Case 3

Dr. Sandip Patel:

We will now move on to case three. This is a case of a 47-year-old Asian woman who had a postinfection chest x-ray after a lingering cough that showed a 2-cm nodule. A follow-up CT was performed that showed persistence of this 2-cm lesion in the right lower lobe, and then a PET/CT showed FDG activity only in the right lower lobe. The patient was sent for bronchoscopic biopsy and EBUS, which confirmed negative mediastinal lymph nodes and primary right lower lobe adenocarcinoma. The patient underwent robotic-assisted VATS lobectomy, with T1c N1 disease with 1 of 14 lymph nodes involved with clear margins. And molecular testing at the time, initial EBUS specimen was insufficient for molecular testing, showed an EGFR exon 19 deletion with a PD-L1 score of 70%.

So, Jessica, maybe I can start with you on this, and I’d love to hear from Greg after. What would this case look like in terms of the diagnostic workup? Would anything be different? And then what would you recommend for this patient next? Either adjuvant chemotherapy for four cycles, radiation therapy, adjuvant immunotherapy for a year, or adjuvant chemotherapy followed by osimertinib for at least 3 years.

Dr. Jessica Bauman:

So, I think this is a similar conversation as our second case in terms of our tumor board, as it really is important to split this of, what local therapies do we have available to us in terms of the patient, comorbidities, pulmonary function tests?

And, for this person, she has an early-stage lung adenocarcinoma that looks to be resectable with a VATS lobectomy. So, a minimally invasive approach that’s surgically resectable upfront. And so, ultimately, in our tumor boards, we’re often thinking about whether this is someone we’re going to approach for surgery upfront. Is there any role for neoadjuvant treatment for this patient? It’s interesting that there wasn’t molecular testing, though this is a fairly young Asian woman, and so that demographic-wise makes you a little bit concerned that there’s potentially going to be a driver mutation as a part of this case, though not necessarily always true. But because of that, I think the role of neoadjuvant therapy certainly plays less of a role in this scenario. We don’t think that this is going to help change the operation in any way.

This is N1 disease. This is not N2 disease. And so, ultimately, I think from the beginning of this, it is appropriate to proceed with surgery to pathologically stage the lung cancer, and then once surgery is able to demonstrate that more carefully in terms of pathologic staging, indeed, we see this is now a stage IIB, and we’re able to get the testing we need with both PD-L1 as well as the NGS testing with an EGFR exon 19 deletion. And this really is exceedingly important because, again, if you just look at PD-L1 in this situation, that would become a red herring in terms of how we would approach this in terms of adjuvant therapy. But the molecular testing really helps guide us in terms of how we’re going to approach this, and ultimately, the data from ADAURA help us make this decision.

The first step for somebody like this would be four cycles of platinum-doublet chemotherapy, as there are decades of data that tell us the benefit of platinum adjuvant-based chemotherapy. And then, I would approach this patient ala the ADAURA regimen with osimertinib after chemotherapy.

Dr. Sandip Patel:

Greg, what would this diagnostic workup and treatment look like in your clinic?

Dr. Gregory Riely:

Yeah. You know, I think it’d look a lot like what you guys did here. The bronchoscopy and EBUS is definitely the approach we like to take to stage a patient. You know, I think thorough staging of the mediastinum is always appropriate. And, you know, no matter if the patient’s got PET-negative disease, it’s very important to do invasive mediastinal staging. You know, sometimes that invasive mediastinal staging can be done on the same day as the operation, where they do it intraoperatively, and they have on-site cytology evaluation. But mediastinal staging is critical, because there is a real false-negative rate for PET, and it’s something that’s important as part of the full evaluation and treatment of a patient with lung cancer.

Now, I think when we get to the treatment, surgical resection, particularly in a 47-year-old person, this person has the wherewithal to benefit from all that we can provide. And so, a good surgery is critical. And then, as Jessica says, follow up with four cycles of adjuvant chemotherapy is perfectly appropriate.

Now, I said, oh, they can handle everything we can throw at them. Does that mean we should throw radiation at them? And I think the true data say that there’s no clear value for radiation in this context. You know, people can read the tea leaves and can find little areas where they might feel there’s some value for radiation, but not in this case, and so I think we can cross radiation off our list.

But after the patient has completed four cycles of chemotherapy, and she’s got a known EGFR mutation, we have clear evidence that says giving osimertinib afterward makes a difference, and so that’s what I’d recommend as well.

Dr. Sandip Patel:

Absolutely, and I think the benefit, the magnitude of benefit, with adjuvant osimertinib for 3 years, disease-free survival hazard ratio in the overall population, stage IB, stage II, stage IIIA, hazard ratio is 0.2. That’s about as good as it gets in terms of disease-free survival that we see in any oncology study. An overall OS hazard ratio about 0.49 at 5 years. So, really showing that we’re making a positive difference.

