Real-World Insights: Rethinking Small Cell Lung Cancer Treatment with Atezolizumab

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic directing the Taussig Early Cancer Therapeutics Program and Co-Director of the Cleveland Clinic Sarcoma Program.

Today I'm happy to be joined by Dr. Heya Batah and Dr. Moaath Mustafa Ali. Dr. Batah is the resident here at Cleveland Clinic and Dr. Mustafa Ali is a medical oncologist. They're here today to talk to us about new insights on the combination of atezolizumab with carboplatin and etoposide in patients with extensive stage small cell lung cancer. Welcome.

Moaath Khader Mustafa Ali, MD, MPH: Thank you.

Heya Batah, MD: Thank you for having us.

Dale Shepard, MD, PhD: Maybe just start, give us a little bit of an idea about what you do here at the clinic, so maybe we'll start with you.

Heya Batah, MD: I'm currently a third year internal medicine resident, and I am applying to hematology oncology fellowship programs.

Dale Shepard, MD, PhD: Good choice.

Heya Batah, MD: Yeah, thank you.

Dale Shepard, MD, PhD: Excellent.

Moaath Khader Mustafa Ali, MD, MPH: I'm Moaath Mustafa Ali. I'm board certified in hematology and medical oncology. I'm actually a leukemia physician. However, I have interest in public health and causal inference and statistics and epidemiology. Examining real-world data is something I'm always interested in.

Dale Shepard, MD, PhD: Today, as it turns out, we're going to talk about retrospective look, real-world data about treatment of extensive stage small cell lung cancer. This is actually, we're going to talk about some data that was presented. Dr. Batah, you presented it at ASCO.

Heya Batah, MD: Yes.

Dale Shepard, MD, PhD: And so maybe give us a little bit of an idea of what even led to you thinking about looking at this in the first place.

Heya Batah, MD: Sure.

We picked extensive stage small cell lung cancer. I think there is the study that showed it that atezolizumab was a new cornerstone treatment with carboplatin and etoposide. I wanted to look further into this because there was a paucity of real-world outcomes when it comes to this treatment. We had a really large patient population and a very long follow-up time, so I wanted to further take a look at that and see how it impacted our patient population.

There was about 561 patients that we had, and we looked at patients from 2010 to 2022. We took a look at extensive stage small cell. We defined that as stage 3B and stage four, and we compared the overall survival progression free survival and response rate between carboplatin etoposide and carboplatin, etoposide, and atezolizumab.

Dale Shepard, MD, PhD: Just to take a really quick pause back, we've talked about real-world data and that sort of data analysis. People might be listening in a whole bunch of different backgrounds, what does real-world data mean?

Moaath Khader Mustafa Ali, MD, MPH: Real-world data is to examine the benefit or the efficacy of drugs in patients who are off clinical trial using data from hostels or from clinics.

I would say the benefit of using that analysis first confirms the clinical trial results. Also, commonly you have a long follow-up duration, which is very useful. It may sometimes help us even account for switching of treatments. It has a benefit for confirming results of clinical trials.

Dale Shepard, MD, PhD: I guess just to further this, hey, we're thinking about clinical trials very, very rigid. By comparison, real-world data could be pretty much anyone. Is that what you found as you looked at the data, that maybe there's more of a diverse group of people that get treated?

Heya Batah, MD: Yeah, we had a very large range of people that got treated.

Actually, we looked at a lot of comorbidities, too. A lot of characteristics within the patient, not just the ages and gender, but also their performance status, their brain metastasis, know other comorbidities such as hypertension, CKD status, the smoking status, alcohol status, things of that nature.

Dale Shepard, MD, PhD: Okay. And so when we think about this analysis, what were the key findings?

Heya Batah, MD: The overall study, we showed that atezolizumab had impact on overall survival and progression free survival, but it was not statistically significant when comparing it to just carboplatin and etoposide.

