Small Cell Lung Cancer Spotlight - Episode 19
Angel Qin, MD, clinical assistant professor of medicine at the University of Michigan, discusses the need for more clinical trials in small cell lung cancer and for more patients to qualify for trials.
The American Journal of Managed Care® spoke with Angel Qin, MD, clinical assistant professor of medicine at the University of Michigan, whose research focuses on lung cancer. Qin discussed the lack of clinical trials in small cell lung cancer (SCLC), efforts to make trials more inclusive, and what these limitations mean in the study of second-line therapies in SCLC. This interview has been edited lightly for clarity.
AJMC®: Dr Qin, to begin, can you discuss what you consider to be the largest unmet needs in small cell lung cancer?
Qin: In my opinion, the largest unmet need is the lack of clinical trials available to our patients with small cell lung cancer. Understandably, small cell lung cancer is not a very common disease—it’s overshadowed by non-small cell lung cancer. But it's a very aggressive disease, for which there really aren't many treatment options. Unfortunately, these patients simply aren’t included in many clinical trials, and/or some of these clinical trials have very stringent eligibility criteria. In my opinion, this eliminates the ability for many patients to be enrolled on these studies. So, I do wish to see more trials developed in this space for our patients.
AJMC®: We've certainly heard the complaint that clinical trials aren't inclusive enough. Are there specific changes you’d like to see in these large clinical trials, perhaps for newer agents, which would make them more inclusive—and more relevant to the populations that you see in practice?
Qin: Many times, clinical trials will mandate a pretreatment biopsy. Understandably, we want to look at correlatives and biomarkers that can predict response or benefit from a therapy. But, from a patient's standpoint and from a disease standpoint, if we're taking a couple of weeks to be able to arrange a biopsy, small cell lung cancer moves at such a pace that in that couple of weeks, you may have missed the window to be able to treat these patients. The other big issue is that many trials will either exclude patients with brain metastases or mandate that their metastases have been stable for a couple of weeks. As we know, brain metastases are such a huge issue in small cell lung cancer that to have these mandates will exclude a lot of patients, and they will not be able to participate in these studies.
AJMC®: The PD-L1 immune checkpoint inhibitors of atezolizumab and durvalumab are the preferred treatment options in first-line therapy with extensive-stage small cell lung cancer when combined with the platinum-etoposide doublet chemotherapy. What are some of the clinical outcomes or safety profile considerations that you consider when you're selecting between these 2 PD-L1 immunotherapies?
Qin: I think that's a great question—to be honest, I really don't think there's much of a difference between the 2 regimens. If you look at the end points that are clinically meaningful—overall survival was very similar on the 2 trials; 12 to 13 months with the combination checkpoint inhibitor versus about 10 months with chemotherapy alone. We're looking at duration of response that's very similar between the 2 as well. Looking at eligibility, you're not seeing major eligibility differences between the 2 that suggest one regimen is superior to the other with respect to patient/disease characteristics. And even if you're looking at the treatment-related adverse events, grade 3 or 4 adverse events occurred about 60% in both studies.
Now, interestingly enough, the atezolizumab study reported a 40% immune-related adverse event [rate] in the group that received atezolizumab versus 24% in the chemotherapy group. But with durvalumab, the [investigators] only report about 20% (iRAEs) with their durvalumab group and 3% in the chemotherapy group, with rash and hypothyroidism being the most common immunology adverse events. I'm not really sure why that would be. Clinically, when looking atezolizumab and durvalumab in other settings, such as non-small cell lung cancer we really don't seem to see a different side effect profile. I think if you look at the atezolizumab group, it's very interesting that 25% patients on the chemo alone group were reported to have an immune-related adverse event, which is obviously not possible since they received placebo, so I don't really interpret that as a true difference. Because the atezolizumab combination was approved first, that's the one I've used. I have not seen the need to switch to the durvalumab combo, given no difference in insurance approval or cost, so to me the 2 regimens are equivalent.
AJMC®:What do you consider when you're selecting a regimen for patients who've relapsed past that first-line therapy in small cell lung cancer?
Qin: So, I think that’s where the lack of clinical trials plays a big role. The [National Comprehensive Cancer Network] guidelines states that for subsequent therapy, a clinical trial should be considered if possible. We're now looking at drugs like topotecan, which has been our standard for so long, and now, of course, the addition of lurbinectedin. In choosing the next regimen, I think about side effects and a patient's performance status.For example, lurbinectedin is 1 infusion; topotecan IV, unfortunately, is a multiple-day infusion, so that can play a big role in tolerability. Topotecan can cause more adverse GI side effects whereas lurbinectedin can cause more myelosuppression. Outside of a clinical trial, I have been using lurbinectedin more often as my second-line treatment.
AJMC®: Speaking of lurbinectedin, it's a new kid on the block in small cell lung cancer, with FDA having granted accelerated approval in June of 2020. Can you speak more on your experience with this drug? You mentioned the adverse events that you might be encountering. Have the clinical trial data lived up to your experience with it in practice? Have there been any clinical pearls you can share about its use in small cell lung cancer?
Qin: Yes, in the lurbinectedin study that led to its approval, one issue is that the study did not allow patients with brain metastases to be enrolled. So, I think you could argue that the patients were probably healthier, if that is a good word, than the average patient with small cell lung cancer. And then there’s the issue with immunotherapy—this study was done prior to the era of patients receiving platinum [chemotherapy] plus a checkpoint inhibitor. So, [if patients in the study] only received the chemotherapy, we don't actually know what the response rate to lurbinectedin is in the post chemo-immunotherapy setting. In the lurbinectedin study, the reported the response rate is about 30%, and I have not been seeing that in my own practice. I have not seen that robust response. Again, is that because my patients have received chemoimmunotherapy? Is it because a lot of them do have brain metastases? I'm not sure that explains it all, but I have not been impressed by lurbinectedin in the real world setting.
AJMC®: What barriers have you encountered in the treatment and management of small cell lung cancer and how have you gone about overcoming those?
Qin: I think the barrier is that for these patients, unfortunately, disease progression can be very rapid and it can be very symptomatic. And often, this does require excellent multi-disciplinary care, which can be hard to really organize. For example, you may need to consult your radiation oncology colleagues in someone with recurrent brain metastasis. The patient has had whole brain radiation already—is additional radiation feasible? You will need to consult your pulmonary colleagues in a patient becoming more symptomatic from thoracic disease; is a stent needed? II think I am lucky in that I do work in a large academic institution where I can contact my colleagues and say, “I need your help on this—can you see this patient ASAP?” But I do think that is a barrier, in that the pace at which the disease moves and the need for multidisciplinary work or collaboration can really impede the timely care of these patients.
AJMC®: Are there any closing thoughts that you want to share with your colleagues?
Qin: In my experience with small cell lung cancer, I think it's really important to remember that this disease is aggressive, and it can travel to places that you don't expect. I never would disregard something that I see on a scan where maybe in other disease processes, you may say, “Well, this is probably not related to cancer.” I've learned in small cell that more often than not, it is related to the cancer. Along the line of brain metastasis, which is such a morbid consequence of small cell lung cancer, I think it’s important to remember that when we do imaging, we shouldn't focus just on the thorax and the abdomen. We really need to make sure that we get routine brain imaging, especially at time of progression because it is so easy to forget. Not all these patients are going to be symptomatic. Most patients I meet with small cell lung cancer that ultimately have brain metastasis don't have side effects from these brain metastases. If patients are not complaining of headaches or imbalance, it’s easy to forget—so I do want to highlight this as a really important area to remember.