How Non-Small Cell Lung Cancer (NSCLC) Treatment Is Improving

Lung cancer is the most common cause of cancer deaths worldwide, and it’s a difficult cancer to treat. That’s partly because there are often no early symptoms, making the disease less likely to be detected when treatment may be more effective.

“Lung cancer can be so deadly because by the time it is diagnosed, it is often at an advanced stage,” says Roy Herbst, MD, PhD, a Yale Medicine oncologist and Ensign Professor of Medicine at Yale School of Medicine (YSM). Dr. Herbst also serves as chief of medical oncology, deputy director for Clinical Affairs, and assistant dean for Translational Medicine at YSM, Yale Cancer Center, and Smilow Cancer Hospital. “More than 50% of the time, it has already traveled from the lung to another part of the body, which makes it very difficult to treat," he says.

But progress in treatment options is providing some patients with new avenues, which could eventually change the prognosis for many.

Many of the successful therapies for lung cancer are aimed at non-small cell lung cancer (NSCLC), one of two main types of lung cancer. NSCLC accounts for 80% to 85% of lung cancer cases, and while tobacco smoking is the most important risk factor, non-smokers may get it as well. Other risk factors include exposure to workplace carcinogens, radon, secondhand smoke, environmental pollution, and having a family history of lung cancer.

The other type, small cell lung cancer (SCLC), generally accounts for 10% to 15% of all lung cancer diagnoses; it tends to grow and spread faster than NSCLC and is almost always caused by years of cigarette smoking.

“If you find NSCLC cancer early, it opens up a whole new panel of therapies,” says Dr. Herbst, who has a special interest in this type of cancer. He champions lung cancer screening with low-dose CT scans, which minimize radiation exposure for anyone who is eligible, and “multimodality care.” The latter includes working with a diverse team of specialists to determine how to best combine a variety of treatments, which, in addition to surgery, might include radiation, targeted therapies, immunotherapy, or chemotherapy.

Dr. Herbst spoke to us about promising treatments available to patients with NSCLC.

I’ve worked for almost 30 years on NSCLC, and I've been fortunate to witness some great advances firsthand. When I started, we had very few treatments for lung cancer—we used chemotherapy, which prolonged life by a matter of months. Since then, I've seen approaches including immunotherapy, targeted therapy, and oral drugs that block tyrosine kinase receptors [proteins on cells that can become overactive and cause cancer cells to grow], which make tumors shrink. Although some of these treatments only work for certain patients—those whose cancer has a molecular abnormality we are able to target with a specific drug—it’s still amazing.

We are also providing people undergoing treatment with a better quality of life. In the past, some patients would have needed to go to the hospital for chemotherapy infusions; now, many can take some of the newer drugs in pill form. These drugs can be taken at home and have less toxicity and fewer side effects than chemotherapy. So, that's been very important.

While these therapies can’t help everyone, they’ve helped raise the five-year survival for NSCLC to 28% overall. That figure includes numbers as high as 65%—for cancer that was limited to the tissue from where it originated at diagnosis—to as low as 9%— for cancer that had already spread beyond the lung to distant organs in the body. But these numbers are getting better every year.

A biomarker is a measurable characteristic in a cell that can identify an error [mutation] that could lead to cancer.

If a person diagnosed with lung cancer has a biomarker, it provides us with valuable information about the mechanism behind cancer growth, which can be a guide to more effective treatment. In NSCLC, we know of nine biomarkers, and about 20% of patients with this type of cancer are affected by one of these biomarkers.

That’s why we perform DNA sequencing on each tumor we diagnose—cancerous tissue obtained in a biopsy is examined to identify those errors. We look to see if the tumor has an oncogene [a gene with cancer-causing potential] that we’ve identified as a biomarker for NSCLC. Depending on what we find, we can offer specific therapies or clinical trials.

We tend to find biomarkers in light smokers and people who have never smoked, except when it’s found in a gene called KRAS—a mutation in KRAS is associated with about 12% of lung cancers and occurs in smokers. We also look for PD-L1, a protein and biomarker that keeps immune system cells from attacking healthy cells. Higher levels of PD-L1 on cancer cells usually portend that the immune system is more involved, so in this case, targeting the tumor with an immunotherapy treatment may be more effective.

Using this kind of information and complete staging—with the help of CT, MRI, and/or PET imaging scans to determine whether cancer has spread beyond the lung—we can personalize the treatment approach. We can then decide if surgery, radiation therapy, or a combination of these treatments with newer therapies might be most effective. So, it's personalized therapy based on the characteristics and stage of the tumor.

Targeted therapy works by killing specific cancer cells without causing harm to normal cells. For people with particular biomarkers, we have several targeted pills that, in many cases, can disrupt the growth and function of cancer cells. Since they don’t affect healthy cells like chemotherapy does, they don’t cause the same side effects.

One area in which targeted therapies are helping significantly is epidermal growth factor receptor (EGFR)-positive cancers, which account for 15% to 20% of patients with NSCLC—especially non-smokers and women. People with the EGFR mutation are especially responsive to treatment with therapies called EGFR tyrosine kinase inhibitors.

