IMpower150: Combining VEGF and I-O Therapy in NSCLC

Alexander Drilon, MD:The purpose behind adding bevacizumab, which is an antiangiogenic agent, to immune therapy is in the same way that chemotherapy may modulate the immune system. There are data for antiangiogenic therapy with a monoclonal antibody added to VEGF for also modulating immune effector cells, which may then help the immune therapeutic do its job, so to speak, when administered in combination.

Justin Gainor, MD:We’ve recently had data from the IMpower150 study. This also focused on nonsquamous patients, and here it is a bit of a more complicated study in that there are 3 different arms to the study: arms A, B, and C. Control group was arm C. This was carboplatin/paclitaxel/bevacizumab, and this was compared against either carboplatin/Taxol, or carboplatin/paclitaxel, and bevacizumab plus atezolizumab or carboplatin/paclitaxel/atezolizumab, so removing the bevacizumab from that arm.

At both AACR and ASCO, we saw data from this study, and it did look like the quadruplet regimen of carboplatin/paclitaxel/bevacizumab/atezolizumab resulted in improvements in both progression-free survival as well as overall survival compared to the control arm of carboplatin/paclitaxel/bevacizumab. So, overall, we have another positive study for patients with nonsquamous histology.

In my mind, I think the uptake of the IMpower150 regimen will probably be less than with the triplet pemetrexed-containing regimen used in KEYNOTE-189. I think part of this has to do with, again, acknowledging cross-trial comparisons. But the KEYNOTE-189 data were quite impressive if one looks at the hazard ratios for survival. Also, in the United States, a pemetrexed backbone is more commonly used due to its favorable safety profile. And so, in my mind, despite having 2 positive studies, I generally employ platinum/pemetrexed plus pembrolizumab for patients based upon KEYNOTE-189.

One key distinction between KEYNOTE-189 and IMpower150 is that KEYNOTE-189 excluded patients with sensitizingEGFRmutations andALKrearrangements. By contrast, those patients were allowed into IMpower150 provided they received the relevant targeted therapy. It was a bit surprising to all of us to see that the benefits to adding atezolizumab to carboplatin/paclitaxel/bevacizumab even extended to theEGFR- andALK-positive subgroups compared with the control arm. The reason this was surprising is because in earlier studies of just using single-agent checkpoint inhibitors, the benefits amongEGFR- andALK-positive patients were quite minimal with just single-agent checkpoint inhibitors. We saw response rates amongEGFRpatients were 10% or less, and in meta-analyses, there was no improvement in survival compared to single-agent docetaxel. And amongALK-positive patients, really the response rates have been 0 in the limited studies to date.

And so, in IMpower150, we saw that now combining chemotherapy withVEGFinhibition and PD-L1 inhibition, it did look like there was an improvement in theEGFR- andALK-positive patients. So, this really represented the first study where we have an improvement with checkpoint inhibition in those molecular subgroups. And I think that’s one of the key take-homes from the IMpower150 data.

Alexander Drilon, MD:I think we should be very careful when we look at new potential biomarkers. And in this trial, the investigators had looked at this T-effector signature, which seemed like there may be a signal for increased benefit in those that fell into the high—T-effector category. And we know that even when we look at PD-L1 and you look at tumor mutational burden, which one can argue are much more vetted in terms of biomarkers, that those biomarkers aren’t perfect in their ability to predict the likelihood of response to immune therapy. I think that looking at this T-effector signature is much more in its infancy compared to those other biomarkers. So, it’s something that I think we should continue to look at on an investigational level. But on a clinical level, I wouldn’t yet jump to rely on this as a potential signature for giving this combination until we see further data come out.

Transcript edited for clarity.