The Search for Effective Therapies in Small Cell Lung Cancer Continues

Joe Leach, MD

While a number of advancements have shifted the field of small cell lung cancer (SCLC), significant challenges remain in treating the disease effectively. From checkpoint inhibition and antibody-drug conjugates to bispecific T-cell engagers (BiTE), chimeric antigen receptor (CAR) therapy, and more, ongoing research is key to finding and enhancing new therapeutic strategies.

Despite strides in biomarker-driven therapies for the treatment of non-small cell lung cancer (NSCLC), SCLC has not seen similar progress. According to Joe Leach, MD, mutations, including retinoblastoma and TP53, are prevalent in patients with SCLC. The lack of effective targeted therapies has resulted in limited clinical impact in regard to comprehensive biomarker testing in this subset of lung cancer.

Leach, medical oncologist, associate medical director for quality and safety at Allina Health Cancer Institute, also delved into the current standard of care, platinum etoposide, which for decades has remained mostly unchanged. Though there has been the recent addition of checkpoint inhibitors for extensive-stage SCLC, which has brought some improvement in progression-free survival, it has not significantly altered overall survival rates.

“Now, there has been a lot of excitement about potential targeted therapies, with 1 in particular, that we are hoping to see approved by the FDA this year, specifically a bispecific antibody, so it has been a lot of work trying to identify targetable pathways,” Leach told Targeted Oncology^TM, in an interview. “I would say there is still a lot of interest in finding targeted pathways, but none that have changed practice.”

In the interview, Leach highlighted the current state and future prospects of treating patients with small cell lung cancer.

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Targeted Oncology: How has comprehensive biomarker testing impacted treatment selection for small cell lung cancer?

Leach: It has had a gigantic impact on the way we think about and treat non-small cell lung cancer. Unfortunately, it has not had that much of an impact in small cell lung cancer. Certainly, we know that there are commonly seen mutations in small cell lung cancer, primarily retinoblastoma and TP53, but unfortunately, we just do not have effective therapies for those. Occasionally we will find an actionable mutation in small cell lung cancer, but it really is not standard of care to do [next-generation sequencing (NGS)] testing; although, I would say most oncologists do at some point. It, unfortunately, has not been very beneficial in terms of finding active therapies.

With the number of potential targets available growing, how can one navigate treatment decisions and potential combination therapies in the space?

The challenge with small cell, frankly, is we have not moved the needle very much in a long time. The standard therapy since I started practice 25 years ago was platinum etoposide. The standard therapy now is platinum etoposide with 1 addition of incorporating checkpoint inhibitors in patients with extensive-stage small cell lung cancer. And we have not made a big impact on survival. Survival has not changed very much.

Now, there has been a lot of excitement about potential targeted therapies, with 1 in particular, that we are hoping to see approved by the FDA this year, specifically a bispecific antibody, so it has been a lot of work trying to identify targetable pathways. DLL3 has probably been the most promising and the 1 of greatest interest, although that also has been kind of not completely successful today. I would say there is still a lot of interest in finding targeted pathways, but none that has changed practice.

What are the latest developments in incorporating immunotherapy into small cell lung cancer treatment regimens?

The biggest demonstration of improved PFS is in patients with extensive-stage, and also advanced small cell lung cancer, in combination with chemotherapy. There was initially a lot of excitement about checkpoint inhibitors, either given alone or as combination therapy based on some earlier phase 1 and phase 2 data. Unfortunately, they turn out not to be quite as active as we had hoped, particularly single agents in both upfront and in second- and third-line therapy.

For example, the combination of PD inhibition along with CTLA4 inhibition, dual checkpoint inhibitor therapy, was promising, but those studies ended up being negative when done in a more rigorous way. The 1 that has panned out is combination therapy with chemotherapy and checkpoint inhibitors. We have 2 checkpoint inhibitors approved in that setting and that has made some improvements. As immunotherapy is in most settings for those who benefit, it can be a tremendous benefit, and in those where it does not work, there can be no benefit. That has been the 1 area that we have made some progress, but more needs to be done.

