Small Cell Lung Cancer Spotlight - Episode 1

Identifying Small-Cell Lung Cancer Subtypes and Potential Therapeutic Targets

January 28, 2021
Rose McNulty

New research from The University of Texas MD Anderson Cancer Center has identified 4 distinct subtypes of small-cell lung cancer (SCLC) based on gene expression, providing possible targets for treatment in a notoriously aggressive cancer type with a limited therapy armamentarium.1

Lung cancer is the second most common type of cancer in the United States, and SCLC makes up about 13% of lung cancer cases.2 Even so, SCLC treatment has seen limited progress in recent years compared with the more common non-small cell lung cancer (NSCLC), which has seen new, more effective therapy options and therefore better patient outcomes.

In SCLC, rapid growth and resistance to treatment contribute to an estimated 5-year survival rate of 27% for patients with limited-stage disease and just 3% for patients with advanced SCLC at diagnosis. The new research, published in Cancer Cell, identifies possible treatment vulnerabilities that will hopefully prove useful in future clinical trials and in planning treatment for SCLC patients and beyond. Three of the subtypes aligned with previous research, but a novel fourth type showed an inflamed gene signature with high expression of multiple immune genes.

The American Journal of Managed Care® (AJMC®) spoke with Lauren A. Byers, MD, associate professor of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center and senior author of the study, to discuss the findings of the study and the treatment landscape of SCLC. The interview is edited lightly for clarity.

AJMC®: Your recently published research in Cancer Cell identified 4 types of small-cell lung cancer. Can you discuss the importance of stratifying those disease subtypes in SCLC?

Byers: As somebody who treats patients with lung cancer, it's been amazing to see how much progress we've had in treating advanced non-small cell lung cancers. And the game-changer for those cancers was the initial identification of EGFR mutations and the development of EGFR inhibitors, so that we had a way to start providing the first targeted therapy for lung cancer. In that setting, and over the last couple years, the number of drug approvals for targeted therapies has just skyrocketed—and that's been reflected [in outcomes]. There was a paper last year in the New England Journal of Medicine talking about how there's been this sharp decline in lung cancer deaths, particularly in non-small cell lung cancer. And that's in part because they are more and more patients where, when they come to see us, we can do biomarker testing. Then, we can really personalize their treatment based on the therapy, whether it's targeted or immunotherapy, that are likely to get the most benefit from.

For small cell lung cancer, we know that this is an incredibly aggressive disease. In most cases, patients already have advanced metastatic cancer by the time it's detected. And for the last several decades—and still—the standard treatments are really a one-size-fits-all approach. So unlike in non-small cell lung cancer, there have not been any clinically validated biomarkers that would let us start thinking about personalized treatment approaches for small cell lung cancer. I think that's really the game changer, and why we're so excited about having this framework where we can now say, “Here are the 4 major subtypes.”

Being able to define those types really gives us a path forward for doing the hard work that comes next. In clinical trials for small-cell lung cancer, especially with new agents that we’re excited about, we can look and start to identify whether there are certain therapies being tested that seem to be especially active and especially beneficial for patients in one of these 4 groups. That really is the next step moving to toward precision oncology or a biomarker-driven approach.

AJMC®: Potential therapeutic targets for those 4 subtypes were also identified. How could this affect future clinical trials and drug development?

Byers: With small-cell lung cancer, because most of the trials in the past have been sort of all comers, if it was an active drug, you might see 1 in 10 patients responding—but you never really knew who the patients were that were getting that benefit from those drugs. I think that the one thing that can happen immediately is that, because we've identified what these 4 major subtypes are—and then there are also other drug-specific biomarkers that are emerging as well—we can immediately, in the current clinical trials that that are taking all small-cell lung cancer patients, begin testing patients that are in those trials for which of those 4 groups they're in. Then when we get to the end of the of the study if we see, for example, a 20% response rate with a certain drug or drug combination, but half of those or 80% of those patients are in 1 subgroup, then we can figure out which patients are most likely to be getting a benefit from that particular therapeutic approach. Then, that lets us design the next trial to do what has gone on for the last several years in non-small cell lung cancer, where you then identify patients for a trial based on a biomarker and then treat them with that drug. You then sort of flip the paradigm from something where you have a minority of patients who are responding to where, if you can identify which group of patients seems to be getting the most benefit, you hopefully get to a point where the majority of patients are having clinical benefit from a biomarker-matched treatment approach.

AJMC®: The analysis also showed that using a full gene panel wasn’t necessary to classify the tumors. What are the implications of those findings?

Byers: I'm very practical about this: If you can't do the test routinely in the clinical setting, then it's not a useful biomarker. Fortunately, biotechnology is continuing to rapidly advance and get more sophisticated. Certainly, we can do things like liquid biopsies that we couldn't do even a very short time ago. For us, the gene signature was really a powerful discovery tool to identify what these major subgroups were. But then it was really important to us to also develop tests that can be readily done in the clinic. That was why we worked together with our collaborators in our pathology group to develop immunohistochemistry assays. So basically the exact same way that we test for PD-L1 levels and the way we diagnose cancer, using immunohistochemistry, we have been working hard and sharing those assays that we've developed where immunohistochemistry could be sort of immediately used as a way to test which subgroup a patients is in. I think that's something that can be moved forward right away. The other thing is that one limitation with small-cell lung cancer is that often, the amount of tissue that's available from biopsies is very small. So I think we're, at the same time, looking at some of the newer technologies and ways where we can do as many biomarkers as possible and the best possible tests from the smallest amount of tissue. We're excited about potential opportunities for developing blood-based ways that we could test the subgroups, as well. What

AJMC®: SCLC is far behind NSCLC in regard to new treatment development, but with approvals of immunotherapies and more recently of a post-platinum-based chemotherapy option in lurbinectedin, things seem to be changing. What therapies or combinations do you see potential in going forward?