I think the big thing that we're taking a look at is that when we went back into our study and we looked at a larger follow-up and we incorporated more things such as performance status and brain metastasis, now we're further taking a look at this and seeing if atezolizumab has a overall impact into our study.

Dale Shepard, MD, PhD: And so when you did the initial analysis, you didn't really find that significant difference. What do you think was the primary driver for that?

Moaath Khader Mustafa Ali, MD, MPH: The primary driver is because we did not have enough follow-up duration, after we collected more data and we had tighter confidence intervals, we were able to show the difference.

Initially in the presentation in ASCO, we found that the addition of atezolizumab to carboplatin and etoposide was associated with improvement in median survival. However, that was not statistically significant. In the biostatistical world, it's known that if you prolong the follow-up, you have tighter confidence interval. Indeed, we found very similar results to the clinical trial. And this just attests to that good study design is usually associated with better outcomes.

The difference in survival and overall survival after we did the further follow-up was one month, which was very consistent with the clinical trial finding.

Dale Shepard, MD, PhD: When you think about one month from a clinical standpoint, you think clinical significance. Is that really clinically relevant? Any thoughts on that?

Moaath Khader Mustafa Ali, MD, MPH: I think for median overall survival, one month in terms of a disease like small cell lung cancer, sometimes it can be of a difference. But it's a one month. Clinically it's not a big difference. The thing that we have to remember as oncologists is atezolizumab is an additional drug, it has additional costs. These are all important for clinical decision.

Yes, it is very true this difference is not big.

Dale Shepard, MD, PhD: I guess one thing, so Heya, you presented this data. One of the things fun is when you present data at a conference like this, you get to interact with people. What kind of discussions did you have with people looking at the poster? Were they surprised? Does it seem like it was consistent with what their perceptions, or did they disagree with your findings?

Heya Batah, MD: Yeah, there was a mix, but I would say a lot of people were surprised. We had a lot of people from the drug companies that were coming up to the poster. I think that was a little shocking to them, given the clinical trial and the use of it in real-world practice. People were very interested in seeing what other further studies we can come up with from this main one.

And so they wanted to follow up with us and see when we went back to look at the longer follow up what other results would come up from this.

Dale Shepard, MD, PhD: And so when you did the longer follow-up, you did incorporate some of these other factors. Were there some of the factors that you think were really more prevalent than others in terms of swaying the data into a positive direction for atezolizumab?

Moaath Khader Mustafa Ali, MD, MPH: I think when we collected further data, we collected more on the ECOG Performance Status. Obviously, that is a very important baseline characteristic confounder that you have a person has to correct for.

In our analysis, we used two methods to correct for baseline characteristics, including multivariable Cox proportional hazards, as well as we use propensity to score weighting. By that we were able to find the result which is consistent with the clinical trial. I think our finding is a true difference. However, as we mentioned, the clinical benefit is not very big.

Dale Shepard, MD, PhD: Again, because of the diversity of people, propensity score weighting, tell us a little bit about what that is and how that might play in.

Moaath Khader Mustafa Ali, MD, MPH: Propensity score weighting is, so first of all, in studies real-world data, you have to adjust for baseline factors. This is what's called confounding, that certain baseline factors can affect the outcome. Without correcting for these confounders, your outcome will be biased.

You can do that by two methods. One of them is Cox proportional hazards model, and then another method that was I would say revolutionized in the last 10 to 20 years is called propensity to score weighting or propensity to score matching. What it does exactly, it looks to the baseline characteristics and give some kind of scoring and try to match patients with each other who have very similar number. For patients who are similar in these baseline characteristics, they get to be compared and have a larger weight in the outcome calculation. Patients who are very different from the others, they tend to have smaller weight and they affect the outcome less. It's a very effective method.

Now, what's better about propensity score analysis compared to Cox proportional hazard is that Cox proportional hazard assumes that the relative hazard is constant. It's proportional and constant throughout the survival, which is commonly not true in the oncology ward. As survival may vary and the survival rates may vary between different arms, it's not always constant and proportional.

