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Chemotherapy/Immunotherapy Combinations in Lung Cancer

Panelists: Gerald J. Berry, MD, Stanford University; David Spigel, MD, Sarah Cannon Research Institute; Heather Wakelee, MD, Stanford University; Anne S. Tsao, MD, MD Anderson Cancer Center
Published: Wednesday, Jul 19, 2017


Transcript:

David Spigel, MD:
Like most cases in cancer research, we tend to do the things that seem obvious. Chemotherapy has been a tried-and-true way to care for people with lung cancer. Immunotherapy has found its way into lung cancer treatment as single-agent therapies. The next logical question is “Well, what if you give both?” And that really is the genesis for how the studies were designed: Let’s take the best chemotherapy that we use in lung cancer care and combine it with immunotherapy. At the preclinical level in modeling, there could be good rationale for why combining chemotherapy and immunotherapy makes sense. If chemotherapy induces the expression of PD-L1—if it releases an antigen as tumors die—that could enhance the T cell response.

In theory, there’s rationale for combining the agents. Some people wonder about the use of other things, like steroids with chemotherapy: Would that blunt the effect of immunotherapy? Those are things we just don’t have the answers to, but that’s why these trials were designed: to take advantage of both effective therapies in lung cancer and give them together. There are a lot of questions still: What should the right dose and schedule be? Should these be given in sequence? If you’re going to use maintenance therapy, what is your maintenance therapy? Is it pemetrexed alone, is it pemetrexed and immunotherapy, or is it both? There are a lot of questions, but we have to start somewhere. The pivotal trials are all fully enrolled, and we’re just waiting on those results right now.

Heather Wakelee, MD: KEYNOTE-021 was a randomized phase II trial—not giving us definitive data—and it’s in contrast to the KEYNOTE-024, which was pembrolizumab versus chemotherapy. That was a randomized phase III trial and definitively practice changing. KEYNOTE-021 was a randomized phase II trial, so not necessarily practice changing yet. That was actually a different question, looking at combination chemotherapy with carboplatin/pemetrexed plus or minus pembrolizumab. It was looking at a 3-drug regimen versus a 2-drug regimen, which was the standard chemotherapy.

This study enrolled patients who had different levels of PD-L1 expression, as opposed to the KEYNOTE-024 trial, which required a 50% expression—the high expressers. This study was open to patients with low expression—less than 1%, 1% to 49%, or greater than 50%. And what the study showed was that, in all of the subgroups, it seemed the 3-drug combination was better than just giving chemotherapy alone—“better” meaning response rates were higher. If you looked at the combination of chemotherapy plus pembrolizumab in the patients with high expression—greater than 50%—the response rates were around 80%, phenomenally high.

But even in those that had very low expression, the response rates were quite high—close to 50%. What was a little unusual, though, was that one of the middle groups—the 1% to 49%—was actually not as high. It’s a randomized phase II trial; we have to keep in mind that there are going to be some variations based on the small sample size. But the trend seemed to support that the 3-drug regimen had a higher response rate than the 2-drug regimen.

The progression-free survival was also better with the 3-drug regimen versus the chemotherapy alone. However, the survival was not clearly better. Maybe it’s too small a sample size, maybe it hasn’t been long enough—we don’t know yet. It’s a very intriguing and hypothesis-generating study, but one that I think we still need to look at further with randomized phase III data.

David Spigel, MD: KEYNOTE-021G was an important study that we heard about this past year. It’s already been published by Dr. Corey Langer and his colleagues. It’s a very simple study. It was just taking patients in the first-line, non–small cell lung cancer setting—specifically, the nonsquamous setting—and giving them the standard of care, which is carboplatin and pemetrexed along with maintenance pemetrexed, or giving them that same backbone of chemotherapy with immunotherapy—in this case, pembrolizumab.

Now, to get on the study, you didn’t have to have a high-expressing tumor—a PD-L1-positive tumor. PD-L1 expression levels were collected, and patients’ enrollment was stratified, or randomization was stratified, by that expression. This trial was designed simply to look at response rates: Could you improve the response rate with immunotherapy and chemotherapy, compared with just chemotherapy alone?

We know from Dr. Langer’s presentation and publication that the response rate was improved—about a 55% response rate, compared with a 28% response rate with chemotherapy alone, which is a remarkable improvement in that response rate. Unfortunately, we’re not seeing clear advantages in terms of survival with this regimen, but this trial was not designed to show survival advantages. It had about 120 patients total in the study, but there’s a phase III trial behind this that will help us to answer that question. An important study showed, at least for now, that a chemotherapy and immunotherapy combination looks better in terms of response rates, compared to chemotherapy alone.

Anne S. Tsao, MD: The KEYNOTE-21 study was a very important randomized phase II study for the field of lung cancer, because it was specifically looking at patients who did not necessarily have PD-L1 immunohistochemistry expression. What it demonstrated in 120 patients, roughly 60 in each arm, was that patients who received the immunotherapy with platinum pemetrexed had a very good response rate. It was much higher than that of those who just received the platinum pemetrexed alone—and this was in patients who did not necessarily have high PD-L1 expression.

This was the first study that actually demonstrated that adding an immunotherapy to frontline chemotherapy in a nonselected group of patients was potentially beneficial. There is an ongoing phase III randomized trial that will, hopefully, continue to show these results, but until that phase III trial reads out, I think we should be cautious and hold off doing this in our patients—until we know for certain that these results hold up.

