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Reverce Study: Outcomes and Impact

Insights From:Tanios Bekaii-Saab, MD, FACP, Mayo Clinic; Andrea Cercek, MD, Memorial Sloan Kettering Cancer Center; Zev A. Wainberg, MD, David Geffen School of Medicine at UCLA
Published: Tuesday, Apr 03, 2018



Transcript: 

Andrea Cercek, MD: The Reverce study was a randomized phase II study in patients with refractory disease who had progressed on standard cytotoxic therapy but were naïve to anti-EGFR therapy. They were all KRAS exon 2 wild-type patients. They were randomized 1:1 to either regorafenib followed by cetuximab with or without irinotecan or cetuximab with or without irinotecan followed by regorafenib. So, the question here was sequencing. This is something that we know very little about. The thinking was, does one help over the other, with regard to overall survival, which was the primary endpoint? The secondary endpoints were progression-free survival -1, with the first line of treatment, as well as PFS-2, with the second line of treatment. And then, importantly, there was a quality-of-life assessment in safety and tolerability.

The data were interesting. The patients that received regorafenib first followed by cetuximab with or without irinotecan had a statistically significant improvement in overall survival—roughly 17 versus 11 months. But, interestingly, the secondary endpoint of the first PFS was equivalent. When they crossed over, the second PFS, there was significant improvement in the patients that received regorafenib first. That was a really interesting finding. It was probably that second PFS that actually contributed to the improvement in overall survival.

Tanios Bekaii-Saab, MD, FACP: The Reverce study informs us about potentially improving our understanding of how we sequence these agents. In fact, it is primarily focused on regorafenib. In comparing CONCUR with CORRECT (the Asian study versus the American study), the Asian study has less preexposure. In the US-based study, patients had to go through EGFR, VEGF, etc, and all of the chemotherapies. What we know, when we look at those 2 studies, historically, is that if you expose patients earlier to regorafenib, they tend to do better. They tend to have longer PFS and longer overall survival.

The Reverce study confirms that in a randomized fashion. Albeit, it’s still a phase II randomized study with the understanding that this was a Japanese patient population. But what was intriguing about this study was that it was primarily powered for overall survival. If we start with regorafenib and follow with cetuximab, versus the reverse, cetuximab followed by regorafenib, the survival is quite prolonged. This essentially tells us the importance of considering regorafenib earlier rather than later.

When I think about sequencing, which I’ve been doing for quite a while in my clinic, it’s not going to change much of my standard. However, I can tell you that for patients with right-sided tumors, where I try to avoid using the EGFR inhibitors, regorafenib will be given before I even consider cetuximab. That applies perfectly to that patient population. On the left-sided, I’m not sure yet. I’m not sure if I would place regorafenib before cetuximab. But I certainly may place it very quickly after cetuximab.

Transcript Edited for Clarity 
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Transcript: 

Andrea Cercek, MD: The Reverce study was a randomized phase II study in patients with refractory disease who had progressed on standard cytotoxic therapy but were naïve to anti-EGFR therapy. They were all KRAS exon 2 wild-type patients. They were randomized 1:1 to either regorafenib followed by cetuximab with or without irinotecan or cetuximab with or without irinotecan followed by regorafenib. So, the question here was sequencing. This is something that we know very little about. The thinking was, does one help over the other, with regard to overall survival, which was the primary endpoint? The secondary endpoints were progression-free survival -1, with the first line of treatment, as well as PFS-2, with the second line of treatment. And then, importantly, there was a quality-of-life assessment in safety and tolerability.

The data were interesting. The patients that received regorafenib first followed by cetuximab with or without irinotecan had a statistically significant improvement in overall survival—roughly 17 versus 11 months. But, interestingly, the secondary endpoint of the first PFS was equivalent. When they crossed over, the second PFS, there was significant improvement in the patients that received regorafenib first. That was a really interesting finding. It was probably that second PFS that actually contributed to the improvement in overall survival.

Tanios Bekaii-Saab, MD, FACP: The Reverce study informs us about potentially improving our understanding of how we sequence these agents. In fact, it is primarily focused on regorafenib. In comparing CONCUR with CORRECT (the Asian study versus the American study), the Asian study has less preexposure. In the US-based study, patients had to go through EGFR, VEGF, etc, and all of the chemotherapies. What we know, when we look at those 2 studies, historically, is that if you expose patients earlier to regorafenib, they tend to do better. They tend to have longer PFS and longer overall survival.

The Reverce study confirms that in a randomized fashion. Albeit, it’s still a phase II randomized study with the understanding that this was a Japanese patient population. But what was intriguing about this study was that it was primarily powered for overall survival. If we start with regorafenib and follow with cetuximab, versus the reverse, cetuximab followed by regorafenib, the survival is quite prolonged. This essentially tells us the importance of considering regorafenib earlier rather than later.

When I think about sequencing, which I’ve been doing for quite a while in my clinic, it’s not going to change much of my standard. However, I can tell you that for patients with right-sided tumors, where I try to avoid using the EGFR inhibitors, regorafenib will be given before I even consider cetuximab. That applies perfectly to that patient population. On the left-sided, I’m not sure yet. I’m not sure if I would place regorafenib before cetuximab. But I certainly may place it very quickly after cetuximab.

Transcript Edited for Clarity 
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