Case 2

Dr. Jessica Bauman:

So, we’ll now transition to our second case. A case of advanced nonresectable disease setting with a patient who also has an EGFR mutation. In this case, our patient is a 70-year-old man who has a history of hypertension and coronary artery disease. He also has a 15 pack-year of smoking, and he presented to his primary care doc with a persistent cough, similarly to our first patient, who also had a lingering cough.

He had a chest x-ray that showed a left lower lobe mass and then had a CT chest that showed a 3-cm left lower lobe mass with mediastinal adenopathy. Because of that, he then went on to see a pulmonologist who ordered a PET/CT and then arranged further testing. The PET showed an FDG-avid mass with hilar and mediastinal lymph node avidity, and there were no other metastatic sites that were concerning at that point in time. A brain MRI was also ordered and was negative.

And then, ultimately, a bronchoscopy to make a true diagnosis was arranged, and the bronchoscopy with endobronchial ultrasound confirmed an adenocarcinoma in the left lower lobe, and there were also lymph node metastases in N1, N2, and N3.

At that time, there was molecular testing that was done as well as PD-L1 testing. The molecular testing showed an EGFR exon 19 deletion mutation, and the PD-L1 showed a PD-L1 of 70%. And so, ultimately, this patient has a diagnosis of a T2 N3 M0, or a stage IIIB, non–small cell lung cancer with an EGFR mutation.

So, ultimately, I’m curious, first I can open this to Greg and Sandip, of what your tumor board discussions look like for a patient like this, perhaps before you even have the molecular testing back.

Dr. Gregory Riely:

Maybe I’ll jump in first with ours. The challenge with every case that’s not clearly metastatic is determining whether the patient has resectable disease. That’s my first decision point in the algorithm is, is this disease resectable or not? And now, you notice I didn’t say potentially resectable. You know, the patient has to see a surgeon who says, yes, I can operate and remove this patient’s cancer completely. And when you have that answer as yes, then you can head down a path thinking about neoadjuvant therapy and whatever that might look like for a given patient and then proceed to surgery. But, if that decision point says no, this patient does not have resectable disease, which I think most people would guess in this context, then we’re heading down a pathway that involves chemotherapy and radiation, and then that decision making is more about patient performance status, molecular testing results, and that kind of thing.

Dr. Jessica Bauman:

Right. Sandip, any other thoughts from your tumor board?

Dr. Sandip Patel:

No. I think, to echo Greg’s point, these discussions are quite similar. Is this an operative case, both in terms of the tumor characteristics, right, N2, N3 nodes invasion, but also host characteristics? Is this a patient who can tolerate a lobectomy if it’s needed? Can this patient tolerate being on a ventilator? So, I think these factors are key.

I think the one thing that really highlights in this case is this a patient with EGFR exon 19 deletion. So, it’s not sufficient nowadays if someone says EGFR-positive. Right. They get an exon 20 insertion, they can have an atypical mutation. So, I think kind of the full street name and address here for the EGFR exon 19 deletion is important. And also, here, the PD-L1 is 70%. And so, it’s a red herring for the use of immunotherapy in terms of a PACIFIC-style regimen or an adjuvant or even neoadjuvant approach or perioperative approach.

And so, I think the molecular information increasingly is part of these multidisciplinary discussions. Unfortunately, the kinetics for sometimes getting back that NGS testing can be slower. And so, to Greg’s point, you’re often discussing the tissue, the histopathologic factors, and the host factors and then waiting for the molecular information after the fact.

Dr. Jessica Bauman:

Agreed. And so, if there were multiple different options for this patient, if you were to think about the role of neoadjuvant chemoimmunotherapy in this patient followed by resection and then immunotherapy vs looking at neoadjuvant osimertinib followed by resection and then osimertinib, or would you prefer nonsurgical management and proceed with chemoradiotherapy followed by immunotherapy ala PACIFIC, or would you do chemoradiation followed by osimertinib. Greg?

