Mutations that Drive Lung Cancer Also Driving Frontiers of Treatment

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 are under development, said Leora Horn, MD, MSc, of the Vanderbilt-Ingram Cancer Center, who presented an overview Friday at the National Comprehensive Cancer Network’s (NCCN) 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 includes both smokers and nonsmokers but has become the more common cancer among smokers in recent decades.¹

KRAS

EGFR

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 and , 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 Dr 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 begins 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 offer 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 co-stimulatory 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 to prevent autoimmune-type responses.

New England Journal of Medicine,

Nivolumab, a PD-1 inhibitor, is an investigational therapy that has received attention since a 2012 article in the ⁴ which 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.

References

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, CDC; 2014. Available at http://www.surgeongeneral.gov/initiatives/tobacco.
2. Phase 3 randomized trials comparing platinum-containing doublets for advanced NSCLC. Medscape Multispecialty. http://www.medscape.org/viewarticle/500190_3. Accessed March 16, 2014.
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 before print 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):2455-65.
5. Inman S. Nivolumab survival benefit extended in updated NSCLC results. OncLive. http://www.onclive.com/web-exclusives/Nivolumab-Survival-Benefit-Endures-in-Updated-NSCLC-Results. Published October 28, 2013. Accessed March 16, 2014.