ROUGHLY 20% TO 25% OF PEOPLE diagnosed with non-small cell lung cancer (NSCLC) will receive surgery and chemotherapy to treat their disease. People with this type of cancer may receive neoadjuvant treatment, using chemotherapy to help shrink the cancer prior to surgery, or adjuvant chemotherapy, which is administered after surgery to ensure all traces of cancer are gone. Even with chemotherapy and surgery, approximately 30% to 55% of people with NSCLC will experience a lung cancer recurrence.

Several studies have found that adding a type of immunotherapy known as immune checkpoint inhibitors (ICIs) before or after surgery for NSCLC extends the time patients live without the disease coming back—which has expanded immunotherapy use, once indicated only for patients with advanced-stage lung cancer, to people who have early-stage NSCLC.

An analysis published Aug. 10, 2023, in the New England Journal of Medicine showed people with stage II and III NSCLC who received the immunotherapy drug Keytruda (pembrolizumab) before and after surgery—an approach known as perioperative therapy—lived longer without a disease recurrence. In the study, almost 800 patients received up to four cycles of a chemotherapy drug with either Keytruda or a placebo before surgery, followed by up to one year of Keytruda or a placebo. In the study, 62% of patients in the Keytruda group survived without disease recurrence at two years, compared with 41% in the placebo group. In addition, 18% of patients in the Keytruda group had a pathological complete response, meaning there were no signs of cancer in surgically removed tissue where the cancer had been, compared with 4% for the placebo group. On Oct. 16, 2023, based on results from this trial, called KEYNOTE-671, Keytruda was approved as a perioperative treatment for early-stage NSCLC—the latest in a series of Food and Drug Administration (FDA) approvals that have incorporated immunotherapy before and after surgery to fend off NSCLC.

Keytruda and other immune checkpoint inhibitors, such as Tecentriq (atezolizumab), have already been approved to treat early-stage NSCLC after surgery. In addition, the FDA approved the immunotherapy drug Opdivo (nivolumab) with chemotherapy before surgery for people with early-stage NSCLC in 2022, after a study found those who took immunotherapy lived without disease recurrence for a median of 31.6 months. The median time to recurrence in the group that received chemotherapy alone before surgery was 20.8 months. As a result of these findings and others, ICIs are currently a standard of care for early-stage NSCLC that expresses PD-L1, says Heather Wakelee, the KEYNOTE-671 study lead author and a thoracic oncologist who specializes in lung cancer at Stanford Medicine in California. PD-L1 is a biomarker that suggests cancer is more likely to respond to immunotherapy. Wakelee notes her research also shows the benefit of ICIs for patients whose cancer does not have high levels of PD-L1 expression.

“The KEYNOTE-671 regimen seems to work for many patients even with low or no PD-L1 expression, but we know that with higher PD-L1 expression, the probability of any ICI therapy working is higher,” Wakelee says.

Medical oncologist Anna Minchom, team leader at the Institute of Cancer Research in London who was not involved with the study, notes the timing surrounding immunotherapy interventions—whether before surgery, after or both—is still an open question, but she is encouraged by the number of studies that show the benefit of using ICIs.

“There are advantages to giving neoadjuvant treatment compared to adjuvant, in theory, because you can give it for a short period of time and you can help shrink the cancer down so that the surgeon’s job is easier,” Minchom says. “There are advantages for giving adjuvant because you’re giving it after the surgery so you have less concern about causing side effects and a delay in surgery, which might happen with neoadjuvant treatment.” Delaying surgery for immunotherapy can come with risks if the cancer doesn’t respond to treatment and spreads, especially if it means the patient no longer qualifies for surgery.  In addition, adjuvant treatment has the potential to be prolonged, which can have a negative impact on a person’s quality of life.

Wakelee suggests patients with early-stage NSCLC who are candidates for surgery talk with their doctors about whether they would benefit from immunotherapy. Some patients, including those who have autoimmune dysfunction, may not be able to take immunotherapy. Patients who have never smoked appear to derive less benefit from Keytruda than those who formerly smoked or currently smoke. Wakelee says that patients with NSCLC should receive tumor testing to check for PD-L1 expression as well as driver mutations, such as EGFR mutations or ALK translocations that could make patients eligible for targeted therapies.

“Any patient with stage II or III NSCLC should have their case discussed at a tumor board or by a panel of experts in medical oncology, thoracic surgery and radiation oncology and have the PD-L1 results and molecular results [for the treatment team and patient] to make the best individual decision,” Wakelee says.