Dr. Heather Wakelee:
Welcome to The ASCO Post Roundtable Series on New Directions in Nonmetastatic Non–Small Cell Lung Cancer. I'm Dr. Heather Wakelee, Professor of Medicine and Chief of the Division of Oncology at Stanford University and Deputy Director of the Stanford Cancer Institute. Joining me today are two fantastic colleagues, and I'll let them introduce themselves.
Dr. Marina Garassino:
Hi, my name is Marina Garassino. I am a Professor of Medicine at the University of Chicago. And I am the Director of the Thoracic Oncology Program. Thank you for having me.
Dr. Tina Cascone:
Hello everyone. Such a pleasure to be here. I'm Tina Cascone. I'm an Associate Professor in the Department of Thoracic/Head and Neck Medical Oncology at MD Anderson. I'm also the Director of the Translational Program at MD Anderson Cancer Center. Thank you for having me.
Dr. Wakelee:
Great. Well, I'm so glad you both could join me. You've both done so much in this field of perioperative therapy in lung cancer. And for the audience, just because we are all such good friends, we'll be using first names as we chat through today.
Today, we will be discussing the treatment of resectable nonmetastatic non–small cell lung cancer with three patient case studies. Our first installment will focus on immunotherapy approaches for resectable non–small cell lung cancer.
So, as we go through our first case, Miss AL is a 68-year-old woman. She has a 70 pack-year smoking history, but quit about 5 years ago. She remains very active. She's walking about 2 miles a day.
She underwent a screening CT scan, and unfortunately was found to have a 3.7-cm right upper lobe mass. This was biopsied. It was confirmed to be adenocarcinoma. We know it was lung, we'll assume TTF-1 positive. And she had further staging which showed that there was uptake on PET in a 10R lymph node. But there were no other suspicious sites besides the main mass and that 10R node.
So, Marina, what additional steps would you consider before you decide on next treatment steps? So, she got a PET. Yeah.
Dr. Garassino:
Yeah. So, basically what is important to do now is to check the mediastinum, so to do the EBUS in all the other stations to be sure that all the stations are clean. And then, test for the PD-L1 expression if possible. And test also for the NGS, so we can have the right approach for the patient. And then, we can discuss everything in the multidisciplinary tumor board.
Dr. Wakelee:
Tina, do you agree?
Dr. Cascone:
Yeah, absolutely. I think I echo what Marina recommended. I think, in this case, this is paramount to have an invasive mediastinal staging, as Marina mentioned. Either with bronchoscopy with endobronchial ultrasound and biopsy, in other centers mediastinoscopies is what is preferred.
And then, of course, once we have those results, the multidisciplinary tumor board is absolutely essential with our thoracic surgery and thoracic radiation oncology colleagues. And I think, after we have completed this portion, just for the sake of being thorough, I would also have an MRI of the brain to make sure there we're not missing any potential occult lesions at baseline.
Many times, patients are symptomatic at this stage. So, I think that's something that we have to keep in mind. And I agree with the molecular profiling, of course once we have got all the results of the consultation and the invasive mediastinal staging.
Dr. Wakelee:
Great. Are there any patients where you wouldn't do the brain MRI?
Dr. Cascone:
Yes. Perhaps I'll take this one first, and then really looking forward to hear Marina's thoughts. This is something that we always discuss in the multidisciplinary tumor board.
Usually, whenever I see a lesion that is greater than 3 cm, if the patient is potentially a resectable candidate, I tend to order an MRI of the brain. If the MRI of the brain is not possible, for reasons that are related to comorbidities, then I will have a CT.
But I tend to be conservative on that if there is a lesion that is greater than 3 cm. And of course, here we also have, at least in the PET, lymphadenopathy positive. So, that's something that I always keep in the back of my mind.
Dr. Garassino:
Fully agree with Tina
Dr. Wakelee:
Yeah, me too. Good. All right. Next provocative question there. You both stated pretty clearly that you would recommend invasive mediastinal staging. Yet, when we look at the emerging neoadjuvant and perioperative chemoimmunotherapy trials, if this patient does have mediastinal nodal involvement, we might consider the same approach of going in with upfront chemotherapy, immunotherapy, assuming we don't find a driver mutation.
