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Mar 11, 2021

Dr. Lauren Byers, associate professor of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, highlights a new study published in Cancer Cell that features a transformative new framework to classify small-cell lung cancer into four subtypes based on gene expression, paving the way for personalized treatment options (DOI: 10.1016/j.ccell.2020.12.014).



ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for ASCO Daily News. My guest today is Dr. Lauren Byers, associate professor of Thoracic, Head, and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center. Dr. Byers is the lead author of a new study published in Cancer Cell that features a transformative new framework to classify lung cancer into four small-cell lung cancer subtypes based on gene expression, and, for the first time, a personalized treatment option for the second most common type of lung cancer.

Dr. Byers serves on advisory committees and receives research funding from AstraZeneca, Genmab, and Sierra Oncology, among other organizations. Her full disclosures and those relating to all episodes of the podcast are available on our transcripts at Dr. Byers, welcome to the ASCO Daily News Podcast.

Dr. Lauren Byers: Thank you, Geraldine.

ASCO Daily News: Small-cell lung cancer is known for its aggressive growth and resistance to treatment with predictably poor outcomes. There has been some progress with immunotherapy and targeted therapy, but can you tell us why advances in small-cell lung cancer have been more modest in recent years? 

Dr. Lauren Byers: We've seen incredible progress in personalizing treatment for patients with non-small cell lung cancer. And for those patients, we routinely use biomarkers, such as EGFR mutations, ALK fusions, or PD-L1 expression, to match our patients to the most effective targeted therapy or to immunotherapy. And this really allows us to have a more personalized approach to their treatment. And last year in the New England Journal of Medicine, there was a very encouraging report showing that deaths from lung cancer had gone down sharply (DOI: 10.1056/NEJMoa1916623). And this was in part because of those improvements in terms of targeted and personalized treatments.

Unfortunately for patients with small-cell lung cancer, which makes up about 13% of newly diagnosed lung cancers, the advances have really been more modest. And to date, we have not had any validated biomarkers for small-cell lung cancer that we can routinely use in the clinical setting. And this means that currently patients are really treated with a one size fits all approach. And this could be chemotherapy in combination with radiation, or chemotherapy plus immunotherapy.

But I think we really in the field had a growing appreciation that small-cell lung cancer was essentially more than one type of lung cancer, and that certain small-cell lung cancers can respond very differently to different treatments depending on what genes are turned on and what's driving the growth of these cancers. And we had had a few leads in terms of what some of the potential biomarkers might be. But we found that many small-cell lung cancers didn't fit into one of the groups or categories that we predicted might be some of the important subtypes.

ASCO Daily News: Right. So can you tell us about the approach that you and your co-investigators used to identify the small-cell lung cancer subtypes based on gene expression data?

Dr. Lauren Byers: So what our group did was we really used that data-driven approach where we took an unbiased computational approach to let the data tell us how many distinct molecular groups are there within small-cell lung cancer. And we did this by looking at gene expression data, so looking at what genes were turned on or off in different patient tumors. And based on this, we found that there were four major distinct molecular subtypes of small-cell lung cancer.

Three of these were ones that we predicted were probably important players. And these are ones that are defined by expressing different transcription factors. These are master regulator genes, specifically the genes ASCL1, NeuroD1, and PALB2 F3. Those three made up three of the four groups that were identified in our study.

But there was a novel fourth group that emerged from this analysis which had not been previously appreciated. And we called this group the small cell lung cancer inflamed subtype, because it really was distinct from the other small-cell cancers by having increased immune cell infiltration and increased expression of multiple immune markers, including higher levels of immune checkpoints.

And so when we saw this, we predicted that this inflamed subtype might be the group that was responding better to immune checkpoint inhibitors, such as atezolizumab. And together with our collaborators on our publication, we had the opportunity then to test whether or not the small-cell inflamed subtype was in fact more responsive to immunotherapy.

And we did this by looking at patient samples, gene expression data from over 250 patients who were treated on the randomized phase III IMpower133 clinical trial (NCT02763579). This was a trial that changed the standard of care for small-cell lung cancer and tested the question for patients with extensive stage disease, whether the addition of atezolizumab's immune checkpoint inhibition to standard front-line chemotherapy with platinum-etoposide could improve outcomes for patients.

And so what we found in this retrospective analysis of the IMpower133 study was that, first, we again found these four major subgroups, including the inflamed group, which made up about 20% of patients. And then as we predicted, one of the really exciting findings from this analysis was that in fact the small-cell inflamed group did have improved survival with the addition of immunotherapy to chemotherapy. In patients that were in that small-cell inflamed group, their overall survival with the addition of the atezolizumab was approximately 18 months as compared to when the inflamed patients received the standard chemotherapy by itself.

