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VEGF and PD-1 Inhibition in Advanced Gastric/GEJ Cancer

Insights From: Manish Shah, MD, Weill Cornell Medicine
Published: Thursday, Aug 16, 2018



Transcript: 

Manish Shah, MD: Ramucirumab is used with paclitaxel in the second-line setting for most patients. Unfortunately, the RAINFALL study, which examined ramucirumab in the first-line setting, was just presented at ASCO and was in fact a negative study. It was a large study of over 700 patients, and the survival curves were really overlapping. There is a suggestion that you can have a higher response rate with ramucirumab, and there may be specific populations that benefit with ramucirumab in the first-line setting. But that’s still investigational. At this point, our focus would be to use Taxol (paclitaxel) and ramucirumab in the second-line setting after progression in the first-line setting with a platinum/5-FU.
 
There’s a lot of research going on with regard to immune checkpoint inhibitors and combination strategies to improve their response rates. To begin with, there is a lot of excitement for PD-1 inhibition in gastric and GE junction cancers. Patients who respond have a durable response, and it’s life-changing. Unfortunately, the response rate is not so high—10% to 15%, really—so 85% of patients are really not benefitting from checkpoint inhibition. We don’t understand the mechanisms of resistance, whether it’s upregulation of T-regs or MDSCs (myeloid derived suppressor cells). Ramucirumab is a VEGFR2 inhibitor and it can modulate the immune microenvironment. It’s very reasonable to examine the combination of pembrolizumab and ramucirumab. So far, it has been examined in a relatively small phase II setting, and the data seem to be really interesting with a median survival of nearly 20 months. I think it needs to be further tested and evaluated. It may be an option to combine them in the first-line setting in the future. More work needs to be done, but it’s exciting.
 
The combination of VEGF inhibition and checkpoint inhibition has been examined in other malignancies as well. The preclinical data suggest that the VEGF inhibitor can alter the immune microenvironment, perhaps eradicating some of the regulatory T cells or MDSCs that may cause resistance to a checkpoint inhibitor like a PD-1 or PD-L1 inhibitor. In colorectal cancer, it was examined in the IMpower study. I think the data are still preliminary, and more work needs to be done still in the combination. The study, as you know, did not give us a very positive signal.
 
Pembrolizumab was recently approved for PD-L1-positive gastric cancer in the third-line setting, and there’s an active drug development program to see if pembrolizumab can be used earlier. Unfortunately, KEYNOTE-061 was reported recently as negative. This was a randomized phase III study comparing pembrolizumab with Taxol in the second-line setting, and it was recently reported at ASCO in 2018. Looking at the Kaplan-Meier curves, what we see is that the initial response to pembrolizumab is not as good as it is to Taxol, but then the curves switch. Those who respond to pembrolizumab have a durable response, so the tail of the curve is greater.
 
All and all, because of that switch, the hazard ratio for the study was negative. That means that as monotherapy, it’s not as good as Taxol. Of course, the control arm in that study was Taxol, not Taxol and Cyramza (ramucirumab), which we know is superior. I don’t think monotherapy in the second-line setting is effective. What we also learned is that PD-L1 staining as a predictive biomarker may still have some virtue. The standard in the third-line setting is a CPS (combined positive score) of greater than or equal to 1.
 
They did an exploratory analysis in KEYNOTE-061 that looked at the CPS score greater than or equal to 10, and in that population, pembrolizumab really seemed to do better with a median survival of 10 months. It may be that with a better biomarker, we can get there, to an era where we give pembrolizumab or checkpoint inhibition without chemotherapy, but we’re not there yet. In the first-line setting, the study just completed and we’re waiting on the result. This was a study in PD-L1-positive patients. It was a combination of chemotherapy with pembrolizumab, pembrolizumab alone, or chemotherapy alone. We’re eagerly awaiting those results.

Transcript Edited for Clarity 
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Transcript: 

Manish Shah, MD: Ramucirumab is used with paclitaxel in the second-line setting for most patients. Unfortunately, the RAINFALL study, which examined ramucirumab in the first-line setting, was just presented at ASCO and was in fact a negative study. It was a large study of over 700 patients, and the survival curves were really overlapping. There is a suggestion that you can have a higher response rate with ramucirumab, and there may be specific populations that benefit with ramucirumab in the first-line setting. But that’s still investigational. At this point, our focus would be to use Taxol (paclitaxel) and ramucirumab in the second-line setting after progression in the first-line setting with a platinum/5-FU.
 
There’s a lot of research going on with regard to immune checkpoint inhibitors and combination strategies to improve their response rates. To begin with, there is a lot of excitement for PD-1 inhibition in gastric and GE junction cancers. Patients who respond have a durable response, and it’s life-changing. Unfortunately, the response rate is not so high—10% to 15%, really—so 85% of patients are really not benefitting from checkpoint inhibition. We don’t understand the mechanisms of resistance, whether it’s upregulation of T-regs or MDSCs (myeloid derived suppressor cells). Ramucirumab is a VEGFR2 inhibitor and it can modulate the immune microenvironment. It’s very reasonable to examine the combination of pembrolizumab and ramucirumab. So far, it has been examined in a relatively small phase II setting, and the data seem to be really interesting with a median survival of nearly 20 months. I think it needs to be further tested and evaluated. It may be an option to combine them in the first-line setting in the future. More work needs to be done, but it’s exciting.
 
The combination of VEGF inhibition and checkpoint inhibition has been examined in other malignancies as well. The preclinical data suggest that the VEGF inhibitor can alter the immune microenvironment, perhaps eradicating some of the regulatory T cells or MDSCs that may cause resistance to a checkpoint inhibitor like a PD-1 or PD-L1 inhibitor. In colorectal cancer, it was examined in the IMpower study. I think the data are still preliminary, and more work needs to be done still in the combination. The study, as you know, did not give us a very positive signal.
 
Pembrolizumab was recently approved for PD-L1-positive gastric cancer in the third-line setting, and there’s an active drug development program to see if pembrolizumab can be used earlier. Unfortunately, KEYNOTE-061 was reported recently as negative. This was a randomized phase III study comparing pembrolizumab with Taxol in the second-line setting, and it was recently reported at ASCO in 2018. Looking at the Kaplan-Meier curves, what we see is that the initial response to pembrolizumab is not as good as it is to Taxol, but then the curves switch. Those who respond to pembrolizumab have a durable response, so the tail of the curve is greater.
 
All and all, because of that switch, the hazard ratio for the study was negative. That means that as monotherapy, it’s not as good as Taxol. Of course, the control arm in that study was Taxol, not Taxol and Cyramza (ramucirumab), which we know is superior. I don’t think monotherapy in the second-line setting is effective. What we also learned is that PD-L1 staining as a predictive biomarker may still have some virtue. The standard in the third-line setting is a CPS (combined positive score) of greater than or equal to 1.
 
They did an exploratory analysis in KEYNOTE-061 that looked at the CPS score greater than or equal to 10, and in that population, pembrolizumab really seemed to do better with a median survival of 10 months. It may be that with a better biomarker, we can get there, to an era where we give pembrolizumab or checkpoint inhibition without chemotherapy, but we’re not there yet. In the first-line setting, the study just completed and we’re waiting on the result. This was a study in PD-L1-positive patients. It was a combination of chemotherapy with pembrolizumab, pembrolizumab alone, or chemotherapy alone. We’re eagerly awaiting those results.

Transcript Edited for Clarity 
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