National Comprehensive Cancer Network Guidelines in Clinical Practice

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The most recent NCCN guideline updates for patients with non-small cell lung cancer (NSCLC) have focused on screening recommendations for genetic aberrations and the introduction of novel targeted therapies to treat patients with these genetic deletions or rearrangements.¹Treatment of patients with NSCLC is moving away from empirical use of chemotherapy in favor of individualized, targeted treatment regimens. According to Alan Sandler, MD, DPM, chief of the Division of Hematology and Medical Oncology at Oregon Health and Science University, “We have a new paradigm where, instead of just throwing chemotherapy at patients in a somewhat empiric fashion, we are now looking at very small subsets of patients who actually have a particular target mutation.”

Despite updates in treatment guidelines, recommendations are not always optimally implemented in clinical practice, for a variety of reasons.²Knowledge of these guideline changes is imperative for achieving the best patient outcomes, but given the large amount of research that has recently come to light, it may be difficult for clinicians to keep up with ever-changing treatment recommendations. Here we present several recent updates in the NCCN guidelines related to treatment of patients with NSCLC.

Erlotinib should not be given as first-line therapy to patients negative for EGFR mutations or with unknown EGFR status.

This guideline update is based on results of the TORCH trial, which indicated that EGFR mutational testing should be conducted in patients with NSCLC. Patients with wild-type EGFR who received firstline chemotherapy had improved survival compared with those who received first-line erlotinib followed by chemotherapy.³Mutational testing should be restricted to patients with non-squamous NSCLC (adenocarcinoma), because patients with pure squamous cell carcinoma are not likely to exhibit EGFR mutations.¹

Large-scale screening for EGFR mutations was evaluated in patients with advanced NSCLC. Of 2105 patients, 350 (16.6%) had EGFR mutations; these mutations were more likely common in women, in never-smokers, and in patients with adenocarcinomas. Researchers concluded that large-scale screening for EGFR mutations is feasible and can play an important role in predicting response to therapy with erlotinib or gefitinib.⁴

Afatinib is indicated for select patients with sensitizing EGFR mutations.

In 2013, afatinib was approved for first-line treatment of patients with metastatic NSCLC and EGFR mutations. In addition, it is recommended as second- line therapy in patients who have disease progression after receiving first-line chemotherapy.¹

Paul Bunn, MD, professor of medicine in medical oncology and head of the division of medical oncology at the University of Colorado, said that afatinib, a second-generation EGFR tyrosine kinase inhibitor (TKI), “binds to the activating mutations in EGFR and it does so irreversibly.” According to Bunn, afatinib binds to T790M, unlike erlotinib and gefitinib. “The unanswered question is whether it is better than erlotinib and gefitinib, and there are trials addressing this.”

Bunn further commented that patients diagnosed with lung cancer should be tested for genetic aberrations. “One of the messages for the community is that even sick patients with lung cancer should have this molecular testing. They may be too sick for chemotherapy, but they are not too sick for these oral tyrosine kinase inhibitors.”

The following additional NCCN guideline changes were made during the past year for patients diagnosed with NSCLC¹:

• Category 1 added to ALK testing. EGFR ± ALK testing should be conducted as part of a multiplex/
• Consider EGFR mutation and ALK testing especially in never-smokers or small biopsy specimens, or mixed histology. EGFR ± ALK testing should be conducted as part of a multi-plex/nextgeneration sequencing (squamous cell carcinoma).
• First-line therapy, EGFR mutation discovered prior to first-line chemotherapy: afatinib added as a category 1 recommendation.
• First-line therapy, EGFR mutation discovered during first-line chemotherapy: recommended treatment options modified to “interrupt or complete planned chemotherapy, start erlotinib or afatinib or may add erlotinib or afatinib to current chemotherapy (category 2B).”
• Second-line therapy: afatinib added as a treatment option.
• Second-line therapy, systemic multiple lesions: consider platinum doublet ± bevacizumab ± erlotinib.

The landscape of NSCLC treatment is changing rapidly, and updates to treatment guidelines in response to emerging data are frequent. According to Natasha Leighl, MD, medical oncologist and assistant professor of medicine at the University of Toronto, Ontario, Canada, “One of the greatest things has been our ability to try to better tailor treatment to the kind of lung cancer a person has. We no longer say ‘just lung cancer’ or ‘non-small cell lung cancer’; we are really trying to subdivide it into groups such as adenocarcinoma, squamous cell carcinoma—and even within those groups, to look at some of the different molecules or gene abnormalities that can drive a cancer’s growth, and a better and smarter way to target a cancer rather than just general chemotherapy.”

Is it still important to histologically subtype NSCLC in this era of molecular testing? Anne S. Tsao, MD, director of the thoracic chemo-radiation program, University of Texas MD Anderson Cancer Center, responds affirmatively. “You have to know the distinction between adenocarcinoma and squamous cell carcinoma because of available treatments. It is absolutely crucial to have the pathologist get adequate tissue and make that distinction.”

According to Grace Dy, MD, Roswell Park Cancer Institute, Buffalo, NY, “Given the importance of molecular profiling, rebiopsy should be highly considered in the setting of inadequate tissue in the initial biopsy sample, particularly in patients who are not candidates for first-line cytotoxic chemotherapy. EGFR/ALK testing appears to be widely accepted now in clinical practice, as I often see referral patients who already have these results pending at the time of consult, some of which in fact are multiplex assays.

“An area of education for community oncologists would be to highlight the importance of knowing the specific platform of testing being performed by the laboratories as less common variants may not be picked up,” Dy concluded.

References

1. National Comprehensive Cancer Network. Non-Small Cell Lung Cancer. Version 3.2014. http://www.nccn.org/professionals/ physician_gls/pdf/nscl.pdf. Accessed March 12, 2014.
2. Salloum RG, Smith TJ, Jensen GA, Lafata JE. Factors associated with adherence to chemotherapy guidelines in patients with non-small cell lung cancer.Lung Cancer. 2012;75(2):255- 260.
3. Gridelli C, Ciardiello F, Gallo C, et al. First-line erlotinib followed by second-line cisplatin-gemcitabine chemotherapy in advanced non-small-cell lung cancer: the TORCH randomized trial.J Clin Oncol. 2012;30(24):3002-3011.
4. Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer.N Engl J Med. 2009;361(10):958-967.
5. Manegold C. Gemcitabine (Gemzar) in non-small cell lung cancer. Expert Rev Anticancer Ther. 2004;4(3):345-360.