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A Closer Look at FIRE-3 and CALGB/SWOG 80405

Insights From:Alan P. Venook, MD, University of California
Published: Tuesday, Jul 26, 2016


Transcript:

Alan P. Venook, MD:
FIRE-3 and CALGB/SWOG 80405 are very interesting dueling studies. They were started around the same time, in 2003 or 2004. FIRE-3 is a European study that built on FOLFIRI as a backbone. The CALGB/SWOG 80405 built on choice of FOLFIRI or FOLFOX because in the United States, FOLFOX is much more popular. FIRE-3 had the same randomizations to cetuximab and bevacizumab as we did. Although in our original study design, we had two biologics together.

Where the rubber meets the road though is where the results are different. Both studies did not select originally, but realized early on that we should be selecting for KRAS wild-type and made that change, made that pivot. FIRE-3’s results showed that cetuximab was superior to bevacizumab in patients in that study by about 3.5 months. Then when they analyzed the all-RAS population, which essentially is getting rid of the patients from your mix who you think won’t respond because they have a RAS mutation, the difference was 7.5 to 8 months between cetuximab and bevacizumab.

We did our study, CALGB/SWOG 80405, and obviously, there are other issues. Like it or not, there’s an industry sponsor in Europe that might have some interest in the results. I don’t think they fabricate things, but they may put a different spin on it or look a little differently at things. Our study was a cooperative group study where our original goal was to look to see a difference. Again, we amended it. We thought patients would live 22 months when we started. They all lived 30 months. And in our study, we saw no difference at all between the two groups. Why is that? In fact, 2 years ago people were trying to figure out who was right and who wrong. Was FIRE-3 right or was CALGB/SWOG 80405 right? I said then and I say now, “Just because you get different data doesn’t mean one’s right and one’s wrong. Let’s try to understand it.”

The FIRE-3 investigators have been incredibly collegial and collaborative, and we’ve worked together to try to figure this out. We put some of our data together, have had a couple of publications, a couple of papers. In this case, what we now have figured out over the course of the last few months—as we get a better understanding of the fact that colon cancer right and left sided are different—is that it may very well be the explanation for why our results are different. Because it turns out in the FIRE-3 study, 77% of the patients had left-sided cancers and in CALGB/SWOG 80405, 68% had left-sided cancers. And because of the way the cancers play out, the way of their prognostic foresightedness, we think that may explain much of the difference. There’s also, of course, just different patterns of care and different things that make results different.

In terms of how do we interpret it, I think we would interpret things the same way FIRE-3 investigators do now. When FIRE-3 came out, it was all about cetuximab beating bevacizumab, and in the United States, we didn’t see that. So, there was a fair bit of conflict. And it also is a function of different societal preferences. In the United States, patients mostly don’t like cetuximab. They don’t like to have the rash; doctors probably don’t like to see patients with the rash. All of these are factors. Until the last couple of months, the FIRE-3 data was met in Europe, most patients started with cetuximab, and in the United States patients could start with either one.

Regarding the recent data that I presented, one of the things that made the presentation more powerful, I believe, is the internal data from FIRE-3 on the left-versus-right-side question. And that data looked almost identical to our data, even though the patients had a very different outcome overall. Two of those data sets together make a pretty compelling story that patients with right-sided colon cancer shouldn’t be treated with cetuximab, and left-sided you could go either way. So, we’ve gone from having disparate results—where there was a big debate—to realizing that in a number of instances, our studies are exactly the same, and I think that’s helped clarify some of these questions.

In CALGB/SWOG 80405, we had 1137 patients. In the sidedness analysis of that there were 46 patients for whom we couldn’t determine the side of the primary. Now, how’d we determine this? Somebody had to go in and look in every medical record to figure out what the side of the primary was because we didn’t get the data in real time. And I believe it’s pretty reasonable. There was a reliable person who got all the data and figured out the sidedness, and that was me. So, at least there was not a research coordinator or somebody getting that data. Again, in our series, in 46 patients I couldn’t determine the sidedness, 66 had transverse colon primaries, 730-some had left-sided, and 200-some had right-sided. If we excluded the transverse colon patients, we had about 700 and 200 in the two different sides.

In terms of the patient characteristics, their diseases are really different. Even though the average age of our patients was only 58 years of age—a very young group for colon cancer—the patients with right-sided cancer were older than those with tumors on the left side. The patients with right-sided cancer were more likely to have peritoneal disease than the left side, where there are more liver metastases. The patients with a right-sided disease tended to present with synchronous disease; they were already stage 4. Not surprising, right? Clinically, we think they’re different. When you look at a big series, they did turn out to have different characteristics.

And, in terms of the results, again, patients with tumors on the left side had a 33-month survival versus 19 months on the right side. With cetuximab, it was 36 months on the left and 16 months on the right in our study. These are really stunning numbers, right? We’re not used to seeing this, we’re used to seeing a 3- or 4-month difference. That’s a lot. And here you have a 20-month difference between treatments based on the side of the cancer. It was really a remarkable result, one that I actually wasn’t convinced was true. I thought maybe they’d screwed up the code, only to then get the FIRE-3 data which showed the same results we had.

Again, I think fundamentally really what it does is it directs us to understand the biology. Because I would emphasize that right and left side is not something magical, it’s the biology of the cancer. The bad genes, such as BRAF, those tumors tend to be on the right side; a confluence of events on one side or the other, and that’s what changes the outcomes. In the future, we’re actually talking of combining our data with FIRE-3 investigators to get power to really figure out if we can’t solve some of these questions.

