Dr. Alder:
Welcome to Integrating Immunotherapy Across the Small Cell Lung Cancer Spectrum, an ASCO Post Roundtable. I'm Dr. Laura Alder, an Assistant Professor of Medicine and thoracic medical oncologist at Duke Cancer Institute. Joining me today are two of my esteemed colleagues and friends. I'm going to let them go ahead and introduce themselves.
Dr. Choudhury:
So I'm Noura Choudhury. I'm an Assistant Professor and a thoracic medical oncologist at the University of Chicago. I'm happy to be here today.
Dr. Cooper:
I'm Alissa Cooper. I'm a thoracic medical oncologist at Dana-Farber Cancer Institute in Boston. Pleased to be here.
Dr. Alder:
Great. Thank you both so much for joining me today. I'm so excited about this conversation. There's been so many exciting changes in small cell lung cancer. So for the first case, we'll start with the management of limited-stage small cell lung cancer. So we'll go right into our first patient. This is JT. She's a 62-year-old female who presents with a persistent cough and hemoptysis. As we get her background information, she's a current smoker, 40 pack-years. She has a history of hypertension and COPD. A CT of the chest is done, which shows a 4.5-cm left hilar mass with ipsilateral mediastinal lymphadenopathy. A biopsy is done, which confirms small cell lung cancer. She has a good performance status and is very active at home. ECOG performance status of 1. So Dr. Choudhury, Dr. Cooper, what additional workup is needed at this point and what's going through your head?
Dr. Choudhury:
Yeah, I can go ahead and get started. So for small cell, especially if we think that this is a presumed limited-stage small cell lung cancer, which is more clinically defined as a small cell lung cancer that is only in one hemothorax that can be encapsulated safely within a single radiation field. Without distant metastases, it's important to confirm the lack of distant metastases and that notably means to get a brain MRI, which is more sensitive at detecting brain metastases, and commonly to also get a PET scan to look for occult disease, specifically things like bony metastases that might be missed on initial CT imaging.
Dr. Cooper:
I would emphasize exactly what Noura said, but I would also just echo that some of the things that end up happening when we get referrals from outside institutions, sometimes their imaging is maybe several weeks old. Always make sure that to repeat the imaging so that we have a fresh baseline just before we are seeing the patient or just when we're seeing the patient. I do think that the challenge of small cell lung cancer is such a quick-moving disease. And so unfortunately, sometimes weeks can make a difference in the upstaging of the disease.
Now in reality, we know that it's not like a metastatic site and a bone grew overnight, but it does take time for radiographically occult disease to become visible. And so it's really important to have a fresh baseline at the time that we're fully staging the patient. And just to really echo, the MRI brain is key, and it's really tricky for patients who, for whatever reason, can't undergo an MRI if they have a pacemaker or other contraindications, but CT head, unfortunately, is not as good of a substitute and so would proceed with caution if you have a patient who hasn't undergone an MRI or can't undergo an MRI for any reason.
Dr. Alder:
It's a great point. Dr. Choudhury?
Dr. Choudhury:
I was going to say going along with that, I completely echo Dr. Cooper's point, that time is really of the essence. And so sometimes specifically depending... One of the scans that I find sometimes difficult to get in a timely manner is actually exactly the brain MRI. So one thing that I have sometimes done, especially if somebody is symptomatic, is I go ahead and start the chemotherapy because we're probably going to add radiation with cycle 2 anyways. I get the brain MRI and if we need to pivot to an extensive-stage diagnosis and treatment, that way I still feel like the patient has gotten some treatment going. So I use that in select cases if circumstances are such that that brain MRI is going to be 2 or 3 weeks delayed and there's nothing that I can do to make that be scheduled sooner.
Dr. Cooper:
I think that's such a great point. And I think that the time is of the essence is such an important concept of this disease, especially in limited-stage where we have a very narrow window to intervene. And I think for that reason, some of the most important thing that can be done at this point in time is immediate call to your radiation oncologist, immediate call to any other sort of consulting services that you need. If you need more tissue, if you need anything, just make sure that everyone is sort of on your speed dial. I've actually thought that there should be a pathology to oncology kind of pipeline, like an urgent page if the diagnosis of small cell is made from a lung biopsy so that we can just get going right away. And so specifically having a quick radiation oncologist on board is key here too.
Dr. Alder:
Yeah, these are great points. I think the highlighting that this is an urgent disease that can change really quickly, the need to start treatment soon. Dr. Choudhury, I really liked your point of if there's any doubt or any concern about that timing, adding a cycle of carboplatin/etoposide until you decide we want to add in radiation, do we want to add in durvalumab if it's extensive-stage? Even sometimes looking for a clinical trial as more and more hopefully are allowing at least one cycle before that decision point needs to be made. And that's always a really good trial designed to incorporate that. But really good discussions. Thank you both.
