The Way of the Future for Treating Early-Stage NSCLC

For years, options for people living with non-small cell lung cancer (NSCLC) were limited, says Dr. Jamie Chaft, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City.

But as cancer therapies advance, treatments that were once out of reach for many patients with NSCLC have become available. A therapy that began its history as a last resort has slowly made its way into frontline settings, and researchers continue to discover novel treatments.

And each new discovery saves lives. One example of progress in lung cancer is the Food and Drug Administration’s (FDA’s) January approval of Keytruda (pembrolizumab) for patients with stage 1B, 2 or 3A NSCLC following resection and platinum-based chemotherapy. Keytruda is an immunotherapy drug that has been approved for a variety of cancers, including advanced (metastatic) lung cancer, but was only recently approved as a post-surgery, or adjuvant, therapy for patients with early-stage NSCLC who have also been treated with chemotherapy.

“This is clearly a very busy space,” Chaft says of NSCLC research. “Postoperative and preoperative spaces were stagnant for decades. And then, in the last 3 years, we’ve now seen some advances, (and) we can bring therapies proven to be beneficial for patients with metastatic cancer into the earlier stage.”

Mechanism of Action and Indications for Keytruda

Like all immunotherapies, Keytruda harnesses the power of the body’s natural immunity to kill cancer. Keytruda is a PD-1 inhibitor, meaning it blocks the production of a cell protein called PD-L1, which is involved in the proliferation of tumor cells and evasion of natural tumor immunity. By blocking PD-1, Keytruda allows the body’s immune system to attack tumors.

“(Keytruda) goes back about eight years at this point in terms of lung cancer,” explains Dr. Dwight H. Owen, a medical oncologist at The Ohio State University Comprehensive Cancer Center-The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute in Columbus. “At least for (NSCLC), the first approvals were only for stage 4 or metastatic disease — and only after previous treatment with chemotherapy.”

Although initial studies earned the drug approvals for use in patients with tumors expressing high levels of PD-L1, further research found that the drug could benefit patients with NSCLC regardless of their PD-L1 status.
This makes Keytruda the second immunotherapy to be approved as a post-surgical treatment in patients with earlier-stage NSCLC. The first, Tecentriq (atezolizumab), was approved in 2021, but that indication only applied to patients with PD-1 expression. One striking thing about Keytruda is that although it is a PD-L1 inhibitor, patients can receive — and benefit — from Keytruda regardless of their PD-L1 expression levels.

“The way that immunotherapy works is, it tries to reorient our own immune system to attack the cancer cells,” Owen explains. “In theory, our immune system should recognize cancer cells as bad actors. They’re not behaving the way that they’re supposed to; they’re growing when they’re not supposed to. So they should be recognized by the immune system, which should attack and
kill them. Some cancers develop a camouflage to protect cancer cells from the immune system. And what these immune drugs do is essentially remove the camouflage, allowing the immune system to recognize, engage, destroy and then remember what those cancer cells look like to go on and destroy other cancer cells.”

What makes the use of immunotherapy important in patients with early-stage NSCLC is that early treatment offers the best chance of a cure.

“Over the last few decades, we’ve realized that surgery alone is curative for some patients with early-stage lung cancer but not nearly as many as we hope,” Owen says. “The reason for that is almost certainly because there is still ‘microscopic’ or ‘micrometastatic’ disease left behind.”

This is when the use of adjuvant therapies that get rid of any remaining tumor cells becomes crucial.

“Taking what we know from metastatic disease from patients who get treated with immunotherapy, we know that when immunotherapy works, it works even better than chemotherapy,” Owen says. “And that’s why we’ve been very excited to see immunotherapy come in earlier into the disease to be able to cure more patients.”

The FDA based its approval of Keytruda for use in early-stage NSCLC on findings from the KEYNOTE-091 trial, which included 1,177 patients with completely resected lung cancer with disease stages ranging from stage 1B to 3A. Investigators in the phase 3 study randomly assigned patients to receive either 200 milligrams of Keytruda or placebo by IV once every 3 weeks for as many as 18 cycles. Most patients (86%) also received platinum-based chemotherapy after their surgeries.

Investigators reported that patients assigned to Keytruda had a median disease-free survival that was nearly a year longer than that of patients assigned to placebo: 53.6 months in the Keytruda group compared with 42 months in the placebo group. This means that patients assigned to take Keytruda after surgery and platinum-based chemotherapy were disease free for 11.2 months longer than those who received placebo following surgery and chemotherapy.

Dr. Michael Rotkowitz, a medical oncologist with Jefferson Health in Sewell and Cherry Hill, New Jersey, notes that the drug’s improvement in disease-free survival is particularly important.