And importantly also, if we looked at across the four small-cell subtypes in terms of how patients did in the inflamed group as compared to the other three groups when there was the addition of the immunotherapy, the benefit really was enriched in that small-cell inflamed where, again, those patients had a much longer survival as compared to patients in the subtypes where their survival was around 10 months or similar to what was seen with the standard chemotherapy. So I think that was really an exciting finding and I think gives us a path forward to think about how we might start personalizing treatment.

The other thing related to this was that the three subtypes that were not as responsive to immunotherapy, the ASCL1, NeuroD1, and PALB2 F23, in our paper we described certain targeted therapies that actually work quite well in preclinical models in those other groups. And so I think it gives us a path forward in terms of the potential to identify a personalized approach for each of the four groups.

ASCO Daily News: Absolutely. Now, I understand in some cases you and your co-investigators observed more than one of the small-cell subtypes within a patient's tumor. Can you tell us about this?

Dr. Lauren Byers: I think one of the really interesting things that we also found in the study was that in some cases we saw more than one of the small-cell subtypes present within an individual patient's tumor. So in a small-cell lung cancer tumor, there could be, for example, cells that were in ASCL1 group, and then others that were expressing markers of the NeuroD1 group. And when we did further investigation into this using some of our preclinical models, we found that one way that these cancers were becoming resistant to chemotherapy was by switching from one subtype to another.

ASCO Daily News: Dr. Byers, did the subtype switching surprise you, and have other investigators seen this before?

Dr. Lauren Byers: This subtype switching was not totally unexpected. There have been other groups that do work in the field of small-cell lung cancer that have also recently reported a similar type of subtype switching. And in the case of our publication, we also found that tumors could switch to the inflamed group.

And I think, again, this provides us additional insights into how small-cell lung cancer adapt and what might be driving resistance. And I think, more importantly, also, as a medical oncologist, this gives us ideas about how we might potentially combine drugs that target more than one subtype to overcome resistance or also the importance of getting repeat biopsies after a patient has relapsed so that we can see what is their current subtype and, again, personalize the treatment to the subtype of their cancer at that time when we're making a treatment decision.

The other thing that we've been very focused on is developing and also sharing ways that we will be able to test for the small-cell subgroups and biomarkers that can be used. So this can be done easily in clinic. And so I think that both from tumor as well as ultimately, hopefully, minimally invasive approaches, such as blood-based testing, will be ways that we'll be able to do this routinely, and then move us forward in terms of having more precision oncology approaches for our patients.

ASCO Daily News: Yes, there are surely new tailored approaches on the horizon as the work continues to find ways to test for the small-cell subgroups in clinic. Dr. Byers, is there anything else you'd like to share before we wrap up our discussion today?

Dr. Lauren Byers: I think I would just say that we're very excited, that we think that this work, together with a lot of the other very exciting work in this field, is opening the door to precision medicine for small-cell lung cancer. And I think this is a very exciting time for our patients and for hopefully seeing accelerated progress because of these findings.

The other thing that I think will be really exciting is that ultimately I think we look forward to having trials where we do start matching patients to specific treatments based on their molecular classification. And I think that also will really help accelerate progress the same way that those types of studies in non-small cell lung cancer have.

And then the last thing I wanted to say is I would just like to recognize Dr. Adi Gazdar, who was a world-renowned thoracic pathologist, and we dedicated our paper to--he really was the father of lung cancer pathology. And he always encouraged all of us in lung cancer research that small cell was not a single disease and that we needed to keep looking and refining what the small cell subtypes were. So I just want to acknowledge his contributions and give the role that he has played on the field for so many of us.

ASCO Daily News: Well, thank you Dr. Byers for telling us about these exciting developments in small-cell lung cancer. I'll just remind listeners of the title of your study published in Cancer Cell is "Patterns of Transcription Factor Program and Immune Pathway Activation Defined for Major Subtypes of SCLC with Distinct Therapeutic Vulnerabilities." Thanks again, Dr. Byers.

Dr. Lauren Byers: Thank you, Geraldine. I really appreciate you having me.

ASCO Daily News: And thank you to our listeners for joining us today. If you're enjoying the content on the podcast, please take a moment to rate and review us, wherever you get your podcasts.


Disclosures: Dr. Lauren Byers

Consulting or Advisory Role: Abbvie, AstraZeneca, PharmaMar, Genmab, Bristol-Myers Squibb, Sierra Oncology, Pfizer, Merck, Jazz Pharmaceuticals, Genentech

Research Funding: Tolero Pharmaceuticals, Sierra Oncology, AstraZeneca (institution), Genmab (institution) 

Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.