Transcript Edited for Clarity
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Transcript:

Alan P. Venook, MD:
FIRE-3 and CALGB/SWOG 80405 are very interesting dueling studies. They were started around the same time, in 2003 or 2004. FIRE-3 is a European study that built on FOLFIRI as a backbone. The CALGB/SWOG 80405 built on choice of FOLFIRI or FOLFOX because in the United States, FOLFOX is much more popular. FIRE-3 had the same randomizations to cetuximab and bevacizumab as we did. Although in our original study design, we had two biologics together.

Where the rubber meets the road though is where the results are different. Both studies did not select originally, but realized early on that we should be selecting for KRAS wild-type and made that change, made that pivot. FIRE-3’s results showed that cetuximab was superior to bevacizumab in patients in that study by about 3.5 months. Then when they analyzed the all-RAS population, which essentially is getting rid of the patients from your mix who you think won’t respond because they have a RAS mutation, the difference was 7.5 to 8 months between cetuximab and bevacizumab.

We did our study, CALGB/SWOG 80405, and obviously, there are other issues. Like it or not, there’s an industry sponsor in Europe that might have some interest in the results. I don’t think they fabricate things, but they may put a different spin on it or look a little differently at things. Our study was a cooperative group study where our original goal was to look to see a difference. Again, we amended it. We thought patients would live 22 months when we started. They all lived 30 months. And in our study, we saw no difference at all between the two groups. Why is that? In fact, 2 years ago people were trying to figure out who was right and who wrong. Was FIRE-3 right or was CALGB/SWOG 80405 right? I said then and I say now, “Just because you get different data doesn’t mean one’s right and one’s wrong. Let’s try to understand it.”

The FIRE-3 investigators have been incredibly collegial and collaborative, and we’ve worked together to try to figure this out. We put some of our data together, have had a couple of publications, a couple of papers. In this case, what we now have figured out over the course of the last few months—as we get a better understanding of the fact that colon cancer right and left sided are different—is that it may very well be the explanation for why our results are different. Because it turns out in the FIRE-3 study, 77% of the patients had left-sided cancers and in CALGB/SWOG 80405, 68% had left-sided cancers. And because of the way the cancers play out, the way of their prognostic foresightedness, we think that may explain much of the difference. There’s also, of course, just different patterns of care and different things that make results different.

In terms of how do we interpret it, I think we would interpret things the same way FIRE-3 investigators do now. When FIRE-3 came out, it was all about cetuximab beating bevacizumab, and in the United States, we didn’t see that. So, there was a fair bit of conflict. And it also is a function of different societal preferences. In the United States, patients mostly don’t like cetuximab. They don’t like to have the rash; doctors probably don’t like to see patients with the rash. All of these are factors. Until the last couple of months, the FIRE-3 data was met in Europe, most patients started with cetuximab, and in the United States patients could start with either one.

Regarding the recent data that I presented, one of the things that made the presentation more powerful, I believe, is the internal data from FIRE-3 on the left-versus-right-side question. And that data looked almost identical to our data, even though the patients had a very different outcome overall. Two of those data sets together make a pretty compelling story that patients with right-sided colon cancer shouldn’t be treated with cetuximab, and left-sided you could go either way. So, we’ve gone from having disparate results—where there was a big debate—to realizing that in a number of instances, our studies are exactly the same, and I think that’s helped clarify some of these questions.

In CALGB/SWOG 80405, we had 1137 patients. In the sidedness analysis of that there were 46 patients for whom we couldn’t determine the side of the primary. Now, how’d we determine this? Somebody had to go in and look in every medical record to figure out what the side of the primary was because we didn’t get the data in real time. And I believe it’s pretty reasonable. There was a reliable person who got all the data and figured out the sidedness, and that was me. So, at least there was not a research coordinator or somebody getting that data. Again, in our series, in 46 patients I couldn’t determine the sidedness, 66 had transverse colon primaries, 730-some had left-sided, and 200-some had right-sided. If we excluded the transverse colon patients, we had about 700 and 200 in the two different sides.

In terms of the patient characteristics, their diseases are really different. Even though the average age of our patients was only 58 years of age—a very young group for colon cancer—the patients with right-sided cancer were older than those with tumors on the left side. The patients with right-sided cancer were more likely to have peritoneal disease than the left side, where there are more liver metastases. The patients with a right-sided disease tended to present with synchronous disease; they were already stage 4. Not surprising, right? Clinically, we think they’re different. When you look at a big series, they did turn out to have different characteristics.

And, in terms of the results, again, patients with tumors on the left side had a 33-month survival versus 19 months on the right side. With cetuximab, it was 36 months on the left and 16 months on the right in our study. These are really stunning numbers, right? We’re not used to seeing this, we’re used to seeing a 3- or 4-month difference. That’s a lot. And here you have a 20-month difference between treatments based on the side of the cancer. It was really a remarkable result, one that I actually wasn’t convinced was true. I thought maybe they’d screwed up the code, only to then get the FIRE-3 data which showed the same results we had.

Again, I think fundamentally really what it does is it directs us to understand the biology. Because I would emphasize that right and left side is not something magical, it’s the biology of the cancer. The bad genes, such as BRAF, those tumors tend to be on the right side; a confluence of events on one side or the other, and that’s what changes the outcomes. In the future, we’re actually talking of combining our data with FIRE-3 investigators to get power to really figure out if we can’t solve some of these questions.

Transcript Edited for Clarity
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