Dale Shepard, MD, PhD: You got to come in and get a project that you've gotten completed to the point where you got to present it. What's next?

Heya Batah, MD: We're actually taking a look now, as Dr. Ali mentioned, incorporating cisplatin and etoposide compared to carboplatin, etoposide, atezolizumab. We're doing further studies on that. And then we're going to write the manuscript for the paper, so we're currently working on that as well.

Dale Shepard, MD, PhD: Excellent. Are you drawing in patients from people that are seen here on our main campus, or are you bringing in things from our regional practices as well?

Heya Batah, MD: All Cleveland Clinic, yes.

Dale Shepard, MD, PhD: That's excellent. We get not only real world, but cross-section of our entire enterprise, so that's good.

Heya Batah, MD: Thank you.

Moaath Khader Mustafa Ali, MD, MPH: One thing I would like to add is that while we were collecting data, we've noticed some patients who have extensive stage small cell lung cancer received indeed cisplatin and etoposide. When we look to their baseline characteristics, yes, indeed, we found that they are on average five years younger than people who get carboplatin plus etoposide or carboplatin plus etoposide and plus atezolizumab.

However, when we did the propensity to score adjustment and the multivariable regression, we found that people who get cisplatin and etoposide they had improvement in overall response. That was statistically significant. The weighted odds ratio for response was 1.5 times higher in cisplatin plus etoposide compared to the other two treatment arms.

That was a very interesting and surprising finding. We think it might be related to the fact that cisplatin in general and among the oncology community, it's thought to be somewhat more effective and more efficacious and has higher cytotoxicity compared to carboplatin. This finding is interesting because the sample size was not small. We had 70 people who got cisplatin and etoposide, so it's something it's interesting and probably should be thought about among the thoracic oncologists.

Dale Shepard, MD, PhD: Yeah, that's a good point. I mean, cisplatin eligibility is certainly an issue, and it does tend to be younger, fitter, that sort of thing. But I guess with the weighting it's still was the overall better response.

Do you think that this preliminary, real-world data might drive even a preliminary study to do a comparison?

Heya Batah, MD: We hope so.

Dale Shepard, MD, PhD: You hope so?

Heya Batah, MD: Yeah, that's the goal.

Dale Shepard, MD, PhD: That'll be the one you're going to talk about next time.

Heya Batah, MD: Yes.

Moaath Khader Mustafa Ali, MD, MPH: Yeah, that's actually should be thought about. I think if treatment of lung cancer in patients who have extensive, say, small cell lung cancer, if it can be managed with cisplatin and etoposide alone without atezolizumab with comparable and possibly even superior outcome, in my opinion, would be better than adding atezolizumab. Because it's less costly and I would say shorter duration of therapy because atezolizumab, you have to give maintenance therapy, which is for a prolonged period.

At the same time, it's slightly associated with improvement in overall survival. But however that needs to be tested in a prospective experimental design where we do randomization.

Dale Shepard, MD, PhD: What's your next project?

Heya Batah, MD: This is the one I'm currently working on, writing the manuscript for this. Other projects I have actually are outside of the small cell lung cancer world.

Dale Shepard, MD, PhD: All right, fair enough.

Heya Batah, MD: Yeah.

Dale Shepard, MD, PhD: Well, I mean it's always important to these things to consider. The clinical trials are done in a very, very artificial situation. People have to fit very, very rigid guidelines, and so it is always nice to have a chance to step back and say, "Does this really, really matter?"

Important work and appreciate you coming and talking about it.

Heya Batah, MD: Thank you so much.

Dale Shepard, MD, PhD: Of course.

Heya Batah, MD: Thank you for having us.

Dale Shepard, MD, PhD: Absolutely.

Moaath Khader Mustafa Ali, MD, MPH: Of course. Thank you for having us.

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