Immunotherapy has emerged as a major therapeutic breakthrough in the treatment of non-small-cell lung cancer (NSCLC), and three drugs are now approved for second-line use.
All three interact with the programmed cell death (PD) pathway, but two of the drugs (nivolumab, Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck & Co) are PD-1 inhibitors, while the third (atezoluzimab, Tecentriq, Genentech/Roche) is a programmed death-ligand 1 (PD-L1) inhibitor. But does this subtle difference in mechanism of action translate into clinical differences between the drugs?
It may, suggests David R. Gandara, MD, director of the Thoracic Oncology Program at UC Davis Comprehensive Cancer Center, Sacramento, California, who was the principal investigator of the atezolizumab pivotal trial used for the drug's approval. The study, known as OAK, was published December 12 in The Lancet. It was reported a few months earlier at the European Society for Medical Oncology (ESMO) Congress in Denmark.
"In contrast to PD-1-directed agents [such as pembrolizumab and nivolumab], PD-L1 agents block the interaction of PD-L1 with PD-1 and B7-1, potentially augmenting tumor-specific T-cell immunity and contributing to therapeutic response in a patient population with low mutational load, such as never-smokers with lung cancer," Dr Gandara told Medscape Medical News.
Patients with tumors expressing high levels of PD-L1 (50% or more PD-L1 expression on tumor cells or 10% or more on tumor-infiltrating immune cells) got the most benefit from atezolizumab.
"In the group with highest PD-L1 expression, the HR [with atezolizumab] was 0.41, quite an extraordinary benefit," Dr Gandara said in an interview.
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Ongoing phase 3 trials are looking at the addition of atezolizumab to chemotherapy with or without the antiangiogenic agent bevacizumab (Avastin, Genentech U.S.) in first-line therapy, Dr Gandara told Medscape Medical News. "If these trials prove positive, they will offer new therapeutic options to large numbers of patients with advanced NSCLC."
OAK Study Details
The international randomized OAK study was conducted in 194 centers ( 31 countries) among 1225 patients with advanced, previously treated NSCLC, who were randomly assigned to receive atezolizumab 1200 mg or docetaxel 75 mg/m2 every 3 weeks.
The primary efficacy analysis, carried out in the first 850 of 1225 enrolled patients, showed that the immunotherapy significantly improved overall survival compared with chemotherapy (median overall survival, 13.8 months vs 9.6 months; HR, 0.73; P = .0003).
The improvement in median overall survival was nearly 4 months, which is slightly more than has been seen in the pivotal trials with the PD-1 inhibitors, when also used second-line and also compared with docetaxel chemotherapy. The authors note that nivolumab has shown a median overall survival of 9.2 months vs 6.0 months (HR, 0.59) in squamous NSCLC and 12.2 months vs 9.4 months in nonsquamous NSCLC, while pembrolizumab has shown a median overall survival of 10.4 months vs 8.5 months (HR, 0.71) at the approved dose of 2 mg/kg in a patient population with NSCLC who expressed PD-L1 in 1% or more of tumor cells.
Atezolizumab reinvigorates patients' immune systems against cancer, and our trial has shown that this has significant results for their survival," lead author Achim Rittmeyer, MD, from the University Goettingen in Germany, said in a statement.
The improved survival benefit was seen regardless of the patient's age, disease histology, or PD-L1 expression status, the authors note.
"Atezolizumab is the first checkpoint inhibitor to provide an overall survival benefit in patient populations who are historically less responsive to these agents, including patients with low or non-detectable levels of PD-L1 expression and never smokers," Dr Rittmeyer and colleagues said.
"Our results affirm that not only the PD-1 receptor but also the ligand components (eg, PD-L1) of the pathway are valid targets for the treatment of lung cancer," they added.
Atezolizumab also has a better safety profile than docetaxel, with a rate of immune-mediated adverse events, including pneumonitis, of less than 2%.
In patients receiving atezolizumab, 14.8% had treatment-related grade 3 or 4 adverse effects and 7.6% had to discontinue treatment.
In patients who received docetaxel, 42.7% had grade 3 or 4 adverse effects and 18.7% had to stop treatment.
One death was reported in the docetaxel group following a respiratory tract infection.
Will Immunotherapy Replace Chemo?
So, will immunotherapy replace chemotherapy in the treatment of NSCLC?
"Maybe…but not immediately," suggest a pair of experts who authored an accompanying editorial, Charlotte Leduc, MD, and Elisabeth Quoix, MD, from the Department of Pneumology at University Hospital in Strasbourg, France.
In an email response to a question about their editorial, Dr Quoix wrote to Medscape Medical News that her answer would be: "The editorialists say 'yes' to atezolizumab as a potential second-line therapy, and 'yes' to the need for more research into the use of checkpoint inhibitors before using them as first line."
Since the 1980s, platinum-doublet chemotherapy has been the standard of care for first-line therapy in advanced NSCLC cancer, "which means in about 85% of white patients," Dr Quoix and Dr Leduc note. Median overall survival is limited to about 8 to 12 months.
Standard-of-care chemotherapy with docetaxel carries a median survival of about 8 months but "at the cost of substantial toxicities," they point out, adding that results with immune checkpoint inhibitors have been positive in all previous trials.
They note that PD-1 inhibitors "have already shown their superiority as second-line therapy compared with chemotherapy, in squamous and non-squamous cell carcinomas with nivolumab, or in patients who have a high level of PD-L1 expression with pembrolizumab."
Despite this, Dr Quoix and Dr Leduc emphasize the importance of remembering patients who may not be candidates for checkpoint blockers, including those with untreated brain metastases, active autoimmune disease, an Eastern Cooperative Oncology Group performance status of 2, or those taking steroids.
More clarification is also needed about optimum treatment schedules and treatment duration, they say. "Combinations of different immunotherapies might also be of interest."
Dr Quoix and Dr Leduc also call for a search "to find a more specific and powerful predictive biomarker, especially in patients with low or undetectable PD-L1 expression.
"The fact that even patients with low or undetectable PD-L1 expression in their tumours might benefit from atezolizumab confirms the imperfection of this biomarker," they say. "It would be unthinkable and unethical to deprive these patients of immunotherapy, even if the overall response rate and the survival benefit are lower than for patients with higher PD-L1 expression."
Funding for this study was provided by F. Hoffmann-La Roche Ltd and Genentech Inc. Dr Gandara reports relationships with Bristol-Myers Squibb, Genentech, and Merck. Six coauthors are Genentech employees, and several others report relationships with pharmaceutical companies. Dr Quoi was an investigator in an immune checkpoint blocker trial for Merck, Bristol-Myers Squibb, and Astra Zeneca. She was also a coinvestigator in the BIRCH phase 2 trial of atezolizumab conducted by Roche. Dr Leduc has disclosed no relevant financial relationships.
Lancet. Published online December 12, 2016.1>