Dr. Alder:
Hello, and welcome to Integrating Immunotherapy Across the Small Cell Lung Cancer Spectrum, an ASCO Post Roundtable. I'm Dr. Laura Alder. I'm an Assistant Professor in thoracic medical oncology at Duke Cancer Institute, and I'm very happy today to be joined by two of my esteemed colleagues and friends. I'll let them introduce themselves.
Dr. Choudhury:
I'm Noura Choudhury. I'm a thoracic medical oncologist and Assistant Professor at the University of Chicago.
Dr. Cooper:
I'm Alissa Cooper. I'm a thoracic medical oncologist at Dana-Farber Cancer Institute in Boston.
Dr. Alder:
Great. Thank you both so much for joining me. So for our third and final case, we will discuss the management of a patient with disease progression after first-line chemotherapy and immunotherapy. I think a lot to discuss, happily, in such refractory settings.
So to start off with, this is patient DK. He is a 65-year-old man with extensive-stage small cell lung cancer. He was treated with carboplatin, etoposide, and atezolizumab for four cycles followed by atezolizumab maintenance. He had a good initial response achieving a partial response lasting 8 months on maintenance therapy. Still has a good performance status, an ECOG performance status of 1, mild fatigue, and no neurological symptoms.
So of course we want to restage whenever we see any concern of disease progression. We also want to do active surveillance of brain MRI and CT scans every 3 months. And so when we do that on his brain, we see new asymptomatic brain metastases. We see four lesions, the largest of which is 1.2 cm. We see a CT scan of his chest showing an enlarging right lung mass and new mediastinal lymphadenopathy. And in his CT abdomen, we see multiple new liver lesions. So what are the treatment options that we would discuss at this point?
Dr. Cooper:
I think this is unfortunately a clinical scenario that we often find ourselves in. I will say sometimes, unfortunately for our patients, they don't get even very far into the immunotherapy maintenance and sometimes even on that first restaging scan on immunotherapy alone maintenance, we already see evidence of progression. Sometimes small cell can be a really just devastating disease. But there are so many more options now for treatment in this second-line setting, so it's a really exciting time to be treating this disease.
Of course, we've all been talking about tarlatamab the last couple of years accelerated approval by the FDA in May 2024. And so many of our institutions have been using this drug as standard of care for now it's coming up on 2 years, which is pretty remarkable. So we all, I think, personally have treated quite a number of patients with tarlatamab at this point.
We also always think about clinical trials pretty much at every juncture of treating small cell lung cancer. It's really interesting that in the NCCN Guidelines, clinical trial enrollment is actually a category 1 recommendation that for small cell specifically, clinical trials are usually to be prioritized and preferred. At this juncture in time, there are a lot of really exciting clinical trials. I do try to prioritize ones that do involve a T-cell engager, whether it's tarlatamab or different companies' DLL3–targeting T-cell engager because we are so excited about the potential durability of responses in those settings. But of course, these T-cell engagers, including tarlatamab, don't work for everybody. So that's why it's super important that we have other clinical trials, for example, antibody-drug conjugates, some of which may be edging towards approval soon, as well as other standard cytotoxic therapies.
Dr. Alder:
Absolutely. Dr. Choudhury, I would love your experience in the administration of tarlatamab for some of our community physicians or anyone else who may be tuning in right now.
Dr. Choudhury:
Yeah. So, an important point about tarlatamab is that the FDA label recommends 24-hour monitoring after both the priming dose and the first target dose on day 1 and day 8. That can be, I think, interpreted a little bit loosely, but our preference at our center is that we do admit patients for that monitoring. When we get referrals from the community, that is sometimes a barrier that we see patients after the second line, like the third or fourth line, because they were reluctant to come to a center that was able to do that because maybe their local oncologists didn't have the capacities to monitor tarlatamab in that way.
But for safety from the various trials that we have, we do think about 25% of patients do have high grade, which is grade 2 or higher cytokine-release or ICANS. And for that reason, when I talk to patients about it, I say that we don't have great predictors of who gets CRS or ICANS. We know that it's about one in four peoples. And for that reason, right now our recommendation is that you are monitored for it. But that is an important point. And I do see that we're having more and more referrals in the second-line setting for tarlatamab. So I do think that is a message that has permeated through the community that as DeLLphi-304 showed, tarlatamab had improved. It really beats investigator's choice chemotherapy in every metric that you could have envisioned. There was really no metric that chemotherapy was better than tarlatamab.