Byers: First, I think one of the great things about this study was that we found a drug that that had activity for each of the 4 groups. So it wasn't just that there was 1 group that was resistant to everything. It was really that certain drugs worked for certain groups. A lot of that has been on the preclinical side, with the exception of the immunotherapy study, where we really were able to validate that in the clinical trial from IMpower133. But I think that's really exciting because many of the drugs that we were looking at and focused on in the preclinical work are currently or about to enter clinical trials for small-cell lung cancer. For example, I'm still very enthusiastic about PARP inhibitors. Myself together with John Heymach originally identified PARP as being overexpressed in small-cell lung cancer, and we did the first study showing that PARP inhibitors had activity in some of the preclinical models. I think that having a subtype that may work especially well for PARP inhibitors is one therapy that I'm excited about.

We also saw, for example, in the NEUROD1 group that, that those small cell lung cancers seem to be very responsive to Aurora kinase inhibitors. And those are those are targeted agents that are currently also in trials for small cells. So I think that gives sort of another opportunity for the inflamed group. I think across the board, we see that there's certainly room for improvement in terms of responses in each of the each of the subgroups, compared with what we currently have with the current standard treatment. I think that, for example, in the inflamed group, there are opportunities for thinking about novel immune approaches that might be especially effective in that group. I'm also excited about tyrosine kinase inhibitors, cell therapy, and BiTE molecules—other ways to engage the immune response and novel ways beyond standard immune checkpoint inhibitors. I think all of those are things that are very exciting, and we'll be seeing a lot going forward with the current clinical trials. What

AJMC®: Can you discuss the significance of the novel fourth group identified in the research in regard to immunotherapy, which has become part of the standard of care in SCLC?

Byers: One of the things we did when we decided to ask the question about the subgroups in small-cell lung cancer is that we really took a data-driven, kind of agnostic approach to say, “Let's let the data tell us how many groups there are, and what are what are the major groups,” rather than just trying to sort of guess or fit it to what we thought it might be. Because we took that approach, we have 3 groups that came out that were things we thought were going to be major players, activated by 3 different genes: ASCL1, NEUROD1, and POU2F3. But the fourth group, the inflamed group—and this was a group of tumors where it was unclear what the biomarker was for those groups based on the work that had been done up to this point—was identified through this data-driven approach. That group has such high expression of multiple immune genes and interferon signatures, like all the things that you would expect from tumors that may be potentially more responsive to immunotherapy. Our hypothesis was that that was probably the group of patients where we did see longer term responses to immunotherapy.

It was really exciting to be able to partner with some of our collaborators and look at the IMpower133 trial. In the IMpower133 study, the inflamed group made up about 18% of all the small-cell lung cancer patients. And if you looked at how that group did with the addition of atezolizumab to chemotherapy, they had essentially a doubling of their survival with the addition of atezolizumab. So that really was the group that was getting the greater benefit from the addition of immunotherapy.

We've still got a lot of hard work to do, and I think, ways that we can improve outcomes for patients and each of those groups through new approaches and combinations and other things that we can do to further enhance response in a more personalized way. But I think that was really one of the most exciting parts about the trial—finding that fourth group and being able to show that those patients did get relatively greater benefit from currently approved immunotherapy agents.

AJMC®: If the findings in regard to treatment vulnerabilities in the subtypes are verified in future research, how might they affect the overall treatment algorithm for SCLC?

Byers: I think first of all, just like with other lung cancer patients, when patients are diagnosed, we would immediately be testing for which group their cancer was in. I expect there'll be additional biomarkers that may be drug-specific. Beyond the 4 subtypes, I think this is an area where we'll continue to see growth in terms of new biomarkers to kind of further refine treatment selection. Ultimately, what I hope and expect to see is that when patients are diagnosed, they are going to be tested upfront for which group they're in. Then, based on clinical trials looking at differences in terms of the benefit of specific treatments for specific groups of patients, that'll let us pick the most effective treatment for that individual patient.

The current standard of care for expansive-stage small-cell lung cancer—which is the majority of newly diagnosed patients—is chemotherapy with immunotherapy. But I think the change that we may see first would be that when patients have completed the chemotherapy and they're doing immunotherapy maintenance, those biomarkers could help guide us in terms of what should we combine with immunotherapy during the maintenance period to get more durable responses or to enhance the immune response. I would expect first to see advances or changes in how we pick therapies, and choose the most effective therapy for patients based on these subgroups. And then ultimately, hopefully as we have more trials and hopefully identify things that are that are particularly effective in certain subgroups, then those would be brought even earlier in the treatment, potentially eventually replacing chemotherapy with a novel combination as sort of a targeted immune combination approach.


1. Gay CM, Stewart CA, Park EM, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell. Published online January 21, 2021. doi:10.1016/j.ccell.2020.12.014

2. Lung Cancer - Small Cell: Statistics. Cancer.Net. January 2020. Accessed January 28, 2021.