Biomarkers in Locally Advanced NSCLC

Heather Wakelee, MD:PD-L1 was the first biomarker that we thought about using for checkpoint inhibitors, which makes sense because they’re blocking PD-1 or PD-L1. We know that PD-L1 levels on the tumor, theoretically, if that’s the target, would make sense to look for that.

There are a lot of different ways of looking for PD-L1. A lot of antibodies were developed. Most seemed to be fairly concordant. As we look across drugs, each of which has its own antibody to look for PD-L1, if you took 1 sample and tested it, pretty similar results could be seen.

When we looked in the second line, in patients who had already had chemotherapy, there wasn’t always a correlation between PD-L1 levels and benefit. The first-line pembrolizumab trial used a high cut point. Only those with high levels seemed to benefit. But the first-line nivolumab trial was a negative study. It didn’t have as high of a cut point, but even those that did have the high cut point didn’t seem to benefit.

With nivolumab, there’s been a lot of work in looking at tumor mutation burden, which isn’t as simple of an assay. You basically have to look at a lot of different genes to get a sense of the total number of different mutations in the tumor. It tends to be that patients with a heavy smoking history have a higher mutation burden. Those with less have less. And in general, there’s more benefit in those who have more. Now, with nivolumab, at least that has been a validated biomarker in several trials. In the most recent data for first-line nivolumab/ipilimumab versus chemotherapy, those who had high tumor mutation burden seemed to benefit.

But it’s not a simple test. PD-L1 testing is a simple test. Immunohistochemistry—1 slide stain. It’s either there or it’s not there. There are different levels. Tumor mutation burden—you’ve got to do a lot of analyses. So, it’s not clear whether we’re going to be shifting completely to that assay. Also, it has been very interesting that the PD-L1 tracks with the pembrolizumab and less with the nivolumab. The tumor mutation burden hasn’t been looked at as much as most of the other drugs, so we don’t know.

When we looked at stage III disease in the PACIFIC trial, the PD-L1 levels seemed to matter, somewhat. If you had higher levels, you seemed to have more benefit. But even those with low levels were benefiting. So, it’s not really helping to make that treatment decision. It might somewhat help with a prognosis, but if you’re deciding whether or not to treat, you’re going to treat everyone. It becomes less important. And, of course, there are other markers being looked at. Everybody I talk to, at different academic centers around the country, around the world—we’re all doing our own testing. We are all trying to figure out, “Well, what’s going to be the best, next additive marker?” But I think there are a lot of different theories there.

Transcript edited for clarity.

• A 64-year-old man presented with shortness of breath and persistent cough of 18 months’ duration; recently, he has experienced chest pain, fatigue, and blood in his sputum. After consulting with his primary care physician, he was referred for oncology evaluation
• Patient history includes
  • Current smoker (1/2 pack day)
  • Hypertension
  • Acute MI at age 60
• Evaluation and follow up testing reveal
  • Non-small cell lung cancer in left lung and 2 lymph nodes (Stage IIIa)
  • WHO performance status: 1
  • Histology: adenocarcinoma
  • EFGR, BRAF,andALK/ROS1mutation status: wild-type
  • PD-L1 status: ≥25%
• He underwent multidisciplinary evaluation and was not a candidate for surgery; he was treated with chemoradiotherapy:
  • Concurrent carboplatin-paclitaxel doublet chemotherapy and radiotherapy (60 Gy)
  • Achieved partial response
• He had no disease progression 20 days after his last radiotherapy treatment, and began treatment with durvalumab