Dr. Cooper:
I just want to underscore something that Dr. Choudhury just said that was so important. We do not know ahead of time who's going to get that CRS at all and get bad CRS, and we don't know ahead of time who's going to have response. And now research into both of these areas is pretty nascent, but it is developing. There's been some real-world investigations in terms of the incidents and severity of CRS and ICANS in the real world compared with the trials. And if there's any sort of predictive markers or factors, it would really be great if we could develop some sort of risk stratification model, something that we can look at the patient in front of us, whether their personal comorbidities or their tumor biology, something about that that we could say, "You would be safe for outpatient. You have to be admitted inpatient." That's sort of my pipe dream that that would be a really informed way to practice, but we do not have that right now. So right now we have to be the most conservative that we can.
The other thing that I really wish we do have, which is maybe slightly developing, is there's some new biomarker work that maybe potentially DLL3 expression might predict who could respond to DLL3 T-cell engagers, including tarlatamab. This is very early in developing work, so it's a little bit hard. Right now we don't test for DLL3 on patients with small cell lung cancer because it is so prevalent, but these are sort of future research questions that I do hope are incorporated into our clinical decision-making because there are patients for whom maybe the T-cell engager is not the best step and we just don't know who those patients are. There are patients for whom potentially one of these ADCs with a topoisomerase 1 inhibitor warhead is actually the next best step, and we just don't have the tools to identify that right now.
Dr. Alder:
Yeah, really well said and great comments talking about clinical trial considerations, I think as you said, Dr. Cooper, a lot of new trials coming out, Dr. Lauren Byers presented an update that the SEZ6-targeting ADC ABBV-706 in the second-line setting showed a really impressive objective response rate of 80% and showing disease control surpassing 6 months.
I think as you said, the sequencing of these agents of making sure that we have more science, more correlatives, more biomarkers to try and predict in what combination or who will derive the most benefit from what is something we're all really eager for. And I think all of us are working on it both at our own institutions and also together, which is really exciting with so many collaborative engagements.
So, jumping back to this case for a second, he does have some CNS metastases, some brain metastases. So, that always brings up the question again, we talked about this in the front-line setting. Do we do radiation first or do we proceed with the next line of treatment in this case, as we've discussed likely tarlatamab? Dr. Choudhury, I would love to hear how you think about that, especially in light of the exciting ASCO data that was recently presented in intracranial efficacy of tarlatamab.
Dr. Choudhury:
Yeah, that's a great point, so I'll first start with that. At ASCO, there were post hoc data presented from the DeLLphi-304 study that was looking at specifically the response because that study did allow asymptomatic untreated brain metastases. And that study did show that there was a 60% reduction in the risk of CNS progression or death when you give tarlatamab compared to chemotherapy. And there was also impressively about a 15% intracranial CR rate, meaning that tarlatamab alone was able to completely get rid of brain metastases without the need for radiation, which is really important for our patients. So, our practice here is patient specific, I would say. If patients are truly asymptomatic, the brain metastases are small. I sometimes roughly use a cutoff of 1 cm, but that's not a hard and fast rule. Then I sometimes do just preferentially start them on tarlatamab and we have a quick re-staging scan to see how that patient is doing.
For other patients, I do go ahead and start SRS, stereotactic radiosurgery. And we actually feel comfortable with the safety of doing that concurrently with tarlatamab. We have not had increased rates of ICANS or CNS toxicity with that. And so I do both of those approaches depending on the patient and the conversations with our radiation oncologist.
Dr. Alder:
Yeah, I think that's really well said. So much of this is patient-dependent involving a multidisciplinary team. And I think as we mentioned before, this is very much a marathon and we want to make sure we're doing the right thing not only now, but for next week, next month, hopefully even maybe next year. I think the hope is with tarlatamab, we do have that tail of the curve where some people do derive long sustained benefit or on the drug for a long time. For someone who does progress on tarlatamab, what are you thinking about for the next line of treatment?
