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IMpower150: Quadruplet Therapy for Nonsquamous mNSCLC

Insights From: Hossein Borghaei, DO, Fox Chase Cancer Center; Corey J. Langer, MD, Perelman School of Medicine; Vassiliki Papadimitrakopoulou, MD, MD Anderson Cancer Center
Published: Monday, Aug 06, 2018



Transcript: 

Corey J. Langer, MD: IMpower150 was a critical trial that included patients who are eligible for angiogenesis inhibition. It also included, in distinction from the KEYNOTE-024 and KEYNOTE-042 trials with pembrolizumab or the single-agent KEYNOTE-189 trial, individuals with molecular aberration. This was essentially a nonsquamous trial, since patients had to be eligible for bevacizumab. The control arm looked at paclitaxel/carboplatin/bevacizumab, the ECOG-4599 regimen that actually led to bevacizumab’s approval. The 2 experimental arms looked at paclitaxel/carboplatin combined with atezolizumab, so it was a direct 1 for 1 comparison between atezolizumab and bevacizumab. Arm B was actually a quadruplet, the ECOG-4599 with atezolizumab added to that: paclitaxel, carboplatin, bevacizumab, and atezolizumab.

It was a huge trial. Over 1200 patients were accrued. The primary analysis was arm B versus arm C, the question of whether atezolizumab actually added to paclitaxel/carboplatin/bevacizumab, and in fact it did. We see an improvement in overall response rate in the mid-60% range versus about 46% or 48%. We see a major improvement in progression-free survival. The median survivals aren’t that much different, with maybe a 2-month advantage of the median survival, but what’s intriguing is that the curves separate increasingly over time. That speaks to a potential synergy that may exist between bevacizumab and the checkpoint inhibitor, atezolizumab. Angiogenesis inhibitors can upregulate VEGF and cause other issues with T-cell suppressors, cells that are potentially inhibited by checkpoint inhibition. So, there may be real synergy occurring.

At ASCO 2018, the final formal survival results are being reported. In fact, we see a 4.5- to 5-month improvement in median survival from the mid 14-month range to 19, 19.5 months. This is quite remarkable. The control group performed at least as well as it had performed in the ECOG-4599 trial, the adenocarcinoma group. The benefit extends and in fact it is even more pronounced in those with EGFR mutations or ALK translocations. The control group has a median survival about 17 months. It has not even been reached in the atezolizumab arm. We see it on the opposite end of the spectrum in patients with visceral dominant disease such as liver metastases. The numbers are lower, but the degree of survival benefit is just as pronounced at 13.5 months versus 9 months or so.

The trial is really unprecedented. We have never seen any other agents added to the ECOG-4599 regimen improve outcomes as we have here. This regimen potentially becomes our go-to regimen in patients who have oncogenic drivers whose disease is really becoming TKI-refractory. The final common pathway for all of our patients with an EGFR mutation, ALK transition, ROS1 mutation, or any of the other major drivers remains chemotherapy. Eventually, the TKIs no longer work.

Vassiliki Papadimitrakopoulou, MD: IMpower150 used several strategies to evaluate for enrichment in terms of benefit from this therapy. Beyond PD-L1 expression, there was a T-cell effector signature that was explored that contained 3 genes. There was also a subgroup analysis for patients who presented with liver metastases. There was benefit associated with high PD-L1 expression as well as high T-cell effector signature. There was also benefit for patients with liver metastases, and that is actually information that is important because liver metastases are thought to represent immunosuppressive tumor microenvironment. Therefore, the improvements that we saw in patients’ progression-free survival in the setting of liver metastases are a very positive signal.

Transcript Edited for Clarity 
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Transcript: 

Corey J. Langer, MD: IMpower150 was a critical trial that included patients who are eligible for angiogenesis inhibition. It also included, in distinction from the KEYNOTE-024 and KEYNOTE-042 trials with pembrolizumab or the single-agent KEYNOTE-189 trial, individuals with molecular aberration. This was essentially a nonsquamous trial, since patients had to be eligible for bevacizumab. The control arm looked at paclitaxel/carboplatin/bevacizumab, the ECOG-4599 regimen that actually led to bevacizumab’s approval. The 2 experimental arms looked at paclitaxel/carboplatin combined with atezolizumab, so it was a direct 1 for 1 comparison between atezolizumab and bevacizumab. Arm B was actually a quadruplet, the ECOG-4599 with atezolizumab added to that: paclitaxel, carboplatin, bevacizumab, and atezolizumab.

It was a huge trial. Over 1200 patients were accrued. The primary analysis was arm B versus arm C, the question of whether atezolizumab actually added to paclitaxel/carboplatin/bevacizumab, and in fact it did. We see an improvement in overall response rate in the mid-60% range versus about 46% or 48%. We see a major improvement in progression-free survival. The median survivals aren’t that much different, with maybe a 2-month advantage of the median survival, but what’s intriguing is that the curves separate increasingly over time. That speaks to a potential synergy that may exist between bevacizumab and the checkpoint inhibitor, atezolizumab. Angiogenesis inhibitors can upregulate VEGF and cause other issues with T-cell suppressors, cells that are potentially inhibited by checkpoint inhibition. So, there may be real synergy occurring.

At ASCO 2018, the final formal survival results are being reported. In fact, we see a 4.5- to 5-month improvement in median survival from the mid 14-month range to 19, 19.5 months. This is quite remarkable. The control group performed at least as well as it had performed in the ECOG-4599 trial, the adenocarcinoma group. The benefit extends and in fact it is even more pronounced in those with EGFR mutations or ALK translocations. The control group has a median survival about 17 months. It has not even been reached in the atezolizumab arm. We see it on the opposite end of the spectrum in patients with visceral dominant disease such as liver metastases. The numbers are lower, but the degree of survival benefit is just as pronounced at 13.5 months versus 9 months or so.

The trial is really unprecedented. We have never seen any other agents added to the ECOG-4599 regimen improve outcomes as we have here. This regimen potentially becomes our go-to regimen in patients who have oncogenic drivers whose disease is really becoming TKI-refractory. The final common pathway for all of our patients with an EGFR mutation, ALK transition, ROS1 mutation, or any of the other major drivers remains chemotherapy. Eventually, the TKIs no longer work.

Vassiliki Papadimitrakopoulou, MD: IMpower150 used several strategies to evaluate for enrichment in terms of benefit from this therapy. Beyond PD-L1 expression, there was a T-cell effector signature that was explored that contained 3 genes. There was also a subgroup analysis for patients who presented with liver metastases. There was benefit associated with high PD-L1 expression as well as high T-cell effector signature. There was also benefit for patients with liver metastases, and that is actually information that is important because liver metastases are thought to represent immunosuppressive tumor microenvironment. Therefore, the improvements that we saw in patients’ progression-free survival in the setting of liver metastases are a very positive signal.

Transcript Edited for Clarity 
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