NCCN: Updated NSCLC Guidelines Hone in on PD-L1 Testing

The National Comprehensive Cancer Network (NCCN) has released updated guidelines on the use of immunotherapy to treat non–small-cell lung cancer (NSCLC), including recommendations on the use of programmed death ligand 1 (PD-L1) testing. The updates were presented during a panel held at the 2019 National Comprehensive Cancer Network (NCCN) Annual Conference, held March 21–23 in Orlando, Florida.

“It’s really a crazy time with a lot of data coming at us,” said Matthew A. Gubens, MD, MS, of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center. “It’s really an exciting time.”

When targetable driver mutations are identified in NSCLC, it’s important to treat those first with targeted agents, not immunotherapy, Gubens emphasized. However, first-line immunotherapy is now recommended for other patients, too.

As part of the updated NCCN Guidelines® for NSCLC, pembrolizumab is now the preferred immune checkpoint inhibitor for patients with 50% or more tumor cells expressing PD-L1. In addition, there is now a Category 1 NCCN recommendation to administer pembrolizumab plus chemotherapy to these patients.

“This should be considered for patients with higher disease burden and for higher symptom burden,” Gubens said.

For patients for whom fewer than 50% of tumor cells express PD-L1, recommended treatments diverge between those with squamous and non-squamous tumors. Patients with squamous NSCLC should receive carboplatin, paclitaxel (or nab-paclitaxel), and pembrolizumab, whereas carboplatin, pemetrexed, and pembrolizumab are preferred for patients with non-squamous tumors.

Patients with non-squamous NSCLC and < 50% PD-L1 expression may also receive carboplatin, paclitaxel, bevacizumab, and atezolizumab, which is also a Category 1 NCCN recommendation. The latter regimen is “perhaps” an option for patients who are not eligible for pemetrexed, Gubens said.

Immune checkpoint inhibitor manufacturers have each developed their own proprietary PD-L1 biomarker assays, Gubens noted. There is generally good correlation between PD-L1 tests, with one exception: SP142 (used for atezolizumab), “which might undercall high PD-L1 expression,” Gubens cautioned.

“Right now, PD-L1 is really the name of the game,” he said. “PD-L1 has utility in the first line to determine the appropriateness of single-agent immunotherapy.”

A number of additional immunotherapy biomarkers are under development, including assays of tumor mutation burden or load (a measure of tumors’ potential overall immunogenicity), MHC expression, IFN-γ sensitivity, lymphocyte counts, immune cell infiltration (intratumoral T-cell counts), LDH and glucose metabolism, and others.

NSCLC has the highest somatic mutation frequency of any cancer type other than melanoma, Gubens noted. Tumor mutation burden assays show promise for selecting patients with metastatic NSCLC for treatment with nivolumab with or without ipilimumab.

Liquid biopsies of tumor mutation burden assessed with peripheral blood draws are also under development. The NCCN Guidelines® note that tumor mutation burden is an “evolving biomarker” that may be helpful in selecting patients for immunotherapy, but that there is not yet a consensus on how best to measure it.

The updated NCCN Guidelines® for NSCLC also note several emerging biomarkers for identifying patients eligible for novel targeted therapies, including MET amplification for crizotinib, RET rearrangements for cabozantinib and vandetanib, and ERBB2 (HER2) mutations for ado-trastuzumab emtansine.

It seems likely that, in the future, “multidimensional and serial” biomarkers that identify changes in tumors and their microenvironments will inform immunotherapy regimen decision-making, with an eye toward avoiding the evolution of acquired tumor resistance to treatment, Gubens said.

“Hopefully, in a few years, we’ll then look back at PD-L1 assays as archaic,” Gubens said.

These updates to the guidelines come 5 years after the first FDA approval of a programmed cell death 1 (PD-1)/PD-L1 immune checkpoint inhibitor. The pace of development continues to gain steam, with more than half a million patients enrolled in clinical immuno-oncology trials testing nearly 1,000 agents, and regimens that target some 300 targets, according to speakers at the panel.