CHICAGO-Pembrolizumab dramatically increases survival for patients with advanced non-small cell lung cancer (NSCLC), in particular those patients with high expression of PD-L1, according to 5-year follow-up data from the phase Ib KEYNOTE-001 clinical trial.
The results of the study, the longest follow-up to date of patients with advanced NSCLC treated with pembrolizumab, represents a marked improvement over 5-year survival rates from the pre-immunotherapy era, which averaged 5.5 percent for advanced NSCLC.
"The uniformly negative outlook that has been associated with a diagnosis of advanced NSCLC is certainly no longer appropriate. 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," said lead author Edward B. Garon, MD, Associate Professor of Medicine at UCLA.
Garon presented the results of the study at a press briefing before the 2019 ASCO Annual Meeting (Abstract LBA9015). The results were published simultaneously online in the Journal of Clinical Oncology (2019; doi: 10.1200/JCO.19.00934).
Pembrolizumab was approved by the FDA in advanced NSCLC in October 2015. One year later, pembrolizumab was approved as a first-line treatment for advanced NSCLC tumors that do not have EGFR or ALK gene mutations, but that express PD-L1 on 50 percent or more of their cells. In April 2019, pembrolizumab received an expanded approval for frontline treatment of patients with stage III NSCLC who could not have the tumors surgically removed or irradiated, or advanced NSCLC with PD-L1 expression levels over 1 percent and no EGFR or ALK gene mutations.
About the Study
When the KEYNOTE-001 trial began in 2011, immunotherapy was not widely available. Most of the 550 participants had previously been treated with systemic or targeted therapies (449 patients) and 101 patients were treatment-naive. The patients enrolled in KEYNOTE-001 were the first cohort to receive pembrolizumab for advanced NSCLC, noted Garon.
All patients received 2 mg/kg of their body weight of pembrolizumab every 3 weeks or 10 mg/kg every 2 or 3 weeks. The protocol was changed to a single dose of 200 mg regardless of body weight every 3 weeks, the typical regimen in clinical practice.
Key Findings
At a median follow-up of 60.6 months, 100 patients (18%) were still alive. The median duration of treatment was 3.3 months. Of those who had not received prior treatment, 23 percent were still alive after 5 years compared with 15.5 percent of those who were previously treated.
Higher levels of PD-L1 expression predicted longer survival. In previously untreated patients, 29.6 percent with PD-L1 expression of 50 percent or more were alive after 5 years compared with 15.7 percent with expression levels below 50 percent. In patients who had been previously treated, 25 percent who had PD-L1 expression levels of 50 percent or more were alive after 5 years compared with 12.6 percent with expression levels between 1 and 49 percent. Only 3.5 percent of patients with expression levels below 1 percent were alive after 5 years.
Among those who received pembrolizumab after undergoing previous treatment, 42 percent had responses that lasted for a median of 16.8 months. For those who received pembrolizumab as initial therapy, 23 percent had responses that lasted a median of 38.9 months.
Immune-related toxic side effects occurred in 17 percent of patients. The most common side effect was hypothyroidism. The most serious side effect seen was pneumonitis, which was not very common, Garon noted. "Safety data are consistent with the known safety profile of pembrolizumab; late-onset toxicity, including immune-related toxicity, was rare."
In conclusion, he stated: "Among the 60 patients who received 2 or more years of pembrolizumab treatment, more than 85 percent had an objective response and the 5-year OS rate exceeded 75 percent. These data confirm the potential of pembrolizumab to improve long-term outcomes for treatment-naive and previously treated patients with advanced NSCLC."
He pointed out that patients with more than 50 percent expression of PD-L1 in clinical practice often receive single-agent pembrolizumab.
Next Steps
The researchers plan to refine their understanding of which patients received the most benefit from pembrolizumab, as well as to identify impediments that prevent the immune system from destroying tumors that combat these mechanisms. They also hope to explore possible combination therapies of pembrolizumab with conventional or other immunotherapies.
ASCO Expert David L. Graham, MD, Medical Director at Levine Cancer Institute in Charlotte, N.C., commented: "These data are similar to what we have seen in other cancers treated with immunotherapy in that there is 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."
Graham added: "We used to have to tell patients their chances down the road were uniformly bad. Now [we know] one in four of them will be around in 5 years. This changes our mindset."
Mark L. Fuerst is a contributing writer.