This article is more than 5 years old. Information may no longer be current.
PD-L1 expression linked to pembrolizumab activity in advanced NSCLC
PHILADELPHIA — Pembrolizumab yielded durable response rates and demonstrated tolerability in previously treated and treatment-naive patients with non–small cell lung cancer, according to study results presented at the American Association for Cancer Research Annual Meeting.
Patients with programmed death ligand-1 (PD-L1) expression in at least 50% of their tumor cells were more likely to respond to treatment with pembrolizumab (Keytruda, Merck), results showed.
Edward B. Garon
“Pembrolizumab is associated with durable anti-tumor activity with greater than 1 year duration of response among patients who responded and it is associated with a very manageable toxicity profile,” Edward B. Garon, MD, associate professor of medicine at the David Geffen School of Medicine at UCLA, said during a press conference. “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 … that pembrolizumab is associated with superior clinical outcomes clearly than what would be anticipated with cytotoxic chemotherapy. In additional, the clinical outcomes of patients with a lesser degrees of staining in certain clinical scenarios may also be better compared with prior data from randomized studies.”
Preliminary data from the training cohort (n = 182) of KEYNOTE-0001 — presented at the AACR Annual Meeting in 2014 — demonstrated the objective response rate with pembrolizumab was higher in patients with advanced NSCLC who had membranous PD-L1 expression in at least 50% of their tumor cells (proportion score ≥ 50%).
Garon and colleagues sought to confirm these results in an independent validation cohort composed of 313 patients with advanced or metastatic NSCLC who had previously been treated or who were treatment naïve. Patients received pembrolizumab in 2-mg/kg doses every 3 weeks, 10-mg/kg doses every 3 weeks or 10-mg/kg doses every 2 weeks.
In the total patient population (n = 495), the ORR was 19.4% and median duration of response was 12.4 months. Median PFS was 3.7 months and median OS was 12 months.
Researchers used an immunohistochemistry clinical trial assay using the 22C3 antibody clone (Merck) for PD-L1 expression in 204 evaluable patients in the validation cohort.
The ORR was highest among patients with a proportion score of at least 50% (n = 73; ORR = 45.2%) compared with patients with a proportion score between 1% and 49% (n = 103; ORR = 16.5%) and with proportion score less than 1% (n = 28; ORR = 10.7%).
The association between ORR and PD-L1 expression persisted in patients whether they were previously treated (proportion score ≥ 50%, ORR = 43.9%) or treatment naive (ORR = 50%).
PFS and OS also were prolonged among patients with a proportion score of at least 50% from the entire population of patients with data on PD-L1 expression (n =356). Median PFS was 6.3 months (95% CI, 2.9-12.5) among patients with the highest proportion score compared with 2.3 months (95% CI, 2.1-4) among patients with the lowest proportion score.
Median follow-up for OS analyses was 10.9 months.
Median OS was not yet reached (95% CI, 13.7-not reached) among patients with the highest proportion score, whereas patients with the lowest proportion score achieved a median OS of 8.8 months (95% CI, 5.5-12).
The median duration of response was comparable among patients with a proportion score of at least 50% (12.4 months; range, 2+ to 22.8+), 1% to 49% (10.3 months; range, 1.4+ to 10.3) and less than 1% (not reached; range, 0.9+ to 10.8+).
Nine percent of patients in the total population experienced a grade 3 to grade 5 adverse event, and 4% of patients discontinued treatment due to toxicity. One treatment-related death occurred due to pneumonitis.
“Neither the drug not the biomarker test is approved for use in this setting at this time, but if I had a patient whose tumor had PD-L1 expression on at least half of the cells and if pembrolizumab was available, I think that I would find the data compelling to look at the drug as the treatment option for that patient,” Garon said in a press release. – by Alexandra Todak
Disclosure: The study was funded by Merck. Garon reports researcher funding paid to his institution from Merck.
Perspective
Back to Top
The most exciting moment for me, personally, in the development of anti-PD–1 drugs was the realization that lung cancer could respond to this form of immunotherapy. In the past, we had tried many different forms of immunotherapy that did not have any impact on lung cancer. Once that realization occurred, we then knew that we should branch out to other kinds of cancers to see if other cancers could also be susceptible to anti-PD–1 therapies, and these drugs are having a major impact in other cancers.
This is the largest study of any PD-1–blocking agent in lung cancer. These are very exciting results in advanced NSCLC. In this study, more than three-quarters of the patients had had a previous systemic treatment for their cancer, and had progressive disease after that. 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. So, these results are especially impressive given this treatment setting.
There is a big push to identify biomarkers for all kind of cancer therapy, so that patients don’t spend time on trials or on therapies that are not going to help them, and so that they’re not exposed to adverse events when they don’t need to be. Certainly, that situation is more clear-cut for the kinase inhibitor class of drugs, where the biology tells us the drug is really not likely to work if the patient doesn’t have a particular mutation. An example is the BRAF V600E mutation in melanoma and treatment with BRAF inhibitors. These data describe a potential biomarker to select patients with lung cancer for anti-PD–1 therapy. But this kind of biomarker is a lot more blurry. Even patients with lower levels of expression of this marker still had notable response rates.