that are receiving some targeted agents like this. We’ve seen good data that have demonstrated that in patients who were either rendered into or remained in an oligometastatic state that they’re on targeted therapies. You’re essentially putting a selection pressure on these patients, and they may develop or stay on stable disease. You can treat those sites of disease with stereotactic radiation therapy or some type of local therapy, and they can stay on their targeted agent and actually derive at a significant progression-free interval even and not have to change into a second-line or third-line therapy.

Benjamin P. Levy, MD: That’s a great point. The selected pressure that happens and then addressing the selected pressure sites with radiation is critical. Maybe this would be the way that I would manage this patient, to start them out on a TKI and see how they did. If they’re doing well, maybe layer in the radiation, at 3 months or when they progression at the sites. I don’t think we’ve clearly ironed that out yet. But I agree. I think there’s a role in oligometastatic disease for each of our mutated lung cancer cases where you can continue the TKI while you’re delivering the radiation, which is important.

Transcript edited for clarity.
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