Edward B. Garon, MD
It has been about 18 months since the first immunotherapy checkpoint agent was approved for patients with non–small cell lung cancer (NSCLC). Now there are 3 monoclonal antibodies that target the PD-1/PD-L1 pathway on the market for the tumor type and the focus has shifted rapidly to establishng immunotherapy as a new frontline standard.
Pembrolizumab (Keytruda) scored a big victory in that battle on October 24 when the FDA approved the PD-1 inhibitor for the frontline treatment of patients with metastatic NSCLC whose tumors show ≥50% PD-L1 expression based on an FDA-approved test and who do not harbor EGFR or ALK aberrations.
The decision opens the door to immunotherapy as initial treatment for approximately one-quarter of patients diagnosed with advanced lung cancer, according to Edward B. Garon, MD, whose research has been critical to the development of pembrolizumab.
“It is exciting to have an expanded group of patients who are now eligible for this drug,” Garon, who is director of Thoracic Oncology at the Jonsson Comprehensive Cancer Center at UCLA, said in a statement.
The FDA’s ruling came just weeks after research presented at the 2016 ESMO Congress demonstrated that single-agent pembrolizumab reduced the risk of death by 40% compared with doublet chemotherapy for previously untreated patients with NSCLC with PD-L1 expression on ≥50% of cells, called a tumor proportion score (TPS).1,2
Pembrolizumab, which the FDA initially approved in a second-line setting in October 2015 on an accelerated basis, also gained full approval status for patients with NSCLC and a TPS of ≥1% who have progressed on platinum-based chemotherapy and targeted therapy, if appropriate, according to Merck, which is developing the drug.
The new indications for pembrolizumab come amid continuing research into the 2 rival agents as potential frontline therapies, as evidenced by findings presented during the 2016 ESMO Congress and ongoing clinical trials.
Nivolumab (Opdivo) initially was approved in March 2015 for patients with metastatic squamous NSCLC following progression on or after platinum-based chemotherapy. That indication was expanded to include nonsquamous tumors in October 2015.
However, nivolumab missed the primary endpoint of improving progression-free survival (PFS) compared with standard chemotherapy in patients with PD-L1 positive NSCLC in the front line.3
The PD-1 inhibitor, which was approved without any requirement for PD-L1 expression, remains under investigation in a phase III frontline trial that randomizes patients by PD-L1 level.
Atezolizumab (Tecentriq) entered the frontline race on October 18, when it became the first PD-L1 inhibitor approved in NSCLC. The FDA granted an indication for patients with metastatic disease with progression during or following platinum-containing chemotherapy or targeted therapy if appropriate, regardless of PD-L1 expression levels.
The approval came on the heels of a strong showing at the 2016 ESMO Congress, where atezolizumab was reported to have reduced the risk of death by 26% compared with docetaxel in previously treated patients.4
The agent is being evaluated for chemotherapy-naïve patients in several phase II and phase III trials.
The following is a summary of key findings for each of the agents:
Pembrolizumab findings in the KEYNOTE-024 trial have been hailed as practice changing.1
The study screened 1934 patients with NSCLC for eligibility, of which 1653 yielded appropriate tissue for testing. Overall, 30.2% of samples expressed PD-L1 on ≥50% of cells by immunohistochemistry. Patients with EGFR- or ALK-positive tumors were excluded.
Of those who met the PD-L1 expression requirements, 305 were randomized to receive pembrolizumab (n = 154) or chemotherapy (n = 151), which most commonly included carboplatin plus pemetrexed (n = 67). In the chemotherapy arm, 46 patients went on to receive maintenance therapy with pemetrexed and an additional 66 patients (43.7%) crossed over to the pembrolizumab arm following progression.
The estimated 6-month overall survival (OS) rate was 80.2% with pembrolizumab versus 72.4% with chemotherapy (HR, 0.60; 95% CI, 0.41-0.89; P
= .005). The median PFS was 10.3 months with pembrolizumab versus 6.0 months with chemotherapy (HR, 0.50; 95% CI, 0.37-0.68; P
<.001). Fewer treatment-related adverse events were seen with the PD-1 inhibitor versus chemotherapy (73.4% vs 90%).
“This data will completely change the management of patients with advanced NSCLC,” lead author Martin Reck, MD, PhD, chief oncology physician, Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Germany, said in a statement. “All endpoints of efficacy and tolerability favored treatment with pembrolizumab, suggesting it should become one standard of care for first-line treatment of patients with advanced NSCLC and high PD-L1 expression.”