An Expert’s Perspective: Non-Small-Cell Lung Cancer

Reviewed by Neha Pathak, MD on November 30, 2020

By Joshua Sabari, MD, assistant professor of medicine, thoracic medical oncology, and phase I drug development, NYU Langone Health Perlmutter Cancer Center, as told to Stephanie Watson

Lung cancer used to be a disease that primarily affected smokers. After the surgeon general came out in the 1960s stating that smoking caused cancer, smoking rates declined significantly. In the late 1990s and early 2000s, we saw a significant drop-off in the death rate for lung cancer. We think that it was mostly due to people quitting smoking.

Now I'm diagnosing more and more people who are younger and were never smokers. In fact, a lot of them have never smoked. Many of these people have gene mutations that drive the development of their lung cancer.

One of the key questions is, why are we seeing this increase in lung cancer in never-smokers? We don’t know, but we suspect it may be related to pollution or radon exposure. Most of the areas where we’re seeing these increases are heavily populated industrial areas.

Diagnosing Lung Cancer Early

Classically, we think of lung cancer symptoms such as shortness of breath, cough, and weight loss. But often, those signs and symptoms are not there until the cancer has spread. By the time most people have symptoms, they already have stage IV disease. That’s why screening is so important, especially in people who are heavy smokers. You want to identify the tumor before it spreads so you can do something about it.

For smokers, we clearly have evidence that doing a low-dose CT scan of the chest will reduce the risk of dying from lung cancer. Unfortunately, most people are still diagnosed with stage IV disease. At that stage, the disease is treatable, but not curable. The goal of treatment is to relieve symptoms and hopefully extend the person's life. Thanks to the implementation of lung cancer screening, I'm seeing an increase in the number of people diagnosed with earlier-stage disease with a high cure rate.

But we still have a long way to go. Probably less than 10% of those who are eligible for CT screening actually get the test. I think part of the reason is a lack of awareness. I also think there’s a stigma related to lung cancer. Breast cancer and colon cancer screenings are high because these diseases aren't seen as being caused by something you did. What I tell people is, "The only thing you need to get lung cancer are lungs." We need to erase this idea that lung cancer only happens in smokers.

Learning More About Your Cancer

Every time I meet a new patient, it’s critical to define the stage of their disease. I want to make sure that I have imaging of the person's whole body -- an MRI of their brain, as well as a PET scan of their chest, abdomen, and pelvis to try to understand where the cancer started and where it has spread. After that, the next step is to obtain a tissue biopsy to define the histology, as well as perform molecular testing that can help guide further management and treatment options.

What Is Non-Small-Cell Lung Cancer?Jamie Chaft, MD, breaks down the history of non-small-cell lung cancer and how new treatments like gene therapy can be revolutionary to treating your condition.277

SPEAKER 1: There are two

major types of lung cancers,

which can affect smokers

and non-smokers alike,

small-cell lung cancer

and non-small-cell lung cancer.

JAMIE CHAFT: I would say,

interestingly, despite all of us

using "non-small-cell lung

cancer" in our everyday lingo,

it actually isn't a thing.

So, "non-small-cell lung cancer"

is a historic term, and it

really meant just that, not

small-cell lung cancer.

SPEAKER 1: Doctors now recognize

it's a group of cancer


including adenocarcinoma,

squamous cell carcinoma,

and a host of rare subtypes.

As researchers have moved

beyond the historic lingo

and narrowed in on these more

specific conditions, they've

started making advances

on this biological chessboard.

But doctors still haven't found

their checkmate.

JAMIE CHAFT: It's very exciting.

As a field, it is constantly


And it certainly keeps us

on our toes.

SPEAKER 1: While people may

still be diagnosed

with non-small-cell lung cancer,

how they're treated

depends on what their cancer

actually looks

like under a microscope.

Old-school chemotherapy can help

some people live longer,

healthier lives.

But scientists have made

big advances

in targeted therapies,

including immunotherapies, which

help the body's

own immune system attack cancer


and a class of drugs called

"small molecule inhibitors."

Researchers have found

that some people's tumors can

have just one genetic change

that can lead

to cancerous cells.

These powerful mutations are

called "drivers."

JAMIE CHAFT: And we have found

that, in the lab,

drugs have been developed

that are highly

specific at blocking

these abnormal proteins.

And it's like stepping

on the gas

and letting the car go,

where we now have medicines

that, not permanently,

but at least with some degree

of durability,

can step on the brake.

SPEAKER 1: The first

of these inhibitors targeted

a protein called

the "epidermal growth factor

receptor," or EGFR.

Researchers found that many lung

cancers had surfaces littered

with the excess product

of EGFR proteins,

so they developed

an EGFR inhibitor to suppress

these growth factors.

It worked, slowing the growth

of cancer cells.

JAMIE CHAFT: And that was pretty


And since then, we've found

many different genes for which

targeted therapies can be

designed and prescribed

in the clinic.

SPEAKER 1: These include

inhibitors for genes like ELK,

MET, RET, KRAS, and more.

But there's still plenty of room

for improvement.

