NSCLC Histology First, Then Mutation Testing, Says NCCN Guideline

CT Screening for Some High-Risk Patients

Nick Mulcahy

March 18, 2011

Dr. David Ettinger

March 18, 2011 (Hollywood, Florida) — There are a host of changes in the updated guideline for nonsmall-cell lung cancer (NSCLC) from the National Comprehensive Cancer Network (NCCN).

Some of the most notable changes, presented here at the NCCN 16th Annual Conference, involve the evaluation process for potential systemic therapy in patients with recurrent or metastatic disease.

The evaluation process now calls for the histologic subtype of the disease to be established before proceeding with epidermal growth-factor receptor (EGFR) testing, said David Ettinger, MD, the NCSLC panel chair and a member of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland.

"Histology matters!," Dr. Ettinger told the NCCN audience.

In the setting of recurrent and metastatic disease, EGFR testing is a category 1 recommendation for 3 histologies: adenocarcinoma, large cell carcinoma, and NSCLC not otherwise specified. The testing is not recommended for squamous cell carcinoma; the guideline newly notes that patients with this form of the disease have an incidence of EGFR mutations of "less than 3.6%" and that this frequency does not justify the testing.

Erlotinib (Tarceva, Genentech/OSI Pharmaceuticals) is recommended as the first-line systemic therapy in patients with the 3 relevant histologies and a positive EGFR mutation. New to the guideline is the clarification that erlotinib is for patients with a performance status of 0 to 4. Also new is the recommendation that gefitinib can be used as first-line therapy in these same patients in "areas of the world where it is available."

EGFR mutations are present in adenocarcinomas in about 10% of Western patients and in about 50% of Asian patients, most frequently in women, nonsmokers, and nonmucinous tumors, says the guideline.

NSCLC patients should also be tested for KRAS mutations, because they are "associated with intrinsic TKI [tyrosine kinase inhibitor] resistance," says the guideline, referring to the TKIs gefitinib and erlotinib. KRAS gene sequencing could be useful in selecting patients for TKI therapy, the guideline notes, meaning that having the KRAS mutation indicates that TKIs will not be effective.

Patients who are positive for KRAS mutation are also unlikely to have anaplastic lymphoma kinase (ALK) rearrangements and, thus, are not good candidates for the investigational agent crizotinib (Pfizer), said Dr. Ettinger. The fusion of echinoderm microtubule-associated protein-like 4 (EML4) and ALK occurs in a subset of NSCLCs, the guideline points out.

Interestingly, EML4-ALK and EGFR mutations are mutually exclusive, for the most part, says the guidelines.

In short, clinicians should order EGFR and KRAS testing and, if EGFR mutation is present, not order EML4-ALK testing, summarized Dr. Ettinger. "All you have to do is to call up the pathologist and send the material over for EGFR and KRAS testing," he told the audience.

But the testing message is not getting through to many clinicians, Dr. Ettinger reported. He told the audience that he routinely sees NSCLC patients at Johns Hopkins from the "5-state area," including Maryland, who have not received molecular testing.

However, another NCCN meeting attendee suggested that clinicians are not deaf to the molecular testing message. Michael Kolodziej, MD, from New York Oncology Hematology in Albany, said that the testing is not yet well-founded on evidence and has not yet become practical.

"The value of molecular testing has yet to be proven," he told Medscape Medical News.

He also said that the promise of molecular testing currently does not jive well with its practicalities for community-based clinicians.

He offered the example of one of his patients — a female nonsmoker diagnosed with NSCLC. Because she fit the profile of patients with EML4-ALK NSCLC, and therefore might benefit from crizotinib, the woman was a candidate for genotyping of her lung tumor tissue.

"It took weeks to get [her testing] sorted out," said Dr. Kolodziej, explaining that the logistical difficulties included the fact that there are "only 1 or 2 commercial labs in the whole country that do the test" for EML4-ALK.

Practical problems with timing also exist for EGFR testing, a problem that Medscape Medical News has reported in the past.

No Routine Screening With CT Yet

The biggest news in lung cancer in the past year might be the results from the landmark National Lung Screening Trial (NLST).

The NLST, which was started in 2002, was conducted at 33 American sites with a cohort of 53,454 former and current heavy smokers, and was stopped early because of efficacy findings. The NLST represents the first time that a screening test has been shown to provide a significant reduction in lung cancer mortality in a randomized controlled clinical trial.

Screening with computed tomography (CT) provided a statistically significant 20% reduction in lung cancer mortality, compared with screening with chest x-ray, said Dr. Ettinger.

Dr. Ettinger reminded the NCCN audience that the organization does not yet recommend routine screening with CT; the risks and benefits need further definition from clinical trial data, including those of the NLST.

However, high-risk patients who are interested in screening should participate in a clinical trial, says the guideline. If that's not possible, then the patient should go to a center of excellence, discuss benefits and risks, and follow an established protocol when having a CT screening.

Dr. Ettinger reports being a consultant to Boehringer Ingelheim, Daiichi- Sankyo, Eli Lilly, Genentech, Merck, Biodesix, Poniard Pharmaceuticals, Prometheus, Shin Nippon Biomedical Labs, and Telik.

National Comprehensive Cancer Network (NCCN) 16th Annual Conference. Presented March 10, 2011.

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