Finally Some Progress For Esophageal Cancer Patients New Immunotherapy Drugs Are Boosting Survival

Esophageal cancer is a disease that causes cancer cells to form in the tissues of the esophagus, a hollow, muscular tube that food and liquid move through when traveling from the throat to the stomach. The wall of the esophagus is made of up several layers of tissue; cancer begins on the inside lining and spreads to the outer layers of the esophagus as it grows. It can be very difficult to treat because in many cases, the disease is diagnosed at a later stage.

Esophageal cancer isn't as common as breast or prostate cancer, but it tends to have a worse prognosis. "Esophageal cancer, we know is a tough one," Dr. Brendon Stiles, a thoracic surgeon at Montefiore Medical Center, told SurvivorNet. "It's one of the cancers with some of the lowest cure rates out there, but like many cancers, if we find it early, we can often treat it effectively."

Patients with advanced esophageal squamous-cell carcinoma (ESCC) who receive first line chemotherapy (meaning they were treated with chemo first) have poor overall survival with the median survival of less than 1 year. Incorporating immune checkpoint inhibitors, such as Nivolumab or Ipilimumab, into that initial treatment might help extend survival. Physicians usually refer the initial treatment as first-line treatment or first-line therapy. This treatment is usually what worked best in clinical trials for people with the same type and stage of cancer. How well your treatment works often varies. Your first-line treatment may not work, may start but then stop working, or may cause serious side effects. Your doctor may then suggest a second-line treatment, also called second-line therapy.

"Immunotherapy is here to stay. And it’s really changed the face of cancer,” Dr. Stiles says.

The currently FDA-approved immunotherapy options for ESCC are:

• Pembrolizumab (Keytruda®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; Keytruda is approved for patients with advanced esophageal that have high levels of PD-L1 expression.
• Nivolumab (Opdivo®): is also a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; but it can be used regardless if they have the PD-L1 protein.
• Ipilimumab (Yervoy®): in May 2022, the United States FDA approved nivolumab, in combination with either chemotherapy or ipilimumab, for the initial treatment plan of patients with advanced or metastatic esophageal SCC, regardless of PD-L1 expression.

How effective are these medications?

An important trial demonstrated that pembrolizumab can improve overall survival in 5 months for patients with previously untreated, advanced ESCC as long as they have high levels of PD-L1 expression. The study was performed by comparing two groups:  one received placebo plus chemotherapy and the other received pembrolizumab plus chemotherapy. At the end of the trial it was confirmed that patients who received pembrolizumab had a longer survival rates and there were no new safety signals, and rates of severe adverse events were similar with and without pembrolizumab.

The FDA approval for nivolumab and ipilimumab came after a study demonstrated that these new drugs improved overall survival in up to 6 months, if compared to patients receiving chemotherapy alone.

About the study

In the Checkmate 648 trial, 970 adults with previously untreated, advanced unresectable, recurrent, or metastatic ESCC regardless of PD-L1 expression were randomly assigned to nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy alone.

Patients receiving nivolumab plus chemotherapy had a significantly longer median overall survival compared with chemotherapy alone (13.2 versus 10.7 months). And patients receiving nivolumab plus ipilimumab also had a significant overall survival benefit compared with chemotherapy alone (12.7 versus 10.7 months).

Patients who had high PD-L1 expression (≥1%) were the ones who had the most benefits. The group that received nivolumab plus chemotherapy had a significantly longer median overall survival compared with chemotherapy alone (15.4 versus 9.1 months)

What is Immunotherapy?

The immune system uses its white blood cells to attack cells in the body that are abnormal or foreign. Cancerous cells have the ability to prevent the immune system from doing its job. The cancer produces certain proteins to protect the tumor from white blood cells. As a result, the body does not recognize the tumor as abnormal. Immunotherapy drugs stop this from happening and ensure the white blood cells recognize the cancer cell properly and attack it. The cancer cells themselves are not necessarily difficult to fight. However, they continue to divide rapidly. So, immunotherapy drugs help a patient's immune system control their cancer on its own before it can spread.

"Immunotherapies are being tested not only in metastatic patients, but also in earlier settings combined with chemotherapy," Dr. Mehta tells SurvivorNet. "These immunotherapies have a survival benefit."

Dr. Steven Rosenberg, Chief of Surgery at the National Cancer Institute, explains how immunotherapy works.

What are checkpoint inhibitors and how do they work?

Simply put, checkpoint inhibitors are a class of immunotherapy drugs that specifically target proteins found either on immune or cancer cells to prevent their binding together. The advent of checkpoint inhibitors in treating cancer is that it doesn't kill cancer cells directly, but it stimulates the immune system to find the cancer cells and attack them while hopefully not affecting other surrounding healthy cells.

Checkpoint inhibitors work on the background knowledge that the immune system can protect our bodies by getting rid of any foreign cell that isn't produced in the body. It sets out to do this by identifying specific proteins (also known as checkpoint proteins) that are only found on normal cells; when it finds them, it binds to this cell to mark it as safe and leave it be.

