Tumors with at least 50% PD-L1 expression associated with unexpected improvement..
Patients with advanced non-small cell lung cancer (NSCLC) had almost a 50% response rate to an immune checkpoint inhibitor if their tumors tested positive for the checkpoint protein, according to data reported here.
Overall response to pembrolizumab (Keytruda) was 45.2% in patients whose tumors exhibited PD-L1 (programmed death-ligand 1) expression in at least 50% of cells. Patients who received the PD-L1 inhibitor as initial therapy had a 50% response rate.
“I think that, with this data, we can now confidently say that in previously treated patients, who have PD-L1 expression in at least half of their cells … pembrolizumab is associated with superior clinical outcomes, clearly, than would be anticipated with cytotoxic chemotherapy,” Garon said during an AACR press briefing.
“The outcomes in patients with lesser degrees of staining, in certain clinical scenarios, may also be better than what is seen with comparators, but complete data on that will require data from randomized studies.”
The results were reported simultaneously in the New England Journal of Medicine.
The PD-1 (L1) receptor/ligand system has a braking effect on immune function, specially T-cell function. Tumor cells that express PD-L1 effectively block the immune system’s ability to attack the tumor. In describing immune checkpoint inhibitors, such as pembrolizumab, researchers have often used the analogy of “taking the foot off the brakes” of the immune system and “giving it the gas.”
Approved in 2014 for advanced melanoma, pembrolizumab has demonstrated activity in multiple types of solid tumors, including NSCLC. Garon reported findings from a phase I study to examine the safety and efficacy of the PD-L1 inhibitor only in patients with advanced NSCLC and to validate PD-L1 expression as a biomarker to identify patients who are more likely to respond to the drug.
Investigators enrolled and treated 495 patients with one of three doses of pembrolizumab and subsequently randomized them to a training group (n=182) or a validation group (n=313) for the biomarker analysis. PD-L1 expression was determined from immunohistochemical staining of tumor samples, and results were reported as the proportion of tumor cells that stained positive for membranous PD-L1.
The training cohort comprised 171 previously treated patients and 11 with no prior therapy. After exclusions, 129 patients remained for PD-L1 expression cutoff values. In the validation cohort, 223 patients had received prior therapy, 90 had no prior treatment, and 156 were included in the PD-L1 expression analysis.
Overall, 19.4% of the patients had objective responses to treatment with pembrolizumab. The patients had a median duration of response was 12.5 months, median progression-free survival (PFS) of 3.7 months, and median overall survival (OS) of 12.0 months. None of the outcomes differed appreciably by dosage.
In the validation cohort, patients whose tumors had at least 50% staining for PD-L1 had an response rate of 45.2%, including 50% in patients with no prior therapy. Patients with PD-L1 expression in 1% to 49% of tumor cells had a response rate of 16.5% (19.2% in untreated patients), and the response rate declined to 10.7% for patients with <1% of cells that expressed PD-L1.
PD-L1 expression ≥50% was associated with a median PFS of 6.3 months, almost double the PFS associated with 1% to 49% expression (3.3 months) and nearly triple the PFS of patients whose tumors had the least PD-L1 expression (2.3 months). Patients with no prior treatment and ≥50% PD-L1 expression had a median PFS of 12.5 months.
Median OS has yet to be reached in the patients with ≥50% PD-L1 expression, regardless of treatment history. For patients with 1% to 49% PD-L1 expression, median OS was 7.3 months in previously treated patients and 16.2 months in the previously untreated subgroup. For the lowest level of PD-L1 expression, median survival was 8.6 and 10.4 months in the previously treated and untreated patients, respectively.
Garon said pembrolizumab was well tolerated. The most common adverse event was fatigue, occurring in about 20% of all patients (all grades). About 10% of patients developed pruritus and decreased appetite. No other adverse event occurred in as many as 10% of patients. Most adverse events were mild or moderate in severity.
Noting that three-fourths of the patients in the study had progressed on prior therapy, press briefing moderator Suzanne Topalian, MD, of Johns Hopkins Medicine in Baltimore, said pembrolizumab exceeded conventional expectations for second- and third-line therapy in advanced NSCLC.
“This is a very difficult-to-treat patient population where the impact of second- and third-line agents is generally not expected to prolong survival,” she said. “These results are especially impressive in this particular treatment setting.”
Topalian pointed out that the PD-L1 expression data are clear-cut, given that patients with less than 50% expression “still had notable response rates.” Garon agreed and said that one of the shortfalls of research on PD-L1 expression has been the inability to identify groups of patients who clearly will not respond to PD-L1 inhibition.
“The data are exciting and will be valuable for practitioners and patients to stratify their likelihood of benefiting,” he added.