In 1997, I was involved in a clinical trial for a targeted therapy drug. I still remember patients with lung cancer who came in, appearing frail and in pain, and weeks later, they would be feeling better. It showed me that, if we give the right drug aimed at the right target at the right time, we can see amazing results. Now, when we use these agents early—after surgery, chemo, or radiation therapy—we often see profound results.

But one problem with targeted therapies is that, with time, the cancer will become resistant and start to grow again. This can happen immediately, or it can take 10 years or more. The idea is that if you have 100 cancer cells and 99 of them are susceptible to the oral drug, one is not. With the next round of replication, that one cell will have a survival advantage. With time, those resistant cells get larger, and then we have a tumor that's growing again and no longer susceptible to the treatment. And that means we move on to other treatments.

Yes, as good as the targeted therapies are, I would say immunotherapy has made a tremendous difference. This kind of therapy activates the body’s immune system to specifically kill cancer cells and is usually recommended for late-stage lung cancer.

Years ago, we would give patients chemotherapy knowing there was a 20% or less chance that they would respond, and the median survival was less than a year. Now, for some patients who are given immunotherapy, there may be a complete response.

Some of the earliest immunotherapy trials were done here at Yale 10 to 15 years ago, and we now have standard-of-care immunotherapy drugs. There are many different ones—specifically, checkpoint inhibitors [drugs that target “checkpoint” proteins that need to be switched on or off to activate an immune response]—that can be used to target NSCLC.

Immunotherapy reactivates the immune system to fight the tumor. In many patients, the tumor doesn't seem to recover from that. I've seen people 14 years after their lung cancer treatment with immunotherapy with no signs of recurrence. We see amazing results from these drugs in about 15% to 20% of patients, and this is great progress.

What’s more, if we identify a cancer early, and it's locally advanced—meaning it hasn't spread beyond the lungs, but the tumor is growing and there are lymph nodes involved—we can give immunotherapy before surgery.

Unfortunately, only a small percentage of patients have that great outcome, so we're trying to understand how we can help those patients who don’t. Either the drugs don't work from the very beginning, which happens in a small number of cases, or they don't bring about a complete response. So, many people will need something else at some point in their lifetime.

I wish I could say that chemotherapy was no longer part of NSCLC treatment, but we find that adding chemotherapy to immunotherapy or targeted therapies sometimes provides at least a synergistic benefit. So, we may use two therapies together.

Chemotherapy may shrink a tumor before surgery, kill any remaining cancer cells after surgery, or be the main treatment for locally advanced or metastatic NSCLC [meaning it has spread to other parts of the body]. A variety of chemotherapy drugs may be given, typically by injection or infusion of a single chemotherapy drug or combination of drugs.

We’ve also learned how to do a better job of providing chemotherapy; for instance, we can give patients antiemetics, which are anti-nausea drugs that work very well. And for lung cancer, we use rather mild chemotherapies and relatively low doses. But there will still be some side effects, and they can include hair loss, mouth sores, low blood counts, and nervous system issues.

The use of low-dose CT scan screening for lung cancer began in 2013. Eligibility was expanded in 2021 to anyone ages 50 to 80 who has a 20-pack-year smoking history (one pack-year is the equivalent of smoking an average of one pack per day for a year) and is currently smoking or has quit within the past 15 years, based on United States Preventive Services Task Force (USPSTF) recommendations.

The American Cancer Society recommends the same screening for anyone who is 50 to 80 years old and smokes or used to smoke, and has at least a 20-pack-year history of smoking.

Still, only 5% of patients who are eligible are getting screened. I urge anyone who is a former smoker or a current smoker who qualifies to have the screening done.

If an imaging test identifies a growth or lump, which may or may not be cancerous, it can lead to a biopsy—a procedure that involves going to the hospital for the removal and examination of a piece of lung tissue. This is how we can identify lung cancer early, which can change a person’s prognosis. Otherwise, the diagnosis usually starts with an incidental finding when someone has, for instance, a cardiac scan, or they go to the emergency room and have a scan for another reason.

But early diagnosis often means the tumor can be removed by surgery. The cancer can still spread, but in the early stages, we can consider a host of other therapies, including those we’ve been discussing—in addition to surgery. This is when there are fewer cancer cells present—and fewer cancer cells that are resistant. If there's one thing I've learned in my 30-year career, it is the value of using the best available therapies early.

A diagnosis of lung cancer is a scary thing. I've dealt with it with my own family and friends.

If you’ve been diagnosed, you want to know what the plan is as soon as possible. You want to know as much about that cancer as you can, as far as the genetic makeup and any biomarkers. And then, especially if it’s found early, you need to think of the best approach, because there may be different paths. For that reason, you should go to a place where you can be seen in a multimodality way—where the surgeon, the radiation oncologist, the medical oncologist, and other specialists are all there.

NSCLC has many treatment options, but it can be a complicated and long journey. I'd say we're still in the early stages of understanding this disease and knowing how to best treat it, but we are starting to see the light at the end of the tunnel.

At the same time, there are still too many people who succumb to this disease, so there are many things we still need to learn. In the meantime, early detection, early surgery, and early multimodality care at a comprehensive center like ours—all of these things are key to the best outcomes for anyone with this disease.