Dr. Cooper:
I'm always thinking about clinical trials. We have a number here that are even for patients who may have had progression on tarlatamab or a T-cell engager. So whether those be antibody-drug conjugates with different targets, so we've talked about SEZ6, but also B7-H3 or potentially even DLL3-targeting ADCs, different modalities, there are radionucleides now, other CAR studies. There's a lot of different mechanisms and modes of delivering treatment now. And again, we still don't know what's going to be the best for any one patient.
Unfortunately, many patients are not eligible for trials at the point of disease progression either because of organ dysfunction or other issues that come up. Or actually more practically speaking, sometimes it's challenging to get them on a trial from a time perspective because they actually just don't have the few weeks to wait to go through the screening process. And so because of that, I do lean on conventional cytotoxic therapy sometimes. Lurbinectedin is certainly my go to chemotherapy that I would involve, but I have used pretty much every cytotoxic therapy that is available for small cell lung cancer, including paclitaxel, irinotecan, temozolomide, and others.
Dr. Alder:
No, those are really good points. Before we wrap up here and go into some supportive care as well, which is always really important, Dr. Choudhury, anything you would like to add about extensive-stage small cell in the later-line settings that we haven't talked about yet?
Dr. Choudhury:
To echo a point that we have said thematically is that I do keep an eye on the brain. If you know sometimes they get referrals from elsewhere where you see that their patients are progressing extracranially and we haven't yet had a brain MRI. So I do just emphasize that we need to keep an eye on the brain. Unfortunately, that's a common area where small cell can progress. And so it's important to continue that routine MRI surveillance throughout.
Dr. Cooper:
And I think that's one of the most challenging areas to get a handle on. Sometimes patients have progressive disease through whole-brain radiation, through SRS on top of whole-brain radiation, through systemic therapies that are supposed to be go-to intracranial control and that is really challenging. I've actually had a number of patients who have either no evidence of disease systemically in the body or all of that disease is so stable and quiet but the brain is just really out of control. And once you've lost local therapy options for the brain, it just becomes really challenging to manage. And so that's one of the areas that we definitely need more work in.
Dr. Alder:
Absolutely agree. And I think it's one of the things when we're meeting with industry, we need that intracranial data, not just from treated brain metastases, but from active progressing brain metastases. It's a huge unmet need, as you spoke very nicely to. And so I'm hoping that that changes and that we are more inclusive, especially for such high need patients.
And so, one of the things before we wrap up is we talked about this in one of the other segments, but really supporting the patient early palliative care, Dr. Choudhury, Dr. Cooper, you both brought this up so nicely. We know it improves quality of life, mood. It helps with symptoms. Early referral can help even with survival. This is a really hard thing to go through. No one should go through it alone or with their family alone. And to that point, patient support organizations we're so lucky to have the Small Cell SMASHERS led by Dr. Misty Shields. We have the LUNGevity Foundation as well as many other sources of hope, of support, of resources. And then of course, making sure that any survivorship, psychosocial, mental health is prioritized. And then also including the caregiver, there can be caregiver burden and fatigue understandably. So really we're making sure that we're assessing the whole situation.
And so some key clinical takeaways here, we've talked about tarlatamab as pretty much the new standard for second line, the importance of clinical trials every single step of the way. We're seeing some new data from ASCO with brain metastases as well with some new antibody-drug conjugates, some updated information there. And lots of clinical trials ongoing, lots of clinical research ongoing. And so I think the message I want to end with is one of hope and one of progress and so many exciting things going on in this setting.
So I would like to thank you so much, Dr. Cooper. Thank you so much, Dr. Choudhury. Your contributions were hugely important and I really enjoyed our conversation today. Thank you so much for joining me.
Dr. Choudhury:
Thank you for moderating this, Dr. Alder.
Dr. Cooper:
Thank you for having us. It's always such a pleasure to have this discussion with colleagues and friends.
Dr. Alder:
Absolutely. So this brings us to the end of the case. Please see the other segments for a further discussion about the latest research in small cell lung cancer or visit ascopost.com. Thank you very much.