One thing that I think there is a lot of interest in is that most lung cancers are not 1 entity, so there have been some subsets identified through gene expression analysis showing that there is an inflamed type of small cell lung cancer that probably benefits more from immunotherapy. That has not quite changed practice yet, but there is obviously a lot of investigation trying to identify those kinds of subsets of patients that we can treat differently.

Can you elaborate on the current antibody-drug conjugate landscape for small cell lung cancer?

There was a lot of excitement about an antibody-drug conjugate. First of all, antibody-drug conjugates have been impacting a lot of different areas of oncology, especially over the last few years. They are not new;’ we have had them for quite a while, but we have seen expansions in both subsets, and breast cancer, I would say, is probably where it has been most commonly, but in lung cancer, too, we have got a couple of antibody-drug conjugates. [Fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu)] was probably the best example of that for HER2-mutated lung cancer and a lot of promising data that will probably expand their use in non-small cell lung cancer.

In small cell lung cancer, the most promising was an antibody-drug conjugate targeting DLL3, which is part of the Notch pathway. Rovalpituzumab tesirine [Rova-T], there was a lot of excitement about that initially, but unfortunately with further larger studies, that drug has not been very effective. We are still trying to identify either a patient subset or more active antibody-drug conjugate that has more activity in small cell lung cancer, but again, we just do not have 1 that has impacted clinical practice yet.

Are there any ongoing clinical trials evaluating the efficacy of antibody-drug conjugates in this space?

There still are some studies that are still looking at Rova-T in different lines of therapy. It initially was being looked at in the more refractory setting, so there are still some ongoing studies looking at it in the sort of earlier biology of the disease and in combination therapy. We are still waiting to see if there is a subset of patients where that will be a benefit.

What can you discuss about the role of BiTE therapies in small cell lung cancer treatment?

The most exciting thing is this drug called tarlatamab [Imdelltra], which has shown some promising data. That was published in the New England Journal of Medicine a few months ago showing, again, in patients with relapsed/refractory disease, so patients that have been through prior chemotherapy, that showed really promising activity. That has been an area where we have not had very good treatments, nothing that truly moved the survival needle in a long time.

Tarlatamab is an antibody that targets this DLL3, which is present on the majority of small cell lung cancers, and then brings CD3 T-cell in. We have seen a lot of promise and efficacy in hematologic malignancies, but we have really not seen 1 in solid tumors, so this is the most promising. In patients where it was effective, the response rate was in the 30% to 40% range, which is pretty good in this setting.

But more exciting is that in many of those patients, the response seems to be a lot more durable. There is a lot of excitement in that area because that could be the first real improvement in treatment in this setting that we have seen in a long time.

What do you think this means for the landscape moving forward?

I think there will be a great need for it. Again, we just do not have effective therapies for these patients. Extensive-stage small cell lung cancer, while initially chemosensitive, unfortunately, almost 100% of time, becomes resistant to that therapy. We just do not have great treatments after that. I think there will be a lot of interest by those patients and their doctors who are looking for therapy for those who are healthy enough.

The drug has some toxicities and so it is probably not the right drug for everybody. We all want to see more data. The number of patients that have been reported so far is relatively small, and so understanding better the kinds of toxicities that we see [is important]. As with this entire class of drugs, there can be some challenging toxicities like cytokine release syndrome, so better understanding of how to manage those toxicities. But also, who does it work for and who does it not and better patient selection.

The target DLL3 was looked at pretty extensively in some of the Rova-T trials, which targeted the same antigen. The issue is it is so commonly expressed that it is probably not going to be a great biomarker for us to select patients. More data on which patients are most likely to benefit and then which it is not going to work for so that they can look at other clinical trials will be important. I think there is going to be a lot of excitement in the thoracic oncology community to have a treatment for this patient population.

Is there any ongoing research evaluating oncolytic viruses or CAR T-cell therapy in this space?