Dr. Gregory Riely:

So, I think, again, you know, for me, is this patient resectable today? And I think, with N3 disease, it’s hard to find a capable surgeon who will say yes to that. And so, I would kind of cross off the neoadjuvant approaches and then think more about that question after I do concurrent chemo RT, because nothing has been shown in the sort of acute phase of concurrent chemo RT to make that better. No preop or no prechemo RT TKI, no TKI during chemo RT has been adequately explored here to consider that.

So, you’re going to give the concurrent chemo RT, which we all have our own favorite combination for, and then the question is, what do you follow it by? And, for this patient, you’ve got sort of two distinct paths you could choose. So, you could say, well, the patient’s got a high PD-L1 score, so I want to follow my concurrent chemo RT with immunotherapy. Or you could say this patient has an EGFR mutation. I want to start with osimertinib after the patient has completed concurrent chemo RT. I think it’s clear when you look at the data that, for patients with EGFR mutations, they just don’t get a lot of benefit out of that immunotherapy approach, and we have very clear data with the ADAURA trial that giving osimertinib after concurrent chemo RT improves outcomes. And so that’s the approach I’d take.

Dr. Jessica Bauman:

Agreed. So, I do think that one of the things that’s really important for this case is exactly what, Greg, you were talking about, is sort of this decision about durvalumab. I think when the PACIFIC trial came out many years ago, the standard of care for unresectable non–small cell lung cancer became chemoradiation followed by durvalumab, but we’ve all known that patients with EGFR mutations don’t do as well with durvalumab. And so, when we have patients like this, it presents a clinical conundrum, because we know that they really haven’t traditionally done well, and so many people observe them. But also, this is a patient population that has a very significant concern for recurrent disease progression. Over 75% of people will progress. And so, this leaves us certainly in a position where more data are desired.

I think that’s what was really exciting when we saw the LAURA study presented last year and published that showed exactly this question of this patient population who got chemoradiation were either given maintenance osimertinib or placebo after their chemotherapy and radiation. And we saw a very statistically significant and clinically meaningful improvement in progression-free survival. The patients who received osimertinib had a PFS of 39 months, and placebo was only 5.6 months in terms of PFS. So very significant hazard ratio. And we also saw in the secondary endpoints a significant improvement in CNS progression-free survival as well as time to development of metastatic disease. And so, the LAURA trial really has changed the standard of care for this patient population in the recent years.

Dr. Gregory Riely:

You know, I think the thing that jumped out to all of us when we first saw the LAURA trial data was just how difficult a time the patients who were on the placebo arm had, with very rapid recurrence, you know, a median progression-free survival of 5 and a half months for what we kind of thought was our best group of people to get concurrent chemo RT. They are definitely not, you know, the kind of old school trials. These patients are younger, healthier. They were generally people with minimal smoking history who had better pulmonary capacity, and they had very rapid recurrence after the concurrent chemo RT, and so that made the outcomes with osimertinib even more impressive.

Dr. Sandip Patel:

And, to add to that more, you know, to Greg’s point, the CNS preventative effect, right, giving osimertinib reduced the rate of CNS metastasis in a stage III population by 83%. And so, the natural history of EGFR mutations is unfortunately a propensity to try to seed the brain, even in the stage III setting. And so, with osimertinib, which is given indefinitely here, right, as opposed to 3 years in the adjuvant setting, we can mitigate that risk.

And, to me, the other aspect that goes with some of these discussions around PACIFIC vs LAURA, even in high PD-L1 case scenario like here, is that the PD-L1 is a bit of a red herring in terms of biology, and also, if and when the patient has progression, because the placebo arm is rough, and that’s effectively what they’re getting the vast majority with IO, the ability to cross over to a front-line small-molecule strategy like osimertinib is limited by our immune pneumonitis risk, and that risk can manifest for up to 6 months, which is longer than the median PFS on the placebo arm of LAURA. So, something to keep in mind in terms of order of operation, as we sometimes box ourselves in in terms of our therapeutic strategies based on some of these side effects.

Dr. Jessica Bauman:

Absolutely. And I do think it was really interesting as a part of LAURA is that many of the adverse events you’d expect from osimertinib, things like diarrhea, rash, decreased white blood cell count, as well as increased LFTs that were mild, but this concern about radiation pneumonitis and pneumonitis, which was increased in the patients who received osimertinib, is one of the concerns about the data from LAURA. Thankfully, most of the patients who did have radiation pneumonitis were able to still go back onto osimertinib as a part of the study, but it definitely makes you think carefully about the potential side effects of the drugs that you’re giving.

