Transcript Related Guidelines

Standard-of-Care Options for Squamous, Low-Level PD-L1 in Advanced NSCLC

H. Jack West, MD · City of Hope


March 24, 2021

Key Takeaways:

  • Pembrolizumab was the first immunotherapy to be shown to work better than doublet chemotherapy in patients with NSCLC with high tumor PD-L1 ≥50%; it was then also shown to have better outcomes in patients with PD-L1 between 1% and 49%.

  • Pembrolizumab plus chemotherapy (cisplatin or carboplatin with pemetrexed) has been shown to be effective for treatment of patients with non-squamous NSCLC that does not have an EGFR mutation or ALK rearrangement.

  • Pembrolizumab has also been shown to be efficacious in treating squamous NSCLC when administered with chemotherapy (carboplatin with either paclitaxel or nab-paclitaxel).

  • Two other treatment options, although not as widely used, for non-squamous NSCLC are carboplatin, paclitaxel, and bevacizumab plus atezolizumab and carboplatin and nab-paclitaxel plus atezolizumab.

  • The combination of nivolumab plus ipilimumab has been shown to be superior to doublet chemotherapy and is FDA approved for patients with PD-L1 ≥1%.

  • A more intensive therapy regimen approved by the FDA in 2020 is nivolumab and ipilimumab plus doublet chemotherapy for two cycles; it was shown to be significantly superior to the platinum doublet alone.

This transcript has been edited for clarity.

In the setting of advanced non–small cell lung cancer with low tumor PD-L1, we have multiple FDA- approved options to choose from. This is based on them all beating an older standard of platinum doublet chemotherapy that was histology appropriate for the patients in the clinical trial in question. The first one to discuss is pembrolizumab, which was actually the first immunotherapy to beat doublet chemotherapy specifically in the patients with high tumor PD-L1 ≥50%. 

That is about 28% or 30% of patients. That was based on the KEYNOTE-024 trial.[1] The KEYNOTE-042 trial looked at the same question of histology appropriate chemo versus pembrolizumab monotherapy but extended the comparison to patients with PD-L1 ≥1%—so, including that 1% to 49% low PD-L1 population. That trial was also positive for a survival benefit over chemo doublet, but the improvement was really driven by the patients with high PD-L1. 

When you look just at the patients with low PD-L1, they did no better than the patients with chemotherapy as first line treatment—despite the fact that those patients who were assigned chemo were not allowed to cross over to immunotherapy subsequently, even though that was a second line standard of care, in the US at least, during the time of this trial. So, though this does have an FDA approval for pembrolizumab, and that extends to patients with low PD-L1, I would not consider it a particularly appealing choice relative to others. 

Since 2018, one of the leading options has been chemo with pembrolizumab. This is based largely on the KEYNOTE-189 trial in patients with non-squamous, non–small cell lung cancer that does not have an EGFR mutation or ALK rearrangement.[2] The addition of pembrolizumab to either cisplatin or carboplatin with pemetrexed was associated with a very clear improvement in efficacy and very manageable toxicity overall that was throughout the entire spectrum from negative PD-L1, to low, to high. 

That became a real standard of care for the non-squamous population. In the squamous population, the KEYNOTE-407 trial looked at carboplatin with either paclitaxel or nab-paclitaxel either with placebo or with pembrolizumab.[3] It demonstrated, like KEYNOTE-189, a significant improvement in survival and many other efficacy endpoints with the addition of pembrolizumab to that chemo backbone for squamous histology. 

This, again, was in patients with negative, low, or high tumor PD-L1. So, this has really become a strong option for many patients. Now, in non-squamous, we also have an FDA approval for the IMpower150 regimen, which is carboplatin, paclitaxel, bevacizumab with the addition of atezolizumab.[4] So, that is an option, though not one that is as widely used, in part because that chemo backbone with the bevacizumab is not especially favored. 

But that benefit was seen across the PD-L1 spectrum, including low PD-L1. There is also an approval for the regimen of carboplatin and nab-paclitaxel with the atezolizumab based on the IMpower130 regimen.[5] Also, an option to consider, but not clearly better than the other ones. 

Now, there are also regimens that use nivolumab-ipilimumab, and the nivolumab-ipilimumab combination alone has been shown to be superior to chemotherapy doublet in the CheckMate-227 trial.[6] This led to an FDA approval in May of 2020 for nivolumab-ipilimumab for patients with PD-L1 ≥1%. So that is an option. It is not clear why you would use it over chemo pembro. But it does preserve the option of giving a platinum doublet upon progression later. Some investigators, some oncologists who have used it feel that they might get the longest, and most robust responses with a nivolumab-ipilimumab backbone. But that has not been clarified. 

Then, finally, there is an everything but the kitchen sink approach that looks at, and gives, nivolumab plus ipilimumab plus doublet chemotherapy for two cycles. This is the CheckMate-9LA trial that was positive for a significant benefit with this four-drug regimen, dropping the chemo doublet after two cycles. It was significantly superior to platinum doublet alone, and that was across the spectrum of PD-L1 across histologies.[7]

So that is also an option. It is FDA approved as of May of last year as well.[8] Rather intensive. But for patients who you really want to give everything to get some control over perhaps rapidly growing high volume disease upfront, that might be an option to consider. All of these are fair options. They have not been compared to each other, and may never be. But they are all reasonable choices in this setting. 


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