In patients with advanced non-small cell lung cancer (aNSCLC), treatment with pembrolizumab significantly increased overall survival (OS), with the greatest benefit seen in those with higher programmed death-ligand 1 (PD-L1) expression, according to updated 5-year data from the KEYNOTE-001 clinical trial, which were presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, and published in the Journal of Clinical Oncology.
Updated results from KEYNOTE-001—the longest follow-up study ever done in patients with aNSCLC treated with pembrolizumab—are significantly better than those from patients treated before anti-PD-1 therapies, with 5-year survival rates that were, on average, about 5.5%. In the current study, 23.2% of chemotherapy-naïve patients and 15.5% of those who were previously treated were alive at 5 years.
“The uniformly negative outlook that has been associated with a diagnosis of [aNSCLC] is certainly no longer appropriate,” said lead author Edward B. Garon, MD, MS, associate professor, Department of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA. “The fact that we have patients on this trial that are still alive after 7 years is quite remarkable. We also have evidence that most patients who are doing well after 2 years on pembrolizumab live for 5 years or more.”
First approved in September 2014 for advanced melanoma, pembrolizumab was then approved in October 2015 for aNSCLC. In October 2016, it gained approval as a first-line treatment for aNSCLC tumors that were free of EGRF and ALK mutations but had 50% or greater PD-L1 expression. In April 2019, pembrolizumab was also granted expanded approval for front-line treatment of patients with stage III NSCLC that was inoperable or who were unsuitable for chemotherapy, or those with aNSCLC with PD-L1 expression of over 1% and no EGFR or ALK mutations.
Pembrolizumab is an immunotherapeutic agent that binds to PD-1, a protein that exists on the surface of T cells. By blocking PD-1, which inhibits immune responses through binding to two ligands—PD-L1 and PD-L2—pembrolizumab frees the T cells, which are then free to mount an attack on the tumor cells.
In this update of the KEYNOTE-001 trial, Dr. Garon and colleagues include 550 subjects with aNSCLC, of whom 101 were treatment-naïve and 449 had previous treatments. Subjects were treated with intravenous pembrolizumab (2 mg/kg every 3 weeks, or 10 mg/kg every 2 or 3 weeks), and followed for a median of 60.6 months. Median OS was 22.3 months (95% CI: 17.1-32.3 months) for treatment-naïve patients, and 10.5 months (95% CI: 8.6-13.2 months) for previously treated patients. Estimated 5-year OS rates were 23.2% and 15.5%, respectively.
In subjects with a PD-L1 tumor proportion scores of 50% or higher, 5-year OS was 29.6%, which is significantly higher than the 15.7% OS rate in those with PD-L1 expression less than 50%. Five-year OS in patient with PD-L1 expression of 50% or more was 25% compared with only 12.6% in those below 50%. Finally, only 3.5% of subjects with PD-L1 expression below 1% were alive at the 5-year mark.
A full 42% of previously treated subjects demonstrated durable responses lasting for a median of 16.8 months. In those who were treatment-naïve and in whom pembrolizumab was the initial treatment, 23% exhibited responses lasting for a median of 38.9 months.
Side effects occurred in 17% of subjects, with the most common being hypothyroidism, and the most serious, pneumonitis. Researchers observed no late-onset grade 4 or 5 treatment-related adverse events.
In an accompanying editorial, Deepa Rangachari, MD, and Daniel B. Costa, MD, PhD—both of Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA—hailed these results and the advent of immune checkpoint inhibitor (ICI) therapies:
“ICIs have rightfully earned their place as a mainstay of care for advanced NSCLC. KEYNOTE-001 and similar trials have unequivocally established that durable long-term responses with previously unseen extension of survival are feasible with ICIs. Five-year survival rates can now be expected for a growing number of patients with advanced NSCLC treated with biomarker-driven use of ICIs in those without actionable alterations or [ tyrosine kinase inhibitors] for those with actionable alterations, thus achieving the quest to offer each patient the most optimally durable, efficacious, and tolerable strategy for their care.”
ASCO Expert David L. Graham, MD, FACP, FASCO, agreed:
“These data are similar to what we have seen in other cancers treated with immunotherapy in that there are a population of patients who can live for 5 years or more. It’s truly remarkable that for more patients than ever before, we no longer have to count survival in months. However, we still have a long way to go to improve outcomes for all advanced NSCLC patients. We look forward to more research helping us determine how to identify these patients.”
Researchers received funding for this study from Merck Sharp & Dohme, Corp.