Updates to NSCLC Guidelines Make Testing at Diagnosis, Resistance Essential

Targeted Therapies in Oncology, May 2017, Volume 6, Issue 5

Updates to the NCCN guidelines for the management of advanced NSCLC stress the importance of multiplexed biomarker testing at diagnosis to aid in the selection of appropriate first-line and subsequent lines of therapy.

Gregory J. Riely, MD, PhD

Updates to the National Comprehensive Cancer Network (NCCN) guidelines for the management of advanced non—small cell lung cancer (NSCLC) stress the importance of multiplexed biomarker testing at diagnosis to aid in the selection of appropriate first-line and subsequent lines of therapy, said presenters at the 2017 NCCN Annual Conference.


The latest version of the guidelines recommends that PD-L1, in addition to molecular analysis, be employed as a biomarker to direct initial therapy, with ≥50% expression established as the threshold for a positive result. The PD-L1 test “decides whether a patient has enough of the marker to warrant initial immunotherapy,” said presenter Gregory J. Riely, MD, PhD.

PD-L1 testing is currently “all over the map,” he added. Immunohistochemistry assays using 28-8, 22c3, or E1L3N as antibodies to detect PD-L1 expression were generally concordant in their findings, but the assay using the SP142 antibody was an outlier that detected significantly less PD-L1 expression in tumor cells than the other 3 platforms.2In addition, PD-L1 expression is likely stable, he said, so there is no clear benefit to a repeat biopsy for assessment of PD-L1 unless the prior sample has been exhausted.

Riely, vice chair, Clinical Trial Office, Department of Medicine, Memorial Sloan Kettering Cancer Center, suggested that institutions should customize their molecular analysis approach. Many use a combination of immunohistochemistry, fluorescence in situ hybridization, and DNA sequencing to detect abnormalities in key genes.


Based on the results of PD-L1 testing and molecular analysis, the NCCN developed an algorithm for initial therapy for patients with stage IV NSCLC. Patients withEGFR,ALK, orROS1mutations or rearrangements at diagnosis, which collectively constitute about 25% of NSCLC, should receive targeted therapy as first-line treatment.

Pembrolizumab (Keytruda) is recommended (category 1) as a first-line choice for patients with NSCLC whose tumors are positive for PD-L1, and negative or unknown for mutations or rearrangements inEGFR,ALK,andROS1, which is the case in about 30% of cases. This recommendation is based on the results of the KEYNOTE-024 trial, which proved pembrolizumab superior to a platinum doublet combination on the endpoint of median progression-free survival (PFS; 10.3 vs 6.0 months; P <.001) as first-line therapy in patients with NSCLC with PD-L1 expression ≥50%.3

The next update to the guidelines will likely include immunotherapy-based combinations, especially given that only about 45% of patients with NSCLC with high PD-L1 expression exhibit a response to first-line pembrolizumab, says Matthew A. Gubens, MD. First up would be pembrolizumab in combination with pemetrexed and carboplatin chemotherapy, which was recently approved for patients with metastatic or advanced nonsquamous NSCLC, regardless of their PD-L1 expression. The results were “quite tantalizing,” according to Gubens, assistant clinical professor of medicine, University of California, San Francisco. The combination showed a response rate of 55% and a PFS of 13.0 months compared with 29% and 8.9 months with carboplatin/pemetrexed.4

Immunotherapy, however, is not the standard of care for patients with mutations or rearrangements inEGFR,ALK, orROS1, he noted. Clinical trial results support the superiority of EGFR tyrosine kinase inhibitors (TKIs) over platinum doublets in patients withEGFR-mutant NSCLC. Patients withALKorROS1rearrangements are recommended for treatment with an ALK inhibitor, such as crizotinib (Xalkori).

Those withoutEGFR,ALK, orROS1mutations or rearrangements who have PD-L1 expression <50% should receive platinum-based chemotherapy according to their histologic subtype, according to the current guidelines. For patients with nonsquamous NSCLC, bevacizumab plus pemetrexed is the preferred initial strategy; for patients with squamous cell disease, pemetrexed without bevacizumab is preferred.


Development of clinical resistance to an EGFR TKI is universal. At progression, a biopsy is necessary to understand the mechanism of resistance. The most common resistance mutation isT790M, which is present in about 60% of patients with anEGFRmutation, said Wallace L. Akerley, MD, senior director of community oncology research and professor of medicine, Huntsman Cancer Institute, University of Utah.

The third-generation EGFR TKI osimertinib (Tagrisso) was associated with a response in 71% of patients as a second-line therapy in patients with T790M resistance. “A striking factor is that the intracranial response is 64%,” he said, with a median PFS of 8.5 months for those with metastases to the central nervous system treated with osimertinib compared with 4.2 months for patients receiving platinum-pemetrexed (HR, 0.32; 95% CI, 0.21-0.49).5

In patients with PD-L1—positive tumors who experience progression after initial treatment with pembrolizumab, the NCCN guidelines recommend an immune checkpoint inhibitor as subsequent therapy (preferred) with nivolumab (Opdivo), atezolizumab (Tecentriq), or pembrolizumab if PD-L1 expression is ≥1% as determined by the 22C3 pharmDx test that was approved by the FDA, said Gubens. Other systemic therapy is also an option with a checkpoint inhibitor as the next line following progression, with nivolumab, pembrolizumab, and atezolizumab all demonstrating similar PFS benefits compared with standard chemotherapy, he added.


  1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non- Small Cell Lung Cancer. V5.2017. https://www.nccn.org/professionals/physician_gls/pdf/nscl. pdf. Accessed April 10, 2017.
  2. Rimm DL, Han G, Taube JM, et al. A prospective, multi-institutional, pathologist-based assessment of 4 immunohistochemistry assays for PD-L1 expression in non-small cell lung cancer [published online March 9, 2017]. JAMA Oncol. 2017. doi: 10.1001/jamaoncol.2017.0013.
  3. Reck M, Rodriguez-Abreu D, Robinson AG, et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823-1833.
  4. Langer CJ, Gadgeel SM, Borghaei H, et al; KEYNOTE-021 investigators. Carboplatin and peme- trexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497- 1508. doi: 10.1016/S1470-2045(16)30498-3.
  5. Mok T, Wu Y-L, Ahn MJ, et al; AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376(7):629-640. doi: 10.1056/NEJMoa1612674.