NCCN NSCLC GUIDELINESS

March 23, 2010 (Hollywood, Florida) — There are a plethora of changes in the updated guideline for nonsmall-cell lung cancer (NSCLC) from the National Comprehensive Cancer Network (NCCN). Some of the changes involve a new staging system, neoadjuvant combined modality therapy for potentially resectable disease, and treatment options for unresectable stage 3 disease.

However, in an interview here before the NCCN 15th Annual Conference, Joan S. McClure, MS, senior vice president of clinical information and publications for the NCCN, highlighted as especially important the changes regarding systemic therapy for advanced or metastatic disease in NSCLC.

In his presentation at the meeting, David Ettinger, MD, the NCSLC panel chair, walked the audience through those changes, starting with first-line therapies.

Dr. Ettinger is from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland.

Advanced Disease: First-Line Therapy Changes

For patients with recurrent or metastatic disease and a performance status (PS) of 0 or 1, there are a number of changes related to first-line therapies.

Erlotinib (Tarceva, Genentech/OSI Pharmaceuticals) has been added, but only for patients who test positive for an epidermal growth-factor receptor (EGFR) mutation.

Bevacizumab (Avastin, Genentech), used in combination with chemotherapy, should be given until progression, the guideline now notes. Previously, the guideline indicated that bevacizumab should only be given if there were "no untreated [central nervous system] metastases," but that restriction has been deleted. The guideline notes that bevacizumab should only be used in patients with nonsquamous NSCLC and no history of hemoptysis.

Pemetrexed should not be given to patients with squamous histology, the guideline now notes. Pemetrexed should also be used in combination with chemotherapy, not as a single therapy, unless it is a maintenance therapy.

For patients with recurrent or metastatic disease and a PS of 0 to 2, the list of first-line treatment options is smaller because, as the guideline notes, these patients have a "greater toxicity and potential for lower benefit" than patients with a PS of 0 or 1.

Cetuximab (Erbitux, Bristol-Myers Squibb) plus vinorelbine and cisplatin is a treatment option for patients with a PS of 0 or 1 and those with a PS of 2. However, as Dr. Ettinger pointed out, cetuximab is not approved for this use by the US Food and Drug Administration. The guideline now emphasizes that a full dose of cisplatin "should be given selectively" in these patients.

Advanced Disease: Maintenance Therapy Is New

In those who do not progress, the NCCN recommends that clinicians either observe such patients or use maintenance therapy. The whole section on maintenance therapy is new in the guideline.

The NCCN recommends 2 kinds of maintenance therapy: continuation or switch.

Continuation therapy refers to the use of at least one of the agents given as first-line therapy beyond 4 to 6 cycles in the absence of progression. It is not recommended that chemotherapy be continued; instead, biologic agents are recommended until unacceptable toxicity or disease progression, notes the guideline.

Continuation therapy can be carried out with bevacizumab, cetuximab, or pemetrexed, according to the guideline.

Switch maintenance therapy is what it sounds like: after first-line chemotherapy, nonprogressing patients are switched to either pemetrexed or erlotinib.

Two separate studies showed a benefit in progression-free and overall survival with the initiation of pemetrexed or erlotinib after first-line chemotherapy in NSCLC patients without disease progression, notes the guideline.

Initiation of pemetrexed is recommended after 4 to 6 cycles of first-line platinum-doublet chemotherapy for patients with histologies other than squamous cell carcinoma.

This is a category 2B recommendation, which means, according to the NCCN, that the recommendation is based on a level of evidence that is lower than categories 1 and 2A, and where "there is nonuniform NCCN consensus, but no major disagreement."

At the 2009 annual meeting of the American Society of Clinical Oncology, where these pemetrexed data were first presented, 2 lung cancer experts told Medscape Oncology that it was not clear if pemetrexed should be maintenance therapy and therefore started immediately after first-line therapy in nonprogressors, or delayed and used as second-line therapy. "There was no crossover design," Dr. Ettinger told the NCCN audience. "We will never know if delayed vs immediate mattered."

Still, in reviewing the progression-free and overall survival advantage of pemetrexed over placebo in advanced patients who are not progressing, Dr. Ettinger summarized: "Those are good data."

Initiation of erlotinib is recommended (also category 2B) by the NCCN as a treatment option after 4 to 6 cycles of first-line platinum-doublet chemotherapy. Data on erlotinib as maintenance therapy were initially presented at the 2009 World Conference on Lung Cancer, as reported by Medscape Oncology.

Advanced Disease: Second- and Third-Line Therapy Changes

For patients with recurrent or metastatic disease and a PS of 0 to 2, platinum-doublet therapy was added as an option for second-line therapy (category 2B) if patients received erlotinib as first-line therapy.

Erlotinib is also recommended as a third-line therapy, once again for those with an EGFR mutation.

"A lot of my colleagues want to have something in reserve," Dr. Ettinger said about waiting until the third line to use erlotinib. "Personally I think it's a mistake — patients may not get that far."

Dr. Ettinger reports having been on the advisory board or speakers bureau or having served as a consultant to AstraZeneca, Bristol-Myers Squibb, Genentech, and GlaxoSmithKline.

National Comprehensive Cancer Network (NCCN) 15th Annual Conference. Presented March 12, 2010.