I’m curious what your take is on the toxicities in terms of giving osimertinib indefinitely and how that has influenced your conversations with patients in rooms.

Dr. Gregory Riely:

It’s kind of interesting to think about that this is a sea change in the way we approach treatment of nonmetastatic cancer. You know, we’ve always had these limited durations of treatment, albeit sometimes long, 1 years, 3 years, or whatever, but this one is indefinitely. I think we’re all impressed by the tolerability of osimertinib or single-agent TKI in the metastatic setting because the comparator is tougher. You know, I think we, similarly, in the adjuvant therapy section that we’ll talk about in just a little bit, the ADAURA data, you know, it was more difficult to take than you might expect, but on the other hand, I think I find that this one is a very manageable one.

As with every treatment that you’re on for a long time without evidence of cancer growing, the conversation kind of comes back to, hey, do I need to keep going with this? And the difficulty is that we don’t have an answer for that today, and when you think about a patient 5 years out from treatment, 10 years out from treatment, how do you think that through? That’s a research question for us to come to in the coming years.

Dr. Jessica Bauman:

Absolutely. And I think one of the pieces of this is that it will be helpful to know what the survival data look like. At least in the first publication, the survival was still only at about 20% maturity. And so, at least as of right now, we don’t know, does this in fact show an improvement in overall survival, or is it really just more progression-free survival?

And so, when we go back to our patient, our initial patient, he finished his chemoradiation and started osimertinib. He initially experienced grade 1 liver function test elevation, rash, and leukopenia, all of which were mild and tolerable. But then, at 3 months, not surprisingly, he developed worsening shortness of breath, and scans showed pneumonitis in the radiotherapy fields. Osimertinib was held, and he was treated with a prolonged steroid taper. And symptoms then resolved, thankfully. The pneumonitis improved on imaging, and he was able to restart osimertinib without further issues. And so, now, he, for an example for us, is tolerating the osimertinib after 3 years and is coming in to see me.

So, I think that takes us to that question that Greg is asking is, how do we approach patients like this? Are there any strategies to figure out who is benefiting from these treatments? Is there any kind of longitudinal biomarker that we can look at? I’m curious what your thoughts are, Sandip.

Dr. Sandip Patel:

Yeah, it’s a great question, and also, for N3 patients, they’re going to get concurrent chemo rads, but for a patient with N1, N2 disease where you could have a robust discussion, especially single-station nonbulky N2, around surgery vs concurrent chemo rads, the cancer cell doesn’t know what strategy the tumor boards selected, right, in terms of the duration. Right. Oh, there’s a surgeon who was a little louder in tumor board. I only need 3 years of osimertinib. Right. And so, you get into these discussions around really what kind of makes the most sense for the patient. Oh, it’s a radiation strategy. It has to be indefinite.

I am hopeful that MRD strategies will help us long term with this. I know these tests are expensive, but treating forever, right, and treating for years is forever. And we get a bit into, and, Greg, I think nicely alluded to this, I like to call it the paradox of duration. Right. The patient who takes it for 20 years and never has cancer come back probably didn’t need it. Right? They probably were cured with their definitive strategy.

Meanwhile, a patient who has progression and maybe now a MET amplification maybe 3 or 4 years in, that’s the patient who actually got some benefit. And then you really get in the question, did we just start the clock earlier, or did we actually benefit this patient’s survival?

And so, I think what I took away from LAURA is the natural history of EGFR-mutated lung cancer with just chemotherapy and just radiation is unfortunately problematic. And I think osimertinib plays a key role in treatment of this patient. Getting appropriate molecular testing. And if anything, we can actually question our local therapies, including chemotherapy and radiotherapy when you start to see control curves look like that relative to the potent effect of osimertinib and what a survival curve that looks like micrometastatic disease as opposed to stage III.

Dr. Jessica Bauman

Right. Well, thank you so much for this discussion of our second case. I think we’re ready to move on to our third case.