Metastatic NSCLC I-O Combination Therapies

Anne Tsao, MD: Tumor mutation burden is 1 of the new biomarkers that we’re looking at right now. The CheckMate 227 trial was looking at ipi-nivo [ipilimumab-nivolumab] versus chemotherapy in chemotherapy plus nivolumab. Now, this was a very complex trial, and so they utilized biomarker tumor mutation burden, which is essentially the number of mutations per megabase, and they used an assay called FoundationOne in the tumor tissue. And what they discovered is that patients who had high TMB, tumor mutation burden—greater than or equal to 10 mutations per megabase was how they defined it— these patients had a higher progression-free survival with the use of immunotherapy, specifically ipi-nivo, ipilimumab and nivolumab, compared with those patients who had low TMB, or less than 10 mutations per megabase.

The patients who received immunotherapy who had high TMB did much better for both progression-free and overall survival when compared with chemotherapy. This is not an accepted standard of care yet because there are a lot of questions. What should the cutoff be for tumor mutation burden? And what assay should we use? Remember, the CheckMate 227 study used a FoundationOne assay. This is a platform that changes. And so other companies may have different cutoffs. So all of this remains to be validated and approved before we can use it for prime time.

Ipilimumab and nivolumab is a very well-tolerated regimen. We’ve given it oftentimes in other thoracic malignancies beyond just non—small cell lung cancer—for example, in small cell and in mesothelioma. So we do know that it can be safe. It can be easy to give. There are patients who tolerate it very well. But it’s important to note that immunotherapies do carry toxicities. And so we do have to watch out for colitis and fatigue. And also any autoimmune events, such as any inflammation—anywhere in the body is usually what I tell our patients—are always a risk. But generally patients do feel pretty good while they’re on this regimen. And it’s certainly important to educate our patients about the toxicities that can occur.

Roy Herbst, MD, PhD: There are actually multiple drugs in this space that are either targeting PD-1 [programmed cell death protein 1] or PD-L1 [programmed death-ligand 1]. Targeting PD-1 we have nivolumab and pembrolizumab; PD-L1, atezolizumab and durvalumab. Atezolizumab is also approved in lung cancer in combination with carboplatin-Taxol-bevacizumab in the frontline setting. That’s based on the results of IMpower150, which is a little more complicated because you have 4 drugs versus 3 drugs. So you have carboplatin-paclitaxel-bevacizumab standard of care all for nonsquamous versus carboplatin-paclitaxel-bevacizumab and atezolizumab. And that had a hazard ratio in a very significant range, so that’s approved. The question is whether that is any better than using chemotherapy with pembrolizumab and not using bevacizumab. Hard to tell because we don’t have a direct comparison.

Bevacizumab is a good drug. It improves chemotherapy. How much difference it’s making here I think still needs to be sorted out. It does have additional adverse effects that it adds. I would use this regimen, though probably I would reserve it for the patients who have EGFR mutations and have failed targeted therapy. Why? Because in the trial, they actually allowed for that to be included. So there are some patients in there, albeit fewer than 10%. That’s not in the US label, to be fully up front, but I believe they have approval for that in Europe. So at this point now, I would probably have had an EGFR-mutated patient who I was going to put on their first immunotherapy, and I’d probably use the IMpower150 regimen.

Benjamin Levy, MD: IMpower131 was a trial specifically evaluating the role of atezolizumab in combination with platinum doublet chemotherapy, specifically for advanced squamous cell patients. This was a very large trial. It was a 3-arm trial comparing carboplatin, nab paclitaxel [paclitaxel albumin-stabilized nanoparticle formulation], to carboplatin, nab paclitaxel [paclitaxel albumin-stabilized nanoparticle formulation] plus atezo [atezolizumab], versus carboplatin, paclitaxel, plus atezo [atezolizumab]. And really the primary analysis was looking at arm B and C, which was carbo-nab-pac [carboplatin—paclitaxel albumin-stabilized nanoparticle formulation] versus carbo-nab-pac [carboplatin–paclitaxel albumin-stabilized nanoparticle formulation] plus atezolizumab, specifically, in a squamous cell patient population. And in this trial we saw that the addition of atezo [atezolizumab] to carbo-nab-pac [carboplatin–paclitaxel albumin-stabilized nanoparticle formulation] improved progression-free survival when compared with carbo-nab-pac [carboplatin–paclitaxel albumin-stabilized nanoparticle formulation] alone. Importantly, however, we didn’t see an overall survival advantage at the time of the presentation.

And so I think this is certainly an interesting trial. We have another trial in squamous cell that did show a survival advantage with a very similar design but with a different immunotherapy. So while it was good to see the progression-free survival advantage in this trial: atezo [atezolizumab] added to carbo-nab-pac [carboplatin—paclitaxel albumin-stabilized nanoparticle formulation] when carbo-nab-pac [carboplatin–paclitaxel albumin-stabilized nanoparticle formulation] alone didn’t translate into an overall survival.