And I've definitely heard surgeons in our tumor board talk about the fact that they don't want to do invasive mediastinal staging twice. And so, some of them would prefer that we just start our neoadjuvant component, and then do that invasive staging after, as they're doing their pre-surgical. And even at the time of surgery, doing that component first, and then not proceeding if there's very extensive mediastinal nodal involvement. Or just proceeding anyway, if they're able to do so.
And so, I think that's still a little bit of an area of controversy. And acknowledging we're all medical oncologists, and whenever my surgical onc colleagues start talking about all the medical oncology part, I'm like, "Uh." So, I don't want to delve too deep into surgical decision making, acknowledging that we're all medical oncologists.
But I'm just curious, are there times where it would make sense? This is a patient that we think would go to surgery, has a lot of things where we think it's unlikely that they're going to have a driver mutation, heavy smoking history. So, it's probable this is someone who's going to get a chemoimmunotherapy approach, at least from first glance.
How does the mediastinal staging help in this case? What would make you decide on a different approach? I guess that's the question. And so, maybe we can talk about that a little bit.
Dr. Garassino:
This is a good question. I'm always in favor of knowing rather than finding at the end, because then sometimes we are not able to evaluate the real response. I think we are just in the beginning of the learning curve with the neoadjuvant immunotherapy in general. So, maybe the paradigm will change in the future. And maybe we will not stage the patients and we will do everything at the end.
But for the time being, I would stick with very conservative approach and not avoid to stage the mediastinum in a proper way. Because just we don't know. So, maybe at the end in 3 years, we will discover that they are right, but not for now.
Dr. Cascone:
I agree with Marina. I tend to be quite conservative for a number of reason. The false-negative rate of PET, especially in this setting, might not be negligible.
And I think we want to be sure, if we're in the true resectable setting, that we really rule out potential occult entry disease because that will definitely change our management. Many times, we also have different degree and extensive discussion with our surgeons if we have N2 multi station, N2 bulky disease as compared to have an N1 solo region, as we see here from the PET in the noninvasive mediastinal staging workup.
So, I agree with Marina. I would do an invasive mediastinal staging at baseline in a mandatory fashion. And then, to your point, I actually would encourage rediscussion of patient in this setting at multidisciplinary tumor board after the induction phase prior to resection.
In real life, in real practice, we see many scenarios where patients were initially considered deemed resectable, for anatomical or functional reason are no longer dispositioned to surgery. So, this is something that, to me, is actually very important to provide to patients in this setting, the resectable setting, the best multidisciplinary approach.
Dr. Wakelee:
Great. Okay. So, further testing comes back on this patient, where an MRI is fine. Invasive mediastinal staging is done, doesn't reveal anything else. We have a PD-L1 level that came back at 85%, so quite high. And the KRAS G12A mutation is found with no other drivers identified.
Let's keep going through this. But I think one of the questions that's going to be a lot in the community is, "How long can you wait for those molecular results in a patient like this where you think the probability of having a driving mutation is low? And what about for those where you think they might be?" So, that's going to be part of it.
But what are the options for treatment at this point? So. This patient's fit. She's 70. She has a 10R node involvement, relatively large primary tumor, high PD-L1. Tina.
Dr. Cascone:
Yes. So, Heather, I think we have several options, based on the standard of care. And I think that the paradigm, as Marina mentioned, will continue to evolve. And we'll see more strategies perhaps in the very near future, being part of the standard of care.
But I think at this point, with these patient factors, and with a tumor board that tell us that the patient is resectable, so is medically operable and is surgically resectable so we can achieve a radical resection, we could disposition the patient to a neoadjuvant immunotherapy-based approach. Because we have ruled out the presence of oncogenic drivers for which targeted therapies in the adjuvant setting would be the standard of care.