There has been and I think it lies in all solid tumors. CAR T is sort of similar to BiTE therapy in that it has been impactful for hematologic malignancies. So far, it has been pretty tough to find a setting in solid tumors where they work. There certainly has been research looking into CAR T. Amgen has a CAR T that they were developing. I think that study is on hold right now, but a lot of people are looking at CAR T and other cellular therapies in this space. I think we still have a ways to go before we will see this as certainly nothing is close to the lab.

There are oncolytic viruses also. We do not have 1 outside of melanoma that has been very effective, but there is an oncolytic virus that is in clinical trials that seems particularly active in neuroendocrine cancers like small cell lung cancer. There are some active studies looking at that. That is another area that we are hopeful that we will see some results from.

What are the unmet needs that still exist in the space?

In earlier stage, limited-stage small cell lung cancer that has metastasized, we think of that as curative disease. But the therapy has not changed in decades, so it is still a combination of chemotherapy and radiation. I think understanding how we incorporate some of these newer therapies into that setting to improve the cure rate, I think, is an important area of unmet need. Control of [central nervous system (CNS)] disease, so small cell lung cancers are notorious for spreading to the brain. We have done things like prophylactic whole-brain radiation, which can have unfortunate toxicities. We still need more effective therapies that are less toxic to reduce the risk of progression in the brain and to treat those who already have spread to the brain.

For extensive-stage disease, incorporating checkpoint inhibitors has certainly been some progress. But we need more impactful therapies, both to extend the efficacy of first-line therapy and also to help patients where that first-line therapy has stopped working. We just have not had effective therapies in a second-line setting.

Are there any advancements in early detection methods or biomarkers that could improve patient outcomes?

Number 1, lung cancer screening is just horrendously underutilized. It has been shown to improve survival, and the patients who are at risk for getting non-small cell lung cancer forming current smokers, those ones that get small cell lung cancer. So, if we could improve the utilization uptake and lung cancer screening right now, we are just at just over 5% of patients who should be getting it or getting it which is just unacceptable. Now, small cell lung cancer, and we think of that as being beneficial for non-small cell, but if patients were getting CT scans every year, and we can identify those cancers at an earlier stage, I think that would be beneficial.

In terms of other ways to identify it, there is a lot of interest in blood-based screening, both in working with patients who have lung nodules and also just for early cancer detection. I think that is an area of great interest. Small cell is tough though, because it is an aggressive disease, and our window of being able to detect it early enough to intervene is really challenging. Our screening tests work better in cancers that have slower doubling times and give a bigger window, so I think early detection is going to continue to be more challenging in the small cell space than in the non-small cell space, but using the tools that we have more appropriately, I think is the first step.

How are experts tailoring treatment strategies for individual patients with small cell lung cancer?

I wish I had a great answer for that, but we do not have great biomarkers for tailoring therapy in small cell lung cancer, in part because we do not have that many therapies. In the non-small cell space, obviously, there has been an explosion, the number of different treatments that we have with tyrosine kinase inhibitors and immunotherapy, but our buckets are still pretty small for small cell. I do think that this characterization of biology through gene expression analysis and identifying patients who might benefit more from immunotherapy, hopefully, will bear fruit and let us identify patients who we should be focusing more on immunotherapy rather than chemotherapy. But again, right now, that is still investigational.

Moving forward, is there anything in the space that is particularly exciting to you?

We are all excited for the BiTE antibody to be improved. As we get more data from that, we are particularly interested to see whether that will impact survival earlier on in the disease. Right now, it is likely going to get approved later on in therapy. I think that is where there is a lot of excitement. We just have not had an effective therapy for small cell in a long time. I still think even though the research immunotherapy has not been quite as promising as we initially hoped, I still think that there is a lot of promise, and they continue to explore immunotherapy in small cell. We just need to identify the right patients, and probably have different approaches to it than what we have got right now.

There are still a lot of avenues of clinical research still going on, so the message to patients is to always ask if there is a clinical trial that I should be looking at whenever [they are] going to be facing a change in therapy. If we cannot get these studies to accrue, we cannot get some of these promising new agents evaluated, and then if effective, approved as fast as we could if we had greater research participation.