Making milestones against non-small cell lung cancer

January 24, 2018, Yale University
Killer T cells surround a cancer cell. Credit: NIH

Hard to detect in its early stages and hard to treat as it advances, lung cancer is the leading cause of cancer mortality around the world, with an estimated 1.6 million deaths each year. New treatments, however, are bettering the odds for people with non-small cell lung cancer (NSCLC), which makes up about 85 percent of lung cancer cases.

"Progress has been enormous in the past 20 years," said Roy Herbst, M.D., Ph.D., chief of Medical Oncology at Yale Cancer Center and professor of Medicine and Pharmacology at Yale School of Medicine.

Traditionally, NSCLC has been treated by surgery followed by chemotherapy or radiation or both. "Options for treatments have improved in recent years with the advent of two classes of drugs, molecularly targeted therapies and more recently immunotherapies," said Herbst, co-lead author on a paper reviewing advances in NSCLC treatment published in the journal Nature. (Co-lead authors include: Daniel Morgensztern, M.D., associate professor of Medical Oncology at Washington University, and Chris Boshoff, senior vice president for Global Product Development for Oncology, Pfizer Inc., and adjunct professor, Yale School of Medicine.)

Molecularly targeted drugs aim to attack cells that have mutated genes such as EGFR that can drive . The Food & Drug Administration (FDA) gave its first approval for an EGFR inhibitor for NSCLC in 2004, and about a quarter of NSCLC now can be treated with various targeted drugs. Research is underway at Yale and many other Institutions to discover additional molecular targets. However, patients eventually develop resistance to these medicines, Herbst said.

Another wave of treatment options began to arrive in 2015 when the FDA approved the first "immune checkpoint blocker" for patients with advanced NSCLC. These immunotherapies clog up mechanisms that prevent the body's immune T cells from attacking tumors, by inhibiting a protein called PD-1 on the surface of T cells or its partner protein PD-L1 on tumor cells. Patients whose tumors show high levels of PD-L1 are generally the best candidates to benefit from such immunotherapies.

To date, immune checkpoint blockers work well for about one-fifth of NSCLC patients. "However, we've seen that although many tumors express PD-L1, many don't, and PD-L1 inhibition won't work for those," said Herbst. "Even among tumors that have high PD-L1 expression, many don't have any T cells in the tumor microenvironment, so that doesn't work either. We need to figure out how we're going to 'warm up' tumors and make them more sensitive to these different therapies." Additionally, as with targeted therapies, most tumors become resistant to immunotherapies over time.

Novel immunotherapies addressing other components of the immune system will be critical to overcome these challenges, Herbst suggested. Another key will be to combine immunotherapies, or to pair them up with chemotherapy, targeted therapy, medicines that suppress the growth of blood vessels, or other forms of cancer treatments.

"We need to move the personalized approach that we've used for targeted therapy to immunotherapy, matching the right patient to the right medicine at the right time," Herbst emphasized.

Other research efforts are creating new approaches to detect lung cancer and track it as it evolves in each patient. Last year, the FDA approved a "liquid biopsy" test for NSCLC that can find certain types of EGFR mutations by sequencing fragments of tumor DNA that circulate in the blood. More advanced tests of this "circulating free tumor DNA" are being developed to support individualized lung cancer treatment. "A liquid biopsy lets you see things in real time, and you can do multiple biopsies because they are less invasive for the patient," Herbst said. "Liquid biopsies are not quite as sensitive as a tumor biopsy, but some evidence suggests that they might actually give a more realistic view of the disease throughout the entire body."

Clinical research in NSCLC is being accelerated by innovative large clinical studies, such as the Lung Master Protocol (Lung-MAP) trial, which has enrolled more than 1400 patients to test a host of targeted drug candidates among previously treated patients with squamous cell lung cancer. Lung-MAP is now extending its scope to test combinations of targeted medicines and immunotherapies.

Herbst directs Yale's Specialized Program of Research Excellence (SPORE) for lung cancer, one of three SPOREs funded by the National Cancer Institute. The program brings together experts in oncology, immunobiology, pharmacology, molecular biology, pathology, epidemiology and addiction science to attack the disease. "We aim to bring results from the lab to the clinic and back again," he said.

"Overall, we're seeing unprecedented benefits for people with NSCLC, but it's a very tough disease," Herbst summed up. "We're still only helping 30 or 35 percent of patients. Our research has to remain novel and innovative. We still have a lot of work to do."

Explore further: Immune therapy drug results in prolonged survival in advanced lung cancer

More information: The biology and management of non-small cell lung cancer, Nature (2018).

Related Stories

Immune therapy drug results in prolonged survival in advanced lung cancer

December 21, 2015
A Yale-led international study in patients with advanced non-small cell lung (NSCLC) cancer resistant to chemotherapy has found a promising weapon in an immune therapy drug commonly used to treat other cancers. The findings ...

Liquid biopsy provides real-time blood test for solid lung cancer tumors

February 27, 2015
In the rapidly changing world of molecular profiling for genetic diseases, cancer researchers are increasingly optimistic about the reality of a simple blood test to monitor and treat solid tumor cancers.

Possible new immune therapy target in lung cancer

October 18, 2017
A study from Bern University Hospital in collaboration with the University of Bern shows that so-called perivascular-like cells from lung tumors behave abnormally. They not only inadequately support vascular structures, but ...

FDG PET shows tumor DNA levels in blood are linked to NSCLC aggressiveness

November 6, 2017
Italian researches have demonstrated a better way of determining the aggressiveness of tumors in patients with advanced non-small cell lung cancer (NSCLC). In a study presented in the featured clinical investigation article ...

Lung cancer patients gain access to new treatment for fourth time in two months

December 2, 2015
The International Association for the Study of Lung Cancer (IASLC) is pleased to hear of another approval by the U.S. Food and Drug Administration (FDA) that helps in the fight against lung cancer—the fourth in two months. ...

Unique lipid profile could help diagnose and treat lung cancer

September 8, 2017
The lipid contents of a fluid that surrounds the lungs in some diseases contains specific fats that could be used as a biomarker to distinguish people with and without lung cancer. It can also identify a subtype of the cancer ...

Recommended for you

Metastatic lymph nodes can be the source of distant metastases in mouse models of cancer

March 22, 2018
A study by Massachusetts General Hospital (MGH) investigators finds that, in mouse models, cancer cells from metastatic lymph nodes can escape into the circulation by invading nodal blood vessels, leading to the development ...

Could a pap test spot more than just cervical cancer?

March 22, 2018
Pap tests have helped drive down rates of cervical cancer, and a new study suggests they also could be used to detect other gynecologic cancers early.

Gene-based test for urine detects, monitors bladder cancer

March 22, 2018
Researchers at The Johns Hopkins Kimmel Cancer Center have developed a test for urine, gathered during a routine procedure, to detect DNA mutations identified with urothelial cancers.

Researchers identify compound to prevent breast cancer cells from activating in brain

March 22, 2018
Researchers at Houston Methodist used computer modeling to find an existing investigational drug compound for leukemia patients to treat triple negative breast cancer once it spreads to the brain.

Researchers examine role of fluid flow in ovarian cancer progression

March 22, 2018
New research from Virginia Tech is moving physicians closer to pinpointing a predictor of ovarian cancer, which could lead to earlier diagnosis of what is know as the "silent killer."

Probing RNA epigenetics and chromatin structures to predict drug resistance in leukemia

March 22, 2018
Drug resistance is a major obstacle to effective treatment for patients with cancer and leukemia. Epigenetic modifying drugs have been proven effective for some patients with hematologic malignancies, such as myelodysplastic ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.