So, in this case, a platinum-based chemotherapy approach plus immunotherapy. Nivolumab as part of the CheckMate 816 paradigm, pembrolizumab as part of the KEYNOTE-671 paradigm, or again nivolumab as part of the perioperative as the 671 paradigm.
I want to mention, you gave us a very important piece of information, 85% PD-L1. So, I'm really curious to hear Marina's thoughts here. So, we are in the high PD-L1 tumor, PD-L1 positive setting. And the choice between a neoadjuvant only approach vs a perioperative approach is something that we all continue to discuss.
And I think probably the major actors in this discussion are really the patients, together with us explaining the data and the benefit that we can achieve with three cycles only of neoadjuvant chemoimmunotherapy based on the CheckMate 816, as compared to four cycles of chemoimmunotherapy in the preoperative setting followed by approximately 1 year of immunotherapy. Something that to me is absolutely critical to discuss with our patients because, at this moment in time, we don't have randomized trial data to tell us what's the contribution of the components specifically from these approaches.
Dr. Garassino:
I fully agree. Tina already did a lecture on this, and so I don't have to resummarize again. But if we look at the data of the 816, we have another ratio of 0.68 compared to another ratio of 0.58 for the 77T. So, we don't know. And the confidence intervals overlap a lot. So, the benefit of the adjuvant component is still a question mark.
And that would be also provocative to say that this patient is PD-L1 85%, so maybe one day we will arrive to the idea that maybe the immunotherapy alone without the chemo will be enough. So, I think that this is clearly part of the research that we will do in the next years. I think there is a lot of importance that will come maybe from the liquid biopsy, but not only the liquid biopsy, because the big problem is we don't know if we are able to revert an MRD positive with immunotherapy.
So, we don't know, if a patient is fully resected and has a liquid biopsy positive, if we are able to turn, just with immune checkpoint inhibitors, the positive into negative. So, I think that is fantastic, that in 2023 we are talking about escalating options and deescalating options. So that, when we started to treat lung cancer, was not an option.
Dr. Cascone:
Heather, may I add an important additional comment. You had a very important question. How much are we willing to wait for molecular profiling coming back? And this is a question that I'm sure all of us get posed by our patients. And this is an important issues because, of course, there are centers where this type of testing results return in more expedited manner as compared to others, where more time is required.
And so, I also want to mention that, in this setting, an upfront surgical resection followed by adjuvant treatment is also potential options as part of the standard of care with the PD-1 positive as part of the IMpower010. That you know very well. And also, regardless of PD-L1 expression in all cohorts as part of this trial. So, just a third option that we have enhanced for our patient to consider.
Dr. Wakelee:
Great, wonderful point. So, this patient actually is treated with carboplatin, paclitaxel, and nivolumab prior to surgery. And this is one of my patients. She hasn't gotten to surgery yet.
And so, at the time of surgery, we will be of course seeing what kind of a pathological response she has had. We don't have any standard ctDNA minimal residual disease testing that I use, so we do a lot of that for research. And I think the question about do we continue the adjuvant or not is one that of course will be a part of upcoming trials, which will be really critical, because we don't know how to pick yet between a pure neoadjuvant and a perioperative.
But this was a great discussion on this case. I'm just going to emphasize a couple of key take homes. One, it's really important to complete staging prior to making any decisions. We emphasize the importance of that multidisciplinary tumor board discussion early, and repeatedly, for these types of cases. We talked about how crucial it is to get that molecular testing, ideally prior to choosing therapy.
But to Tina's last point, if this is someone you really feel like surgery would be a good choice upfront, going to that first, and then you can make the decisions once you have all of that molecular testing back, especially for someone where there's a high pretest probability, is very reasonable. PD-L1 testing can be very helpful and informative in making that decision treatment.
And then, for patients with stage II and III non–small cell lung cancer, neoadjuvant chemo-IO, perioperative chemo-IO, surgery followed by IO, or adjuvant IO after surgery and chemotherapy are all very appropriate options. And again, it takes that multidisciplinary discussion.
So, this brings us to the end of the case. And please see the other segments for further discussion about the latest data in non–small cell lung cancer or visit ascopost.com. Thank you.
