Mutations That Drive Lung Cancer Also Driving Frontiers of Treatment

NCCN Guidelines Updates
Published Online: May 15, 2014
Mary K. Caffrey
A more individualized view of what drives the onset of non-small cell lung cancer (NSCLC) is raising treatment hopes as new therapies emerge and enter development, said Leora Horn, MD, MSc, of the Vanderbilt-Ingram Cancer Center, who presented an overview March 14, 2014, at the National Comprehensive Cancer Network’s (NCCN’s) 19th Annual Conference: Advancing the Standard of Cancer Care, held in Hollywood, Florida.

Once upon a time, asking what kind of lung cancer a patient had would yield 1 of 4 answers: large cell carcinoma, small cell carcinoma, squamous cell carcinoma, or adenocarcinoma; this last type afflicts both smokers and nonsmokers but has become more common among smokers in recent decades.1

That limited view meant limited treatment, even though lung cancer causes more deaths than any other type in the United States.1 Today, however, oncologists are gaining a greater understanding of what sets cancer in motion at the molecular level; nearly a dozen mutations, notably KRAS and EGFR, are now known to account for about half of lung cancer cases.

For years, lung cancer waited for a game changer. As Horn showed with results from the ECOG 1594, and in other studies, multiple comparative combinations were producing few differences in
survival, although there were differences in toxicity and cost.2 Horn noted the 2010 results of the AVAiL trial, which found no overall survival (OS) benefit for patients taking bevacizumab, a monoclonal antibody, with chemotherapy, compared with those taking chemotherapy alone.

Results published in October 2013 by the American Society of Clinical Oncology3 did show a small difference in progression-free survival (PFS) between patients taking pemetrexed with a combination of bevacizumab and carboplatin (median PFS = 6.04 months) compared with those taking paclitaxel and the bevacizumab/carboplatin combo (median PFS = 5.5 months). Greater differences were seen in OS, which were 12.55 months for the pemetrexed arm compared with 13.4 months for the paclitaxel arm.

Enter biomarkers and targeted therapy, and the differences begin to grow. Horn showed a series of results comparing gefitinib with traditional chemotherapy combinations for patients with EGFR-positive mutation, and the outcomes were stark. A roundup of studies comparing targeted therapies with traditional regimens typically had differences in PFS of 5 months, with 1 study involving erlotinib reporting a difference of 8.5 months.

What’s coming in immunotherapy may raise even more optimism. There is increased understanding of PD-1, as well as its ligand PD-L1, and their roles in NSCLC; PD-L1 is overrepresented in
both adenocarcinoma and in squamous cell lung cancer, which are most common among smokers. Immunotherapy targets T-cell activity, which is regulated by a balance of costimulatory and inhibitory signals known as checkpoints. The body’s self-regulation through these checkpoints enables it to respond to infections and prevent tumor progression, as well as prevent autoimmune- type responses.

Nivolumab, a PD-1 inhibitor, is an investigational therapy that has received attention since a 2012 article in the New England Journal of Medicine4 reported on its effects on patients across multiple cancers, including NSCLC. It gained further notice from ASCO in 2013 and at the World Conference on Lung Cancer in October 2013. Survival rates at 1 year with nivolumab were 42% and reached 24% at 2 years, according to the median 20.3-month follow-up.5 Horn also reviewed the side effects, which were relatively limited in the NSCLC cohort.

In current trials, nivolumab is being tested against chemotherapy as second line in PD-L1–positive NSCLC patients, and nivolumab is being tested with and without ipilimumab in small-cell lung cancer. There are 25 trials involving the drug; besides NSCLC, there are phase 3 trials involving melanoma and renal cell carcinoma.5

An anti-PD-L1 monoclonal antibody, MPDL3280A, is currently under study in combination with bevacizumab and chemotherapy; like nivolumab, it is being studied for other cancers. A related agent is being studied as a second-line therapy in combination with docetaxel. EBO

 At the 19th Annual Conference of the National Comprehensive Cancer Network (NCCN), held March 12-15, 2014, experts reviewed research and presented updates to the NCCN Clinical Practice Guidelines in Oncology. The conference also featured a roundtable discussion on how the early months of implementing the Affordable Care Act are affecting the delivery of cancer care. Beyond treatment for cancer, NCCN issued updates to last year’s survivorship guidelines as well as new recommendations in the realm of cancer screening.
For complete NCCN guidelines, create a profile and visit:
For the August 2013 NCCN Bone Health Task Force Report, visit:

1. The health consequences of smoking—50 years of progress: a report of the Surgeon General. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2014.

2. Phase 3 randomized trials comparing platinum-containing doublets for advanced NSCLC. Medscape Multispecialty. Accessed March 16,

3. Patel JD, Socinski MA, Garon ME et al. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer [published online October 21, 2013]. JCO.

4. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Eng J Med. 2012;366(26):2455-2465.

5. Inman S. Nivolumab survival benefit extended in updated NSCLC results. OncLive. http://www Published October 28, 2013. Accessed March 16, 2014.
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