“What we know historically is that for stage 2, 3A and even stage 1, the recurrence risks after surgery are over 50%,” Rotkowitz says. “The KEYNOTE-091 trial shows a reduction in recurrence risk — a marked disease-free survival benefit. I think this will be practice changing.”

Although a small minority of patients included in the study did not undergo platinum-based chemotherapy, those who did receive chemotherapy appeared to fare significantly better than those who did not.

Using both chemotherapy and immunotherapy appeared especially effective. In KEYNOTE-091, the median length of disease-free survival for patients who underwent platinum-based chemotherapy and were assigned to Keytruda was reported at 58.7 months compared with 34.9 months among patients who underwent chemotherapy but were assigned to placebo.

There were some limitations in the KEYNOTE-091 study. For one, experts were quick to point out that because it was designed several years ago, it makes use of a cancer staging system that is now out of date. By the current staging system, patients in the KEYNOTE trials would all be considered to have disease in stages 2 to 3.

Additionally, one subgroup of patients expected to benefit most from the therapy did not. “The (Keytruda) data showed improvement of disease-free survival irrespective of PD-L1 expression,” says Chaft. “Though oddly, it showed that patients with tumors that did not highly express PD-L1 did not benefit as much.”

Chaft added that she suspects this data point was a statistical anomaly rather than an indication of the drug’s true therapeutic benefit in this subset of patients.

Limitations and Side Effects

Patients should be aware that Keytruda does come with side effects, although oncologists consider the drug to generally be well tolerated. Most commonly, patients taking Keytruda by itself have experienced nausea, fatigue, muscle and joint pain, rash, constipation, diarrhea, itching, decreases in appetite, fever, coughing and hypothyroidism, a condition in which the thyroid gland produces lower quantities of thyroid hormone than it should.

“The caveat is that anytime you escalate treatment, you are increasing the risk of side effects,” Owen says.

In the KEYNOTE-091 trial, hypothyroidism reportedly occurred in 22% of patients, whereas hyperthyroidism, or an overactive thyroid gland, occurred in 11%. Furthermore, 7% of patients reportedly experienced more severe organ inflammation including pneumonitis, or inflammation of lung tissue. Two patients in the study died of myocarditis (inflammation of the heart).

n general, Chaft says immunotherapies are very well tolerated but says that doctors considering Keytruda for patients with early-stage NSCLC should do so on a case-by-case basis.

“We certainly don’t want to harm patients by trying to increase their chances of a cure,” she explains. “Many of these patients are cured already, either by the surgery or the chemotherapy. Looking at the patient as a whole, what is their likelihood to benefit from the immunotherapy versus harm?”

Chaft and Owen also point out that people with certain genetic alterations, such as those with EGFR and ALK tumor aberrations, are more likely to benefit from treatments targeting those mutations rather than Keytruda.

“If their tumors are driven by one of these genetic alterations, they’re not likely to gain benefit (from Keytruda) and would be more appropriately directed toward a targeted therapy,” says Chaft.

Another important factor for doctors considering Keytruda in this setting is whether the patients have any autoimmune diseases, Chaft notes. In this situation, she says, Keytruda should be avoided.

Unmet Needs and the Future of NSCLC Treatment

Cancer treatments continue to evolve, particularly in the area of immunotherapy. Rotkowitz pointed out that more and more often, patients receive chemoimmunotherapy before surgical resection, even as adjuvant therapies advance.

“There’s been a huge push toward chemo-immunotherapy before surgery, and those patients get chemotherapy with (the immuno- therapy drug) Opdivo (nivolumab),” he says. “On the other side, there’s been a huge emphasis on moving (therapies) to the front line.”

Chaft agrees.

“Considering preoperative chemoimmunotherapy really may be the way of the future,” she says.

Regulatory approval and the release of new data have already begun to reflect this trend. The FDA in March 2022 approved Opdivo combined with platinum-doublet chemotherapy as a neoadjuvant (presurgical) treatment in early NSCLC.

Keytruda also recently made headlines for another NSCLC study, in which Keytruda plus chemotherapy followed by surgery and post-surgical treatment with Keytruda improved event-free survival (the time after treatment ends that a patient is free from complications or events that treatment aims to prevent
or delay) in patients with stage 2, 3A and 3B NSCLC.

Chaft notes that in the coming year, data from two additional studies of immune checkpoint inhibitors also will become available, adding to the growing body of evidence and treatment options for immunotherapy in lung cancer.

Chaft was also an investigator on a recent study of adjuvant Opdivo.

Additional research is also being done in the metastatic setting, with immunotherapy as well novel targeted therapies, says Rotkowitz. Investigators are evaluating options like CAR-T (cell-based) therapy and anti-CLTA-4 (another immune checkpoint like PD-L1) agents.

Real progress continues at a rapid pace.

“There’s a tremendous amount of research going on,” he says. “A tremendous amount of innovation.”

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