Updated Guidelines for Treating Stage IV NSCLC: Trying to Keep Up

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Heather A. Wakelee, MD

In late August 2015, Gregory A. Masters, MD, and colleagues published an update to the ASCO guidelines for systemic therapy for stage IV non–small cell lung cancer (NSCLC), summarized in this issue of The ASCO Post.1 This builds on the full guidelines published in 20092 and the additional switch maintenance published in 2011.3

In the rapidly changing world of lung cancer, it is important to highlight the fact that this update is based on reports from 73 phase III randomized controlled trials published through February 2014 and was approved for publication in February 2015. The recommendations focus on the paradigm shift that has occurred in lung cancer therapy since 2009 and thus refer specifically to decisions based on histology and molecular subtype. The guidelines do not yet reflect the approvals of the first wave of checkpoint inhibitors, specifically the programmed cell death protein 1 (PD-1) inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) as second-line treatment options for advanced NSCLC.4,5 Discussions of these agents are included in the text of the update but not in “The Bottom Line” summary of the guidelines.

The guidelines reflect the highest level of evidence and have been developed through a rigorous ASCO Clinical Practice Guideline Committee review process. In the rapidly changing oncology landscape, such a rigorous process serves an important role in establishing standards at a set period of time but cannot always be nimble enough to reflect all relevant changes in practice. Clinical guidelines help to improve the consistency of care and set benchmarks for providers, patients, policymakers, and insurance carriers6 but will by necessity lag behind “real time” given the time necessary to go through the rigorous process involved.

First-Line Options

The current guidelines remain unchanged in recommending combination cytotoxic (preferably platinum-based) chemotherapy for untreated patients without EGFR-sensitizing mutations or ALK rearrangements and a good performance status (0–1 and select patients with performance status 2). They include a mention that bevacizumab (Avastin) may be considered with carboplatin/paclitaxel for nonsquamous histology but provide no significant comment on the use of bevacizu­mab with platinum/pemetrexed (Alimta), given insufficient evidence for or against that combination.

Use of first-line targeted therapy in molecular subtypes of NSCLC is emphasized with a focus on EGFR-activating mutations treated with erlotinib (Tarceva), gefitinib (Iressa), or afatinib (Gilotrif) and on ALK-translocated tumors treated with crizotinib (Xalkori), with a strong recommendation rating for these agents. Though many other molecular subsets of NSCLC are now identified in addition to the EGFR and ALK subsets, only ROS1 rearrangements are mentioned, with a suggestion to use crizotinib in that setting but only as an informal consensus.

The guidelines appropriately refer to differences by histology for adenocarcinoma and squamous cell carcinoma and additionally mention, with an informal consensus, consideration of platinum plus etoposide as an option in patients with large-cell neuroendocrine carcinoma. Maintenance therapy recommendations include stopping first-line cytotoxic chemotherapy at progression or after four cycles, with the options of continuation maintenance for those on first-line pemetrexed-containing regimens or switch maintenance utilizing pemetrexed (or less preferably erlotinib) for those on a nonpemetrexed regimen (assuming nonsquamous histology for use of pemetrexed).

The first-line options thus have not significantly changed but emphasize consideration of histology and, in particular, molecular subtypes when making first-line treatment decisions. Readers are referred to other ASCO guidelines specifically addressing molecular markers7 and palliative care.8 Mention is made of the importance of palliative care and that chemotherapy selection decisions should not be made or altered based on age alone; however, individual care plans taking comorbidities into account are critical.

Second- and Third-Line Options

The guidelines for second-line therapy also include reference to approvals of docetaxel, erlotinib, gefitinib, or pemetrexed for nonsquamous disease and docetaxel, erlotinib, or gefitinib for squamous cell carcinoma. There is a brief discussion of ramucirumab (Cyramza) with a statement that “the role for vascular endothelial growth factor inhibitor therapy in the second-line setting is not clear.”

Use of cytotoxic combination chemotherapy for patients previously treated with a first-line EGFR or ALK inhibitor is endorsed, as is the use of ceritinib (Zykadia) for patients who have previously received crizotinib for ALK-positive NSCLC. Based on the timing of guideline development, the recent approvals of nivolumab and pembrolizumab as second-line therapeutic options are not included in the recommendations. Thus, the second-line recommendations must be viewed in this context.

The new ASCO guidelines note that “data are not sufficient to make a recommendation for or against using cytotoxic drugs as third-line therapy; patients should consider experimental treatment, clinical trials, and continued best supportive (palliative) care (no change from previous recommendations).” Erlotinib “may be recommended” for patients with performance status 0–3 who had not  previously received erlotinib or gefitinib. However, with the recent approvals of nivolumab as a second-line option for nearly all NSCLC patients or pembrolizumab for patients with tumor PD-1 ligand (PD-L1) expression, the use of third-line therapy will increase.

The future directions section of the guidelines emphasize these pending changes and also mention newer agents that will likely be available shortly, including next-generation therapy for patients with disease progression on first-generation EGFR inhibitors and currently available ALK inhibitors.

Important Considerations

As outlined in the “Limitations of Research” section, this is a rapidly evolving world, and data to support clinical practice patterns can evolve to such an extent as to limit the utility of the guidelines in a short period of time. As the authors stated, “With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read. The information is not continually updated and may not reflect the most recent evidence.”

Importantly, the guidelines do emphasize the communication between the patient and physician about goals of care and treatments and, in particular, the noncurative nature of currently available options. Given the limitations of trying to set standards based on a snapshot in time in a world of rapid change, the current ASCO guidelines of systemic therapy for stage IV NSCLC do an outstanding job of compiling existing high-level data to support first-line therapeutic decisions and clearly defining treatment standards for second- and third-line therapy in the preimmunotherapy era. ■

Disclosure: Dr. Wakelee has had a consulting or advisory role with Peregrine, ACEA Biosciences, Pfizer, Helsinn, Novartis (uncompensated), Clovis Oncology (uncompensated), and Genentech/Roche (uncompensated) and has received research funding (paid to Stanford University) from Genentech/Roche, Novartis, Clovis, Exelixis, Celgene, Bristol-Myers Squibb, AstraZeneca/Medimmmune, Gilead, Pfizer, and Xcovery.


1. Masters GA, Temin S, Azzoli CG, et al: Systemic therapy for stage IV non–small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 33:3488-3515, 2015.

2. Azzoli CG, Baker S Jr, Temin S, et al: American Society of Clinical Oncology clinical practice guideline update on chemotherapy for stage IV non–small-cell lung cancer. J Clin Oncol 27:6251-6266, 2009.

3. Azzoli CG, Temin S, Aliff T, et al: 2011 focused update of 2009 American Society of Clinical Oncology clinical practice guideline update on chemotherapy for stage IV non–small-cell lung cancer. J Clin Oncol 29:3825-3831, 2011.

4. Brahmer J, Reckamp KL, Baas P, et al: Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373:123-135, 2015.

5. Garon EB, Rizvi NA, Hui R, et al: Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372:2018-2028, 2015.

6. Woolf SH, Grol R, Hutchinson A, et al: Clinical guidelines: Potential benefits, limitations, and harms of clinical guidelines. BMJ 318:527-530, 1999.

7. Leighl NB, Rekhtman N, Biermann WA, et al: Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/ International Association for the Study of Lung Cancer/Association for Molecular Pathology guideline. J Clin Oncol 32:3673-3679, 2014.

8. Smith TJ, Temin S, Alesi ER, et al: American Society of Clinical Oncology provisional clinical opinion: The integration of palliative care into standard oncology care. J Clin Oncol 30:880-887, 2012.

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