And then, we turn to the side effects one would expect from osimertinib. In this study, it’s the same dose you get in the metastatic setting or the post concurrent chemo rad setting, 80 mg. And, here, there wasn’t as much of a concern on radiation risk because there wasn’t radiation in the locally advanced setting, but interstitial lung disease was something to pay attention to. About 2% of patients, especially with patients who’ve had surgery. Something for us to keep in mind.

Now, one thing I’ve noticed, I’d love to hear from both of y’all, is that my patients who get a diagnosis of metastatic non–small cell lung cancer start osimertinib 80 mg, they come into clinic not feeling well because of their cancer, and so, they’re able to stay on 80 mg, because they get a really dramatic improvement in all their cancer-related symptoms. But for my patients who are basically minimally symptomatic from their cancer, whether it be stage III or more localized, at least in my clinic, often had to do more dose reductions, especially because they’re in it for the long haul. Here for 3 years in the locally advanced setting after chemo rads for 4 years.

So, in this case, this patient had fatigue and paronychia, and it was really starting to affect her livelihood. And so, we did do a dose reduction. The first dose reduction for osimertinib is to cut it in half. So 80 mg to 40 mg. She continued to do well. Every 3 months, had CT scans, no evidence of disease.

And then we were left with the question on what to do at year 3. And so, I’d love to get your sense on toxicity management and what do you guys discuss in year 3? You’re told this is an important therapy to keep the cancer away. Is it suddenly not important in year 4 and beyond? Jessica, I’ll start with you. What do these conversations look like in your clinic?

Dr. Jessica Bauman:

 So, I do think that this is a challenge. The data from ADAURA show 3 years of osimertinib. And so, I think that, as of right now, that’s the FDA-approved approach for patients like this. And I think that although, yes, the toxicities can become chronic and a little bit difficult to manage, they are still often, we think of them from an oncology perspective, as they’re easier to manage than a new diagnosis of metastatic progressive cancer in the brain or the bone or whatnot.

And so, I do think the 3-year mark is a challenge in terms of patients who are doing well, who are tolerating it decently well, and to have them go off, and it will be really important for us to get more data in that space in terms of MRD testing. If there’s some way to say, do they have disease still present that they’re benefiting from osimertinib? And I think, like the other case where, once you get to year 5, 10, or 20, if you were to be able to continue the osimertinib that long, then perhaps, you know, okay, this patient probably was cured even with early therapy. But I think the challenge is, do we really take them off, or is it going to be like breast cancer, where you have 5 years of hormonal therapy, then 10 years of hormonal therapy? And that’s how we’re going to start approaching osimertinib in this population.

Dr. Gregory Riely:

Yeah, and I think really the crux of the challenge is knowing what’s their true disease status? You know, it’s sort of easy for us to look at the data and make clear, but then we know that, buried in that data, there is, maybe it’s a third of the patients with stage II disease were cured by their initial surgical resection, and all of the torture we put them through is worthless. And, by contrast, you know, among the group of patients who were destined for recurrence, you know, some of those you might actually cure with your chemotherapy, with your osimertinib, but, at what point have you cured them? And at what point are you still suppressing? And we don’t have the perfect knowledge to know today.

That said, you know, when I get to the 3-year mark, I’m nudging toward stopping. You know, that’s the default plan. That’s what we lay out from the start, and I think it’s the right thing to do. The occasional patient with severe concern about wanting to stay on, I’ll continue for them because it’s not unreasonable, but in general, that strategy should be to stop because that’s what the data say, and there’s a decent chance for a lot of these folks that they’ve been cured along the way.

Dr. Sandip Patel:

Absolutely. We had a curative-intent strategy, and yet we’re telling folks, here, take this pill we give in the metastatic setting every day. And so, I think these discussions are difficult for our patients. I think these discussions are difficult at tumor board.

I think, you know, the themes we’ve heard, and I want to thank you, Gregory and Jessica, for your insights here, have been around molecular testing, getting folks appropriate treatment, making sure the PD-L1 is interpreted in the context of the patient’s mutations, making sure we get a good mediastinal assessment. Right. It’s not just the PET/CT, but it’s actually the pathology that matters.

And so, with this, I want to thank Greg and Jessica for a really nice discussion around adjuvant treatment from the ADAURA study. This brings us to the end of our discussion of these three case studies in the management of patients with EGFR-mutated non–small cell lung cancer, with a focus on targeted therapy. And I’d like to again thank my colleagues, Dr. Greg Riely and Dr. Jessica Bauman, for participating in this important clinical conversation and for sharing their expertise with us today.

Dr. Gregory Riely:

Thank you, Sandip.

Dr. Jessica Bauman:

Thanks, Sandip.

Dr. Sandip Patel:

Thank you.