After causing a sensation at the recent European Society for Medical Oncology (ESMO) meeting, the new data for pembrolizumab (Keytruda, Merck & Co) in the first-line treatment of non-small cell lung cancer (NSCLC) have now secured an approval from the US Food and Drug Administration (FDA).
Pembrolizumab is now the first immunotherapy to be approved for first-line use in NSCLC and is expected to change practice, experts said at the meeting. Up to now, a chemotherapy doublet has been the standard of care, except in patients with NSCLC who have targetable mutations (EGFR or ALK).
Several immunotherapy agents are already approved for second-line use in NSCLC, among patients who have stopped responding to chemotherapy, but pembrolizumab is the only agent approved in the first line.
The new indication restricts the use of pembrolizumab to patients with NSCLC who do not have EGFR or ALK genetic tumor abnormalities (found in about 20% of NSCLC cases) and whose tumors have high programmed death ligand-1 (PD-L1) expression (tumor proportion score of 50% or more), as determined by an FDA-approved test. (In the pivotal clinical trial, this was found in about 30% of screened patients with NSCLC and without mutations.)
Superior to Chemo
The approval for the new indication is based on results showing that pembrolizumab was superior to chemotherapy in the first-line setting.
These results come from the phase 3 KEYNOTE-024 study, which was presented at a presidential session at ESMO and simultaneously published in The New England Journal of Medicine (NEJM).
This study was conducted in 305 patients with advanced NSCLC who hadn't yet received treatment and whose lung cancer biopsy specimens showed no targetable mutations (EGFR or ALK) and showed high expression of PD-L1.
In this patient population, pembrolizumab alone had results superior to those of a platinum-containing doublet chemotherapy: median progression-free survival times were 10.3 vs 6 months (hazard ratio [HR], 0.50), respectively.
The secondary endpoint of overall survival (OS) was also significantly improved with pembrolizumab. OS at 6 months was 80% vs 72% (HR, 0.60) and 1-year OS was 70% vs 54%.
The significant reduction in risk for death (by 40%) was "remarkable" because it was seen despite a high crossover rate (50%), commented lead investigator Martin Reck, MD, chief oncology physician, Lung Clinic, Grosshansdorf, Germany. He was referring to the patients in the chemotherapy group who were given pembrolizumab upon disease progression.
Pembrolizumab also showed a higher overall response rate (45% vs 28%) and a longer response duration (median, not reached for pembrolizumab vs 6.3 months with chemotherapy).
Toxicity was lower with immunotherapy compared with chemotherapy (grade 3/4 adverse events: 27% vs 53%), and the incidence of all adverse events was lower with immunotherapy.
Experts at the ESMO meeting reacted to the new results with enthusiasm, and several suggested that pembrolizumab should be considered a new option, and a new standard of care, in the first-line treatment of NSCLC.
"For the first time, we will be offering immunotherapy first line to our lung patients," commented Stefan Zimmerman, MD, from the University Hospital in Lausanne, Switzerland. The landmark trial showed that pembrolizumab offers better efficacy and lower toxicity than chemotherapy, he said.
"This study may change practice for the treatment of patients with advanced NSCLC. It is the first time a therapy has improved progression-free survival over the current standard first-line treatment with platinum-based doublet chemotherapy," commented Johan Vansteenkiste, MD, PhD, from University Hospitals, Leuven, Belgium.
Discussing the results, Jean Charles Soria, MD, PhD, from Gustave Roussy Institute, Villejuif, France, agreed. "We have probably got a new standard of care," he said, but he questioned how many patients would be candidates.
The researchers said that about 30% of NSCLC tumors show the PD-L1 expression of 50% or greater that was used as the cutoff in this trial. However, this trial also excluded patients who had brain metastases and autoimmune conditions, as well as those taking steroids, he said, so the patients in this trial probably represent only 10% of the patients seen in clinical practice.
In addition, several experts highlighted the fact that for patients with EGFR or ALK mutations, targeted agents directed at these mutations remain the treatment of choice.
In an NEJM editorial that accompanied the study results, Bruce E. Johnson, MD, from Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts, noted that patient populations who benefit from the two different approaches — targeted therapy and immunotherapy — are quite different.
Most patients in KEYNOTE-024 with pembrolizumab as first-line therapy were men, more than 90% were current or former smokers, and approximately 20% had squamous lung cancer.
In the trials of targeted agents used as first-line treatment, about 90% of the three oncogenic drivers (EGFR mutations or ALK or ROS1 rearrangements) were found in patients with adenocarcinomas, and most of those patients were women and had never smoked.
All Patients With NSCLC Must Be Tested
Reacting to the new findings at the ESMO meeting, Corey Langer, MD, from the University of Pennsylvania, Philadelphia, said that a key point is that all patients with newly diagnosed NSCLC should have biopsy samples tested for mutations and PD-L1 expression status and that "this testing should be done reflexively, as these patients cannot wait."
Patients with tumors showing mutations (as mentioned above, about 20% of all NSCLC cases) should be treated first line with targeted agents, and those with high PD-L1 expression (about 30% of the remaining 80%) should receive immunotherapy with pembrolizumab, he suggested.
For the remainder, chemotherapy remains the standard of care.
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Cite this: Pembrolizumab Approved in US for First Line in NSCLC - Medscape - Oct 25, 2016.
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