Immunotherapy Strategies in the Updated NCCN Guideline for NSCLC Hinge on PD-L1 Testing

December 2019 Vol 10, No 12


Lung Cancer
Matthew A. Gubens, MD, MS

The updated National Comprehensive Cancer Network (NCCN) guideline for non–small-cell lung cancer (NSCLC; version 3.2019) is focused on improving patient outcomes with immunotherapy. Pembrolizumab is listed as the preferred first-line immune checkpoint inhibitor for patients with ≥50% of tumor cells that express PD-L1. First-line immunotherapy is restricted to NSCLC without EGFR or ALK mutations.

“PD-L1 testing is really the name of the game,” said Matthew A. Gubens, MD, MS, Associate Professor, UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, who presented the updated NCCN guideline and the rationale for the selection of preferred therapies at the NCCN 2019 Conference.

In addition to first-line pembrolizumab monotherapy in patients with high PD-L1 expression and no mutations, the Category 1 first-line options for this patient population are the following combinations of chemotherapy and immunotherapy:

  • Carboplatin or cisplatin plus pemetrexed and pembrolizumab
  • Carboplatin plus paclitaxel, bevacizumab, and atezolizumab

In patients achieving stable disease with those regimens, the use of maintenance therapy with pembrolizumab alone, pembrolizumab plus pemetrexed, or with atezolizumab and/or bevacizumab is also a Category 1 recommendation.

PD-L1 Expression

Although PD-L1 is not an optimal biomarker, it is currently the best one for assessing eligibility for immune checkpoint inhibitors, said Dr Gubens.

The preference for pembrolizumab in patients with high PD-L1 expression is based on the results from the KEYNOTE-024 study, in which pembrolizumab improved overall survival versus chemotherapy in patients with PD-L1 expression ≥50%. For patients with PD-L1 expression of 1% to 49%, “probably the most important patients in terms of our clinical care, there was no significant benefit for pembrolizumab versus chemotherapy,” Dr Gubens said, although pembro­lizumab did show an overall survival benefit in the overall cohort.

Therefore, the NCCN panel did not recommend pembrolizumab for patients with PD-L1 expression of 1% to 49%. In these patients, the NCCN recommends chemotherapy plus pembrolizumab as the preferred therapy, based on KEYNOTE-189, in which this regimen reduced the mortality risk by approximately 50% versus chemotherapy alone.

The 4-drug regimen of carboplatin, paclitaxel, bevacizumab, and atezolizumab is recommended for patients with nonsquamous NSCLC on the basis of the IMpower150 clinical trial, in which the addition of atezolizumab to chemotherapy reduced the mortality risk by 22%. The 4-drug combination outperformed chemotherapy alone at every level of PD-L1 expression, leading to its approval by the FDA in December 2018, “and is why atezolizumab/carboplatin/paclitaxel/bevacizumab is listed as a Category 1 option for nonsquamous patients,” he said.

In patients with PD-L1 expression of <50%, distinguishing nonsquamous from squamous NSCLC is important for the selection of therapy. For patients with nonsquamous disease, the combination of carboplatin, pemetrexed, and pembrolizumab is the preferred choice. The combination of carboplatin, paclitaxel, bevacizumab, and atezolizumab is another option, especially for patients who are ineligible for treatment with pemetrexed.

Squamous Cell NSCLC

“Squamous cell carcinoma, unfortunately, hasn’t had as much research focused on it, because the patients were often sicker,” said Dr Gubens. “They often are smokers…and haven’t benefited from the targeted therapy revolution in non–small cell lung cancer.”

The preferred Category 1 first-line treatment in patients with squamous cell NSCLC is the combination of pembrolizumab plus carboplatin with paclitaxel or nab-paclitaxel, based on KEYNOTE-407. In this study, adding pembrolizumab to chemotherapy reduced the mortality risk by 36% versus chemotherapy alone in treatment-naive patients with squamous cell disease. The advantage to pembrolizumab was realized regardless of PD-L1 status.

The pembrolizumab-pemetrexed combination “is an important advance in the care of our squamous cell patients,” said Dr Gubens.

Targeted Therapy

Single-agent immunotherapy underperforms in patients with driver mutations such as EGFR or ALK. Patients with EGFR or ALK mutations were excluded from the KEYNOTE studies, Dr Gubens noted.

The IMpower150 clinical trial included 108 patients with EGFR or ALK mutations, demonstrating that the addition of bevacizumab to chemotherapy plus atezoliz­umab leads to better outcomes in these patients. This finding “suggests that there’s some interplay between bevacizumab and immunotherapy,” he said.

Tumor Mutation Burden

One day, PD-L1 expression may be “archaic” as a biomarker, said Dr Gubens. Tumor mutation burden (TMB) is an evolving biomarker that may be helpful in selecting patients for immunotherapy, “although there is no consensus on how to measure TMB,” according to the NCCN guideline. Patients with high TMB are a population distinct from those with high PD-L1 expression, and TMB also predicts response to immunotherapy, Dr Gubens added.

The CheckMate 227 clinical trial enrolled 1739 treatment-naive patients with metastatic NSCLC and no known driver mutations, showing that patients with ≥10 mut/Mb had significantly improved outcomes with nivolumab plus ipilimumab compared with chemotherapy. For patients with lower TMB, immunotherapy was not superior to chemotherapy.

Blood-based TMB assays are especially promising, Dr Gubens pointed out. One such assay that used a cut point of 16 mut/Mb to define high TMB showed a 35% reduction in the risk for disease progression with atezolizumab compared with docetaxel in the high-TMB group.

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