So for this patient, she has a staging workup, and so FDG PET-CT confirmed the left hilar mass we had discussed as well as is mediastinal lymph nodes and there's no distant metastases. Brain MRI with and without contrast is done and that confirms no evidence of brain metastases. So after both the PET and the brain MRI, this is confirmed as limited stage or T2B N2 stage 3A. And as Dr. Choudhury mentioned, that is something amenable within one radiation treatment field. And as you both mentioned, it's so important to involve multidisciplinary care from the very beginning so it's not to delay anything in a patient's workup treatment plan and then eventual therapy. And usually that's a multimodal approach no matter the stage in small cell lung cancer. And so moving on, what treatment options would you discuss on the day that you see this lady to discuss her imaging?
Dr. Cooper:
Yeah. So for a limited-stage small cell lung cancer like this with a mediastinal node involvement, the standard of care is concurrent chemo and radiation together. Typically, four cycles of platinum-based chemotherapy, usually the chemotherapy may proceed the radiation by a few weeks or so just sort of logistically with planning. Typically, you do try to mix in the radiation as soon as is feasible, ideally probably by cycle two or so. And whether that decision is BID radiation or once-daily radiation is, I do leave that discussion to my radiation oncology colleagues about what ends up being feasible for the patient. BID is a bit of a tough thing to coordinate sometimes for patients with jobs and other things going on, but we do know there may be a slight benefit to the BID radiation schedule. So I sort of leave that discussion to the radiation oncology colleagues and talk about chemotherapy as sort of the medical oncology backbone.
In 2026, of course, the standard of care is now in the era of the ADRIATIC trial. So this was a huge benefit for our patients. It looked at the incorporation of durvalumab after concurrent chemoradiation. Once patients had received concurrent chemoradiation and had not had progression, so that's pretty key, that they had a scan at that time point and had not experienced progression to go on to receive durvalumab vs placebo for up to 2 years. And that study was wildly positive and very exciting. A couple of years ago when it was presented at ASCO, the median overall survival was markedly improved from about 33 months to about 55 months. The hazard ratio was 0.7. I think there was a lot of discussion about why checkpoint inhibitor was so much more beneficial in this setting than potentially for extensive-stage disease. I do think it's interesting, the hazard ratio is actually about the same, so hazard ratio of 0.7, but this has really become entrenched complete standard of care that now everyone who is sort of eligible for a checkpoint inhibitor should have a discussion about durvalumab after concurrent chemoradiation.
Dr. Choudhury:
Yeah, I think I want to emphasize, as Dr. Cooper mentioned, that it really should be after concurrent chemo radiation because interestingly NRG-LU005 was actually also a large clinical trial that investigated atezolizumab instead of durvalumab, but the atezolizumab was actually given concurrently with chemotherapy and radiation. And it's a negative trial. So we are seeing dramatically different results. Yes, the immune checkpoint inhibitor is different in the two trials, but I think probably, and what most of us are likely agree with is that it's really the timing of how the immunotherapy is given that's important. So I think some people might think you should just give it sooner if you can and we actually have data, at least for this particular treatment setting, that that's not really the case.
Dr. Cooper:
Yeah, it's really interesting. And people have theorized why might that be? There's thought potentially that the radiation is damaging the lymphocytes, which are needed to then sort of be stimulated by the checkpoint inhibitor. So perhaps it's sort of like shooting yourself in the foot to give them both at the same time, but really very interesting and glad to have these data. It does actually, now we've seen this in two settings because we saw it in the study that Dr. Choudhury just mentioned as well as in PACIFIC-2, which was a very similar design in the non–small cell lung cancer setting. And so, I think now we have plenty of data, that this is a strategy we should not be pursuing for our patients.
Dr. Alder:
Absolutely. I think the data builds, as you both said, even in limited-stage or extensive, that concurrent chemotherapy radiation with immunotherapy does not offer benefit but can, in fact, have real risks. And that was presented at ASCO this year too in the extensive-stage setting that we'll get to in a bit. But I think you both brought up really great points. For this patient starting on concurrent chemotherapy and radiation, usually with the backbone of carboplatin and etoposide, the etoposide is given on days 1 through 3, which can be challenging for some patients, and carboplatin is given on day 1. And then it's every single day radiation, 5 days a week, and hopefully always encourage supportive services to be involved. It's a high ask for our patients. A lot of them are living very busy lives outside of this diagnosis, so any support is always very important.
As Dr. Cooper mentioned, after finishing concurrent chemoradiation, hugely important to restage. So that means both systemic and a brain MRI. We want to make sure we don't forget about the surveillance brain MRI during the whole disease course, and we'll talk a little bit more about that. And as Dr. Choudhury and Dr. Cooper mentioned, after chemotherapy, if they do have that response, then we start durvalumab per the ADRIATIC trial. And so Dr. Choudhury, when someone's finishing up concurrent chemotherapy radiation, would love to hear how you frame prophylactic cranial irradiation or PCI.