JAMIE CHAFT: I envision

that, in the future,

lung cancer care is going to be

exceptionally different.

SPEAKER 1: Right now,

targeted therapies are

slow to start, because doctors

need lots of data,

including tumor biopsies,

to make sure they're choosing

the right treatment.

The wait can be

hard on patients.

JAMIE CHAFT: And, as a provider,

we do our best to reassure

people that the best therapy is

usually far better

than a quick therapy,

and it's something that's often

really hard to wrap your head


In 20 years, we will likely

be making our diagnoses based

on a blood test, not

on a biopsy, and we'll probably

be monitoring therapy based

on serial blood tests, where we

can track the tumor

and its evolution

through the blood,

and hopefully target and tailor

therapy to be maximally

effective in that setting.

SPEAKER 1: Researchers will also

continue to improve

on immunotherapies through

research on the patients who

respond well to the treatment

and those who don't.

JAMIE CHAFT: My personal wish

list is to improve cure rates,

and really to take all

of these interventions

that we've shown

to be

beneficial in stage-four disease

and move them into the earlier


SPEAKER 1: But here's one move

patients and providers can make


JAMIE CHAFT: We still need

the primary care physicians

and the pulmonologists

across the country to believe

in lung cancer screening,

and to believe that we can

change outcomes if we screen

and identify these cancers


Jamie Chaft, MD<br>Medical Oncologist at Memorial Sloan Kettering/delivery/aws/13/e6/13e6b0fc-f866-4679-8fee-b2cc6ce7c3f4/bb5750b5-e7e8-412d-b3b0-54ce000cd1b1_302574_1_nsclc_brief_breakdown_non_small_cell_lung_cancer_012021_,4500k,2500k,1000k,750k,400k,.mp401/21/2021 12:00:0018001200brief breakdown non small cell lung cancer/webmd/consumer_assets/site_images/article_thumbnails/video/brief_breakdown_non_small_cell_lung_cancer_video/1800x1200_brief_breakdown_non_small_cell_lung_cancer_video.jpg091e9c5e820e695f

Biomarker testing is critical in people with lung cancer. I need to know if there are any gene alterations, such as EGFR, KRAS, or ALK. These mutations will affect which treatment I choose.

If there are no genetic alterations, the next thing I look at is PDL1 expression (programmed death ligand-1). The way I like to think about PDL1 is as a disguise on the cancer cells. If someone's PDL1 expression is high, their cancer is very well-disguised and their immune system can't recognize and attack it. Cancers with high PDL1 expression respond well to certain immunotherapies. People with low PDL1 expression need a combination of immunotherapy and chemotherapy.

What Treatments Are Right for You?

If somebody has an early-stage cancer, I’m going to refer them to a surgeon. Surgery is a mainstay for early-stage cancers. In stage IV cancer, there’s really no role for surgical therapy, because the cat’s already out of the bag. The cancer has spread.

Five or 10 years ago, we had only one treatment for late-stage cancer -- chemotherapy -- and its success was limited. Chemotherapy kills cancer cells, but unfortunately it can also kill normal cells. So it causes side effects such as fatigue, nausea, vomiting, and weakening of the immune system.

Now we have better treatments for stage IV cancers. There’s targeted therapy, which targets certain proteins or gene mutations that help the cancer cells grow. It’s very important that I understand upfront if someone has a mutation that I can act upon, because it changes their survival time and it changes the therapies that are available to them. There are now seven different genetic alterations for which there are approved therapies. Five years ago, there were only two targeted therapies approved.

There's also immunotherapy, which helps the immune system better recognize and attack the cancer. There has been a lot of excitement over the last 4 to 5 years, with multiple approvals of different immunotherapy drugs. There are cytokines and cancer vaccines that rev up the immune system response. And recently, there has been a lot of work using adoptive T-cell therapies. We're harnessing our own immune cells to try to get them to better recognize the cancer.

Who Can Benefit From a Clinical Trial?

Right now, clinical trials are mostly an option when standard treatments stop working. I think we need to change that. We need to think about what will give someone with lung cancer the best chance of a response, the longest-lasting response, and the best quality of life.

At every stage and with every treatment decision that I make with a patient, I’m always looking at what clinical trials are available. If I see a clinical trial that I think has a better chance of working than the standard therapy that's available, I’m going to recommend it.

How Has Lung Cancer Survival Improved?

The average survival for someone with stage IV lung cancer used to be about a year to 16 months. Now, with the use of targeted drugs, the overall survival can be greater than 3 years for certain people. Treatment with immunotherapy has resulted in people who are alive and thriving at 5 years. We don’t have 10-year data yet, but people are starting to talk about the "C" word -- cure -- for people with stage IV disease who have responded well to immunotherapy.

People with lung cancer are definitely living longer and doing better. I hope in my lifetime that we have the ability to cure stage IV disease.

WebMD Feature


Joshua Sabari, MD, assistant professor of medicine, thoracic medical oncology, and phase I drug development, NYU Langone Health Perlmutter Cancer Center, New York City.

© 2021 WebMD, LLC. All rights reserved.