Transcript Edited for Clarity
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Transcript:

David Spigel, MD:
Like most cases in cancer research, we tend to do the things that seem obvious. Chemotherapy has been a tried-and-true way to care for people with lung cancer. Immunotherapy has found its way into lung cancer treatment as single-agent therapies. The next logical question is “Well, what if you give both?” And that really is the genesis for how the studies were designed: Let’s take the best chemotherapy that we use in lung cancer care and combine it with immunotherapy. At the preclinical level in modeling, there could be good rationale for why combining chemotherapy and immunotherapy makes sense. If chemotherapy induces the expression of PD-L1—if it releases an antigen as tumors die—that could enhance the T cell response.

In theory, there’s rationale for combining the agents. Some people wonder about the use of other things, like steroids with chemotherapy: Would that blunt the effect of immunotherapy? Those are things we just don’t have the answers to, but that’s why these trials were designed: to take advantage of both effective therapies in lung cancer and give them together. There are a lot of questions still: What should the right dose and schedule be? Should these be given in sequence? If you’re going to use maintenance therapy, what is your maintenance therapy? Is it pemetrexed alone, is it pemetrexed and immunotherapy, or is it both? There are a lot of questions, but we have to start somewhere. The pivotal trials are all fully enrolled, and we’re just waiting on those results right now.

Heather Wakelee, MD: KEYNOTE-021 was a randomized phase II trial—not giving us definitive data—and it’s in contrast to the KEYNOTE-024, which was pembrolizumab versus chemotherapy. That was a randomized phase III trial and definitively practice changing. KEYNOTE-021 was a randomized phase II trial, so not necessarily practice changing yet. That was actually a different question, looking at combination chemotherapy with carboplatin/pemetrexed plus or minus pembrolizumab. It was looking at a 3-drug regimen versus a 2-drug regimen, which was the standard chemotherapy.

This study enrolled patients who had different levels of PD-L1 expression, as opposed to the KEYNOTE-024 trial, which required a 50% expression—the high expressers. This study was open to patients with low expression—less than 1%, 1% to 49%, or greater than 50%. And what the study showed was that, in all of the subgroups, it seemed the 3-drug combination was better than just giving chemotherapy alone—“better” meaning response rates were higher. If you looked at the combination of chemotherapy plus pembrolizumab in the patients with high expression—greater than 50%—the response rates were around 80%, phenomenally high.

But even in those that had very low expression, the response rates were quite high—close to 50%. What was a little unusual, though, was that one of the middle groups—the 1% to 49%—was actually not as high. It’s a randomized phase II trial; we have to keep in mind that there are going to be some variations based on the small sample size. But the trend seemed to support that the 3-drug regimen had a higher response rate than the 2-drug regimen.

The progression-free survival was also better with the 3-drug regimen versus the chemotherapy alone. However, the survival was not clearly better. Maybe it’s too small a sample size, maybe it hasn’t been long enough—we don’t know yet. It’s a very intriguing and hypothesis-generating study, but one that I think we still need to look at further with randomized phase III data.

David Spigel, MD: KEYNOTE-021G was an important study that we heard about this past year. It’s already been published by Dr. Corey Langer and his colleagues. It’s a very simple study. It was just taking patients in the first-line, non–small cell lung cancer setting—specifically, the nonsquamous setting—and giving them the standard of care, which is carboplatin and pemetrexed along with maintenance pemetrexed, or giving them that same backbone of chemotherapy with immunotherapy—in this case, pembrolizumab.

Now, to get on the study, you didn’t have to have a high-expressing tumor—a PD-L1-positive tumor. PD-L1 expression levels were collected, and patients’ enrollment was stratified, or randomization was stratified, by that expression. This trial was designed simply to look at response rates: Could you improve the response rate with immunotherapy and chemotherapy, compared with just chemotherapy alone?

We know from Dr. Langer’s presentation and publication that the response rate was improved—about a 55% response rate, compared with a 28% response rate with chemotherapy alone, which is a remarkable improvement in that response rate. Unfortunately, we’re not seeing clear advantages in terms of survival with this regimen, but this trial was not designed to show survival advantages. It had about 120 patients total in the study, but there’s a phase III trial behind this that will help us to answer that question. An important study showed, at least for now, that a chemotherapy and immunotherapy combination looks better in terms of response rates, compared to chemotherapy alone.

Anne S. Tsao, MD: The KEYNOTE-21 study was a very important randomized phase II study for the field of lung cancer, because it was specifically looking at patients who did not necessarily have PD-L1 immunohistochemistry expression. What it demonstrated in 120 patients, roughly 60 in each arm, was that patients who received the immunotherapy with platinum pemetrexed had a very good response rate. It was much higher than that of those who just received the platinum pemetrexed alone—and this was in patients who did not necessarily have high PD-L1 expression.

This was the first study that actually demonstrated that adding an immunotherapy to frontline chemotherapy in a nonselected group of patients was potentially beneficial. There is an ongoing phase III randomized trial that will, hopefully, continue to show these results, but until that phase III trial reads out, I think we should be cautious and hold off doing this in our patients—until we know for certain that these results hold up.

Transcript Edited for Clarity
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