Dr. Choudhury:
Yeah, that's a great point. So I would say that historically, PCI has been considered the standard of care treatment along with the management of limited-stage small cell lung cancer, but practically speaking, PCI is known to have significant neurocognitive risks that can be permanent, which is an important factor that I counsel my patients. And those risks do increase with older patients, which many of our patients with small cell are. So while it's always a discussion, I have it with patients as well as our radiation oncologist also has the same discussion with patients. What I tend to emphasize is that there have not yet been randomized clinical trials in the era of frequent MRI surveillance that show that PCI actually improves outcomes such as overall survival. The data supporting PCI was done in settings where regular MRI surveillance was not mandated in those particular protocols.
And so, what I more traditionally offer patients now is that we can very closely monitor with brain MRIs; and I do specify it should be a brain MRI, as we've discussed. It's always a shared decision-making, but I would say I probably lean more towards the practice of not recommending PCI. Of course, there are always specific patient preferences to take into account, but I do emphasize the lack of randomized data in the setting of frequent MRI surveillance.
Dr. Cooper:
Yeah, I 100% agree. And I think it does also depend a bit upon the culture of the radiation oncology colleagues at the institution where you practice. I think it's really important to present a united front to the patient because you don't want them to be hearing that it's really recommended by one doctor, but then it's sort of not recommended by the other doctor. And I've struggled with this because my bias as well is also to lean away from PCI in the era of close MRI surveillance, also in the era of ADRIATIC. So we sort of have multiple competing new data, which we need to see how this plays out a bit. I will say ADRIATIC did have subset analyses of people who had prior PCI, no-prior PCI, and those hazard ratios were pretty similar. I think the prior PCI was slightly higher than the no-prior PCI, but they were overall pretty similar to each other, and again, was sort of a subset analysis.
So again, I think we're all really looking forward to a randomized prospective trial to compare head-to-head strict MRI surveillance with PCI in a forward-looking fashion. I think we're all a little bit swayed by the experiences that our patients have. And I have had a number of patients who have had just morbidity from PCI and are cured from their disease, but go on to have a number of challenges after that. And for someone who really wants to emphasize quality of life, I do support MRI surveillance.
Dr. Alder:
Yeah, great points. Great points, both of you. And as mentioned, the MAVERICK trial that was done through SWOG will hopefully give us a little bit more data here. It did include extensive-stage and limited-stage. So we'll see how the numbers play out and what we can learn in that setting. And then one other thing I wanted to mention for future directions, there's DeLLphi-306 comparing tarlatamab in the limited-stage setting to placebo. Would love to hear your thoughts and excitement level on that upcoming strategy.
Dr. Cooper:
Yeah, I think what we really wish we had were the data of tarlatamab vs durvalumab in this setting, or tarlatamab plus durvalumab vs durvalumab. I think incorporating a placebo arm makes the data a little bit challenging to interpret in the era of where durvalumab is now the standard of care. So will be interesting to see the results. I'm not sure how we'll really interpret or approach them given that the standard of care has changed during the conduct of that study, unfortunately. So would be great instead to see a combination strategy, T-cell engager plus checkpoint inhibitor in the limited-stage setting. I think that would be great.
Dr. Alder:
Agreed. Dr. Choudhury, we'll talk about this again in the metastatic setting, but at ASCO, we just saw intracranial efficacy in extensive-stage small cell lung cancer, but given that it does show very good efficacy and CNS protection, does that influence how you think about it possibly interacting in the limited-stage setting too?
Dr. Choudhury:
Yeah, absolutely. So again, I think my bias is more towards not offering PCI to patients. So I guess in that respect, knowing that tarlatamab has intracranial efficacy, it would only strengthen that viewpoint. But I would say that, again, we'll talk about it more in the context of extensive-stage disease, but we do know that maybe there are small brain metastases that you can comfortably monitor if someone's getting tarlatamab instead of proactive radiation. But from the limited-stage perspective, it would only make me feel more comfortable that there may be a diminishing role for PCI if you know that tarlatamab maintenance would be an accepted strategy.
Dr. Alder:
Absolutely. Great. So I think the key clinical takeaways that, appreciate you both discussing with me in such amazing detail, everyone needs a brain MRI diagnosis, also really needed for surveillance throughout their journey. We talked about ADRIATIC as a new standard of care in limited-stage small cell lung cancer, which is the incorporation of immune checkpoint inhibitor. Durvalumab after concurrent chemo radiation. Talked about PCI, both the risks and the possible benefits and the need for really an informed decision-making involvement of radiation oncology and really assessing the patient's understanding and goals. And then for future directions, DeLLphi-306 and data from MAVERICK may be helping us a little bit with the PCI question. So that brings us to the end of this case. Please see the other segments for further discussion about the latest research in small cell lung cancer or visit ASCOPost.com. Thank you.
