Advances in Non-Small-Cell Lung Cancer Treatment

Reviewed by Brunilda Nazario, MD on December 07, 2020

Doctors once thought non-small-cell lung cancer (NSCLC) was one disease. Most people got the same treatment -- chemotherapy (chemo) -- especially if their cancer had spread to other parts of the body. 

Now, doctors know there are many different types of NSCLC, with “more coming down the pike,” says Nathan Pennell, MD, a medical oncologist specializing in thoracic cancer at the Cleveland Clinic’s Taussig Cancer Institute.

That means treatment plans are no longer once-size-fits-all. Instead, treatments like targeted therapies and immunotherapy are tailored to each person’s tumor.

Targeted Therapies

Some cancer cells have gene changes (also called mutations) that help them grow and spread. The goal of several targeted therapies is to block those changes. The FDA has approved medicines to treat seven different gene mutations that can drive NSCLC:

  • EGFR
  • ALK
  • BRAF
  • ROS1
  • RET
  • MET

One drug targets the growth of tumors on blood vessels:

Epidermal growth factor receptor -- or EGFR -- is the most common. It’s a protein on the surface of cells that helps them grow and divide. If you have too much EGFR, your cells grow faster than normal.  Medicines called EGFR inhibitors stop this growth.    


Karen Reckamp, MD, co-directs the lung cancer and thoracic oncology program at City of Hope in Duarte, CA. She says targeted therapy has completely changed the way doctors manage lung cancer. Now, before you start treatment for advanced NSCLC, you’re likely to have genetic testing to see if you have a mutation that might help guide your treatment.

Reckamp says this new way of doing things has changed the game for many people with advanced NSCLC.

“We don’t talk about a cure,” Reckamp says. “But the tumor shrinks, people feel better, go back to work, and have a better quality of life.”

Targeted therapies also have drawbacks. Some only work for the small number of people who have gene mutations that respond to a certain targeted therapy. About 15% of people with lung cancer have EGFR-positive lung cancer. The numbers are much smaller for other gene changes.

The medicines also have side effects, like:

  • Skin rash
  • Diarrhea
  • Liver damage
  • Bone marrow problems


Reckamp says these usually aren’t as severe as side effects from chemotherapy.

“For most people, the side effects are pretty tolerable, and they do pretty well.”

Another problem is that targeted medicines often stop working, eventually.

“Cancer cells find ways to survive and overcome the toxic treatments we’re giving them,” Reckamp says. “When that happens, you have to try a different treatment.” 

Still, she says targeted therapies have greatly improved the odds for people with NSCLC.

“With chemotherapy alone, [extending life] by 1 year was as good as we could get. Now, with these therapies in addition to chemo, it’s not uncommon for patients to live 2, or even 5 years.”


Your immune system normally destroys cancer cells. But tumor cells are sneaky and can find ways to evade your body’s best defenses. If you have NSCLC, some cancer cells may churn out a protein called PD-L1. It attaches to another protein, PD-1, on important immune T cells. This is called an immune checkpoint, and it tells your T cells to leave the tumor alone.  


One way to get around this is with medicines called checkpoint inhibitors. They prevent PD-L1 and PD-1 from getting together. This unleashes your immune system, so it’ll be at full power against cancer cells. But healthy cells get caught in the crossfire.

“Immunotherapy can cause inflammation anywhere in your body from head to toe,” Reckamp says. “When your immune system never turns off, you can get something resembling an autoimmune disease like rheumatoid arthritis. Or you can have problems with your thyroid, liver, bladder, kidneys, and heart.

“And this can happen anytime -- even after you’ve stopped treatment. But most symptoms can be well-controlled with high-dose steroids.”

Your doctor won’t suggest immunotherapy unless your tumor tests positive for high levels of PD-L1. The test isn’t always correct, though, and some tumors that test positive for PD-L1 may not respond to immunotherapy.  

Still, Reckamp says immunotherapy is a better choice than chemo for most people who have it, despite the severe side effects and hefty price tag. It may even keep working after you stop taking it.

In the Pipeline

Reckamp says to look for improvements in targeted medicines and smarter drugs that can outwit and outlast cancer cells.

“There are lots of clinical trials focused on overcoming resistance to targeted medicines and immunotherapy, and combining these with chemotherapy to improve not just the length of a [person’s] life, but also the quality,” she says.

How Mutations Can Change Your Game Plan"If you think of cancer as a bus that’s going fast down the hill, the mutation is driving it," says Suresh Ramalingam, MD. How does knowing the specific mutation help with treatment?133



develop either due to a series

of mutations,

or in some instances,

a single mutation.

Knowing what kind of mutation

is driving

a particular patient's cancer

often helps us to come up

with therapies that are very

specific to that particular


If we take lung cancer,

adenocarcinoma is by far

the most common subset.

It's for that subgroup

of patients where mutations have

proved to be valuable tools

or valuable markers

to guide therapy.

So when somebody has lung

adenocarcinoma, we recommend

molecular testing

for those patients

at the time of diagnosis

so we can make the best

treatment decisions for them.

When we talk about mutations,

the ones that we are

particularly interested in

are the driver mutations.

If you think of cancer as a bus

that's going fast down the hill,

the mutation is driving it.

So if you know the mutation,

then that gives you

an opportunity to block

the mutation,

and these targeted therapies

do just that.

And that results in tumor


That results and improvement

in symptoms.

And often, results

in long-term survival

of the patient.

So these are robust benefits

that we did not have

until individualized therapy

based on genomic status

of the patient's tumor.

The most common mutation we see

is the KRAS mutation, which

is seen in about 25%, 30%.

Then other mutations that we see

include EGFR.

We have ALK, BRAF, RET.

Those are some of the more

common mutations.

All of these mutations

have different therapies

associated with them

that improve their survival,

that provide the opportunity

for them

to experience long-term life,

and good quality of life

as well.

So the treatment options

for each individual mutation

is different.

For some mutations, there's even

more than one therapy, so you

get to pick and choose which one

might be best suited

for the given patient sitting

in front of the physician.

So knowing what

the molecular status is

is incredibly important

before you treat a patient

with lung cancer.

Suresh Ramalingam, MD Oncologist, Winship Cancer Institute/delivery/aws/1c/47/1c47a4b2-c892-3c2b-a502-e1c5f2524e49/091e9c5e81e3559d_funded-expert-feature-non-small-cell-lung-cancer_,4500k,2500k,1000k,750k,400k,.mp402/10/2020 10:44:0018001200photo of doctor/webmd/consumer_assets/site_images/article_thumbnails/video/funded_expert_feature_non_small_cell_lung_cancer_video/1800x1200_funded_expert_feature_non_small_cell_lung_cancer_video.jpg091e9c5e81e3559d
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Karen Reckamp, MD, co-director, lung cancer and thoracic oncology program, City of Hope, Duarte, CA.

Nathan Pennell, MD, medical oncologist, Cleveland Clinic’s Taussig Cancer Institute.

American Cancer Society: “Targeted Therapy Drugs for Non-Small Cell Lung Cancer.”

Johns Hopkins Medicine: “What are Immune Checkpoints, and How Can We Block Them?”

Dana-Farber Cancer Center: “What Is a PD-L1 Test?”

Andrews, A. Treating with Checkpoint Inhibitors -- Figure $1 Million Per Patient, American Health & Drug Benefits, 2015.

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