Identifying Small-Cell Lung Cancer Subtypes and Potential Therapeutic Targets

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 Compared with the more common non–small cell lung cancer (NSCLC), which has seen new, more effective therapy options and improved patient outcomes, SCLC has lacked therapeutic advances.

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 other cancers. Three of the identified subtypes aligned with outcomes of previous research, but a novel fourth type showed an inflamed gene signature with high expression of multiple immune genes.

Recently, Evidence-Based Oncology™ (EBO) spoke with the study’s senior author, Lauren A. Byers, MD, associate professor of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center, to discuss the findings and the treatment landscape of SCLC. The interview is edited lightly for clarity.

EBO: Your recently published research in Cancer Cell identified 4 types of SCLC. Can you discuss the importance of stratifying those disease subtypes?

Byers: As somebody who treats patients with lung cancer, it’s been amazing to see how much progress we’ve had in treating advanced NSCLCs. 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 few years, the number of drug approvals for targeted therapies has just skyrocketed—and that’s been reflected [in outcomes]. A paper last year in the New England Journal of Medicine discussed how lung cancer deaths have sharply declined, particularly in NSCLC.³ And that’s in part because in more and more cases, when patients first 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 they are likely to get the most benefit from.

SCLC is an incredibly aggressive disease. In most cases, patients already have advanced metastatic cancer by the time it’s detected. For the last several decades—and still—the standard treatments are really a 1-size-fits-all approach. Unlike in NSCLC, no biomarkers have been clinically validated that would let us start thinking about personalized treatment approaches for SCLC. 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 SCLC, especially with new agents that we’re excited about, we can look and start to identify whether certain therapies that are being tested seem to be especially active and especially beneficial for patients in 1 of these 4 groups. That really is the next step in moving toward precision oncology or a biomarker-driven approach.

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

Byers: With SCLC, because most past trials have been sort of for 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 who were getting that benefit from those drugs. Something that can happen immediately in the current clinical trials that are taking all SCLC patients is that, because we’ve identified what these 4 major subtypes are—and other drug-specific biomarkers are emerging as well—we can begin testing them to find out which of those 4 groups they’re in. Then, when we get to the end of the of the study and we see, for example, a 20% response rate with a certain drug or drug combination, but half 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 NSCLC, which is where you identify patients for a trial based on a biomarker and then treat them with that drug. You then [can hopefully] sort of flip the paradigm from a situation in which you have a minority of patients responding, to one in which, 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.

EBO: 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 become 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, we have been working hard and sharing those assays that we’ve developed using immunohistochemistry, [so they] could be immediately used as a way to test which subgroup a patient is in. I think that can be moved forward right away. Another limitation with SCLC is that the amount of tissue that’s available from biopsies is often very small. So, at the same time, we’re looking at some of the newer technologies and ways to [test for] as many biomarkers as possible and get the best possible test [results] from the smallest amount of tissue. We’re excited about potential opportunities to develop blood-based methods to test for the subgroups, as well.

EBO: SCLC is far behind NSCLC in new treatment development, but with approvals of immunotherapies and, more recently, lurbinectedin, things seem to be changing. Going forward, what therapies or combinations do you think have the most potential?

Byers: First, a great thing about this study was that we found a drug 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 [the research] has been on the preclinical side, with the exception of the immunotherapy study; we were able to validate [the results] in the clinical trial from IMpower133^.4

But now, it’s really exciting because many of those drugs that we focused on in the preclinical work are currently in, or about to enter, clinical trials for SCLC. For example, I’m still very enthusiastic about PARP inhibitors. John Heymach, MD, PhD, [and I] originally identified PARP as being overexpressed in SCLC, and we did the first study showing that PARP inhibitors had activity in some of the preclinical models. Having a subtype that may work especially well for PARP inhibitors is [exciting].

Also, we saw in the NEUROD1 group that those SCLCs seem to be very responsive to Aurora kinase inhibitors, and those are targeted agents that are also currently in trials for SCLC. That allows another opportunity for the inflamed group. Across the board, we see that there’s certainly room for improvement in terms of responses in each of the subgroups, compared with what we have with the current standard treatment. For example, there are opportunities for thinking about novel immune approaches that might be especially effective in the inflamed group. I’m also excited about tyrosine kinase inhibitors, cell therapy, and BiTE [bispecific T-cell engager] molecules—other, novel ways to engage the immune response beyond standard immune checkpoint inhibitors. These things are very exciting, and we’ll be seeing a lot going forward with the current clinical trials.

EBO: 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 thing we did when we decided to ask the question about subgroups in SCLC is that we really took a data-driven, kind of agnostic approach. We said, “Let’s let the data tell us how many groups there are, and what the major groups are,” rather than just trying to guess, or to fit it to what we thought it might be. Because we took that approach, we have 3 “major player” groups activated by 3 different genes: ASCL1, NEUROD1, and POU2F3. But the fourth group, the inflamed group—comprised of a group of tumors in which the biomarker was unclear, based on the work that had been done up to this point—was identified through this data-driven approach. That [fourth] group has such high expression of multiple immune genes and interferon signatures—all the [signs] that you’d expect from tumors that may be potentially more responsive to immunotherapy. Our hypothesis was that in this group we’d see the longer-term responses to immunotherapy.

It was really exciting to partner with some of our collaborators and look at the IMpower133 trial, in which the inflamed group made up about 18% of all the SCLC patients. And if you looked at how that group did, the addition of atezolizumab to chemotherapy essentially doubled their survival. So that really was the group who was getting the greater benefit from the addition of immunotherapy.

We’ve still got a lot of hard work to do. We can improve outcomes for patients in each of those groups through new approaches and combinations and other things to further enhance response in a more personalized way. But 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.

EBO: 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: First of all, just like with other lung cancer patients upon diagnosis, I hope and expect that we would immediately test to determine which group their cancer was in. I expect there’ll be additional biomarkers that may be drug-specific. Beyond the 4 subtypes, I think we’ll continue to see growth in terms of [finding] new biomarkers to further refine treatment selection. Then, based on clinical trials looking at differences in terms of the benefit of specific treatments for specific groups of patients, we’ll pick the most effective treatment for that individual patient.

The current standard of care for expansive-stage SCLC—which is the majority of newly diagnosed patients—is chemotherapy with immunotherapy. The change that we may see first is that when patients have completed 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, those would be brought in even earlier in the treatment. Potentially, eventually, we could replace chemotherapy with a novel combination as a targeted immune combination approach.

References

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. https://www.cancer.net/cancer-types/lung-cancersmall-cell/statistics
3. Howlader N, Forjaz G, Mooradian MJ, et al. The effect of advances
in lung-cancer treatment on population mortality. N Engl J Med.
2020;383(7):640-649. doi:10.1056/NEJMoa1916623
4. Liu SV, Reck M, Mansfield AS, et al. Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (Impower133). J Clin Oncol. 2021;39(6):619-630. doi:10.1200/JCO.20.0105521.