Keytruda Found Safe and Effective in Patients with Advanced NSCLC

Edward Garon, MD

Pembrolizumab (Keytruda) had an overall response rate (ORR) of 45.2% among a cohort of patients with high PD-L1-expressing non—small cell lung cancer (NSCLC) in the phase I KEYNOTE-001 trial. Regardless of PD-L1 expression, the PD-1 inhibitor was shown to be safe and effective, with an ORR of nearly 20% in the overall study population. The results were presented at the 2015 AACR Annual Meeting and simultaneously published online in The New England Journal of Medicine.

“These results have the potential to substantively change the way that lung cancer is treated,” said lead author, Edward Garon, MD. “The effectiveness of pembrolizumab in treating patients with NSCLC and the prolonged duration of their responses is quite exciting,” added Garon, who is medical director of Thoracic Oncology at UCLA’s Jonsson Comprehensive Cancer Center.

The KEYNOTE-001 trial included 495 previously treated and treatment-naïve patients with advanced or metastatic NSCLC. The total population comprised a training set of 182 patients and a validation set of 313 patients. Pembrolizumab was administered at three dosages: 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks. The researchers assessed patient responses every 9 weeks.

In the entire study population, the ORR was 19.4% and median overall and progression-free survival were 12.0 and 3.7 months, respectively. The median duration of response was 12.4 months.

“The median duration of response exceeded a year among responders regardless of the degree of PD-L1 expression, which is one of the exciting outcomes with this class of drug,” said Garon.

In the validation group, researchers were able to evaluate PD-L1 expression in 204 patients using an IHC clinical trial assay (CTA). Patients were divided into three groups, based on whether they had membranous PD-L1 expression in their tumor cells of ≥50% (n = 73), 1%-49% (n = 103), or <1% (n = 28).

ORR in the three groups was 45.2%, 16.5%, and 10.7%, respectively. The results were comparable but slightly better among patients who had not received prior therapy versus those who were previously treated.

Survival data were also presented at AACR for 356 patients in the total population whose PD-L1 levels were evaluable by the CTA. After a median follow-up of 10.9 months, OS was not yet reached in the high PD-L1 group (n = 119) and was 8.8 months in both the intermediate (n = 161) and low (n = 76) PD-L1 groups. PFS was 6.3, 3.3, and 2.3 months in the three groups, respectively. The duration of response was similar in the three cohorts at 12.4 months, 10.3 months, and not yet reached.

“In addition to being the largest data set of lung cancer patients treated with this type of drug, this is the first independent validation that PD-L1 expression in tumors is clearly a marker of response,” said Garon.

Overall, pembrolizumab was considered tolerable. Grade ≥3 adverse events occurred in 9% of patients. Immune-related adverse events reported in ≥2% of the population included pneumonitis, hypothyroidism, and infusion reactions. Pneumonitis was the cause of the one treatment-related death in the study.

Pembrolizumab, which is already approved for patients with advanced melanoma, received an FDA breakthrough therapy designation in October 2014 for patients with EGFR-negative and ALK-rearrangement—negative NSCLC whose disease has progressed on or following platinum-based chemotherapy.

Merck, which manufactures pembrolizumab, is hoping that the drug will become the second PD-1 inhibitor approved in lung cancer. In March, the FDA approved nivolumab (Opdivo) for the treatment of patients with advanced squamous NSCLC who have progressed on or after platinum-based chemotherapy.

For his part, Garon seemed to indicate he would welcome pembrolizumab as an addition to the lung cancer armamentarium. “Neither the drug nor the biomarker test [used in KEYNOTE-001] 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 EB, Rizvi N, Hui R, et al. Efficacy of pembrolizumab (pembro; MK-3475) and validation of PD-L1 expression as a biomarker in patients (pts) with non-small cell lung cancer (NSCLC): findings from KEYNOTE-001. Presented at: 2015 AACR Annual Meeting; April 18-22; Philadelphia, PA. Abstract 9109.