However, sometimes cancer cells can trick the immune system by displaying these same proteins and bind to the immune cells, switch them off and start to divide and reproduce, which manifests in the onset of cancer.

Nevertheless, checkpoint inhibitors can help with this by specifically targeting these proteins found on normal or cancer cells to prevent this binding and keep the immune cells alert to any foreign cells to be able to find and stop cancer cells.

PD-L1 and PD-1 inhibitors

PD-L1 is a protein found on cancer cells while PD-1 is a protein found on normal cells. When they bind to each other, the immune system fails to recognize the cancer cell and switches off its defense mechanism marking the cancer cell as a normal cell. Between 40% and 50% of people with esophageal cancer have this protein,

Antibodies that target PD-L1 on cancer cells play a critical role in preventing the binding between normal and cancer cells (PD-L1 and PD-1) which activates the immune system (specifically T-cells) to recognize the cancer cell and stimulate an immune response.

Examples of PD-1/PD-L1 inhibitors are: Pembrolizumab (Keytruda) and Nivolumab (Opdivo).

CTLA-4 inhibitor

Similarly, CTLA-4 is an immune checkpoint found on T-cells, so by inhibiting the binding process, it switches on the immune system to find and attack cancer cells. Ipilimumab is a CTLA-4 inhibitor that was recently approved by the FDA for treating esophageal squamous-cell carcinoma.

Are You a Good Candidate for Immunotherapy?

"Once you do get diagnosed, ask what's the stage," Dr. Stiles said. "Patients should never be afraid to push doctors and say, 'What are the treatment options at my stage? Do I need multi-modality therapy?' That means therapy with more than just surgery or more than just radiation with chemotherapy."

To determine if immunotherapy is the right treatment option for you, here is what will happen:

• Your doctor will likely test your tumor's PDL-1 level when you have a biopsy. If your tumor has a high PDL-1 level, you may be able to get pembrolizumab plus chemotherapy. It can be used to treat locally advanced (meaning it has spread into nearby tissues) or metastatic (meaning it has spread to distant organs) squamous cell esophageal cancer.

• The results of a PDL-1 test are sometimes reported as a score, which represents the percentage of cancer cells that test positive for PDL-1. The higher your score, the more likely that immunotherapy is a good treatment approach for you.

Your doctor might consider pembrolizumab even if you have low PD-L1-expressing ESCCs, especially in younger patients. But it’s important to emphasize the uncertainty of benefit, potential toxicity, and financial cost.

What makes this new approval different than fellow immunotherapy drug Keytruda (pembrolizumab), which was approved by the FDA last year for ESCC patients with the PD-L1 protein, is that patients will be able to access Nivolumab (Opdivo) for treatment regardless of if they have the PD-L1 protein.

The Potential for Side Effects

Chemotherapy side effects, such as nausea and hair loss, can be tough but they are fairly predictable by now. Checkpoint inhibitor side effects are a bit trickier to predict.

Dr. Mohana Roy, clinical assistant professor at Stanford University School of Medicine, tells SurvivorNet that about nine out of every ten of her patients feel fine on these medications. "The 10 percent is where we run into trouble," she adds. The most common side effects include the following:

• Fatigue
• Rashes
• Diarrhea
• Weakness
• Headache
• Impaired thyroid function

The biggest worry is that by unleashing the body's immune system, this treatment might trigger damaging inflammation. Essentially, your body could start to attack its own organs, which can be a major issue. If this happens, the side effects are often irreversible and you may have them for life.

"You do not know who it will affect and who it will not," Dr. Roy says. "When I start someone on immunotherapy, I say, 'Anything weird, I need to know about it.'"

If you suffer from baseline autoimmune problems, you might have a flare-up of your condition. You should carefully discuss with your doctor how to use these drugs safely.

Living With Esophageal Cancer

Esophageal cancer is more commonly diagnosed in men, who stereotypically have a more difficult time asking for help when they are struggling mentally.

"The esophageal cancer population is a unique population," Dr. Raja Flores, a thoracic surgeon with Mount Sinai Health System, told SurvivorNet. "Many of the people who develop esophageal cancer are men who are taking care of their families, who are proud, who are strong, who are self-reliant. So when they get faced with this diagnosis and this real vulnerability, they get depressed in a way that can make them crawl up in bed and not want to get outand that's when the family comes into play."

Dr. Flores stressed the importance of having a good support system in place. Having close friends or family members there to rally for you when you feel the lowest can make a huge difference in how a patient handles treatment.

Questions to Ask Your Doctor

• How aggressively should we treat my cancer?
• Am I eligible to receive immunotherapy? Am I more, or less, likely to respond to this treatment?
• What is my tumor's PDL-1 level?
• If I my tumor’s PDL-1 level is ≥ 1%, will it change the course of my treatment?
• What are the most common side effects of immunotherapy?

Learn more about SurvivorNet's rigorous medical review process.

---