Participants found to have nodules at high risk of developing into lung cancer are randomized to either observation, the current standard of care, or treatment with the PD-1 inhibitor pembrolizumab.
The drug protects an immune response against tumors by blocking activation of the PD-1 checkpoint on T cells. To treat lung cancer, it’s given for two years, or until disease progression or side effects, mainly various types of inflammation, warrant discontinuance.
In this clinical trial, participants receive a total of four doses every three weeks over three months. “That dosage is based on the drug’s history in clinical trials. It’s a balance between efficacy and reducing the likelihood of toxicities,” Zhang says.
Zhang’s research on the spectrum of growths, ranging from precancerous nodules to fully invasive disease, show precancers are more vulnerable to immune attack than full-blown cancer, which is armored with a more complex array of genomic variations and creates an immunosuppressive environment.
Precancerous lung growths more vulnerable to immune attack
“Preneoplasia has a naïve molecular profile and stronger immune surveillance,” Zhang says, “so we have an opportunity kill these growths before they can evolve into advanced disease.”
The clinical trial is open to two classes of participant, both of whom are found to have precancerous nodules growing in their lungs: those who have never had lung cancer and those who’ve been treated for stage I disease.
After CT imaging identifies nodule growth over three months, researchers apply a risk algorithm developed by Brock University in Canada that takes into account such factors as age, family history, nodule size, location and number. Those found to be at high risk proceed to the clinical trial.
Early stage lung cancers can be treated with either surgery or radiation with curative intent. However, in addition to recurrence of the treated tumors, the risk of developing a second independent primary lung cancer goes up by 1% a year regardless of having lung nodules. Therefore, these patients are at much higher risk and may benefit from early intervention.
Another potential benefit from screening for this lung cancer prevention trial is to identify cancers earlier. When patients with lung nodules have high algorithm scores indicating the possibility of stage I disease, a biopsy is performed. Eight potential participants for this clinical trial have been found to have stage I lung cancer and proceeded to standard of care surgery or radiation.
The principal endpoint of the clinical trial is shrinkage of the high-risk nodules after six months. After that, participants receive standard of care follow-up. The main secondary endpoint is reduction of the incidence of lung cancer over three years.
“It is, of course, way too early to say whether treatment is working,” Zhang says. “But if it does work in this trial, it would lead to longer, larger, more definitive trials for lung cancer management and prevention.”
While targeted therapies and immunotherapy have benefited some patients with advanced disease, lung cancer remains the leading killer among cancers.
Preclinical research underpins immunotherapy clinical trial
Improved imaging technology has led to an increase in identifying precancerous nodules, either through CT scanning of past or current heavy smokers for lung cancer or as “incidentalomas” discovered via imaging for other injuries or diseases.
Standard of care for these growths in the United States is observation. As a result, little has been known about the molecular make up and immune surveillance of these growths – called indeterminate pulmonary nodules (IPN).
In some other countries, these IPNs are surgically removed. Zhang forged collaborations with colleagues in Japan and China to collect samples. He then led research to characterize their genomes and immune surveillance.
A paper describing the ever-greater genetic complexity from precancerous growth to full malignancy was published earlier this year in Nature Communications.
Despite their heavier tumor mutation burden, which provides abundant targets for immune attack, advanced lung cancers fashion an immunosuppressive microenvironment. Precancerous nodules, Zhang found, had greater penetration by T cells even with their simpler genomes.
Subsequent experiments in mouse models of precancerous nodules showed that anti-PD-1 immunotherapy decreased the incidence of lung cancer.