FDA Grants Priority Review to Pembrolizumab in Lung Cancer

Edward Garon, MD

The FDA has assigned a priority review designation to the PD-1 inhibitor pembrolizumab (Keytruda) as a treatment for patients with advanced non-small cell lung cancer (NSCLC) across all histologies whose disease has progressed on or after platinum-containing chemotherapy, as well as a targeted agent in EGFR- or ALK-positive patients. A final approval decision will be made by October 2, 2015.

The priority review follows a breakthrough therapy designation for pembrolizumab that was granted by the FDA in October 2014. This designation and the priority review are based on data from the phase I KEYNOTE-001 trial, which were presented at the 2015 AACR Annual Meeting. The results showed that pembrolizumab had an ORR of nearly 20% among 495 previously treated and treatment-naïve patients with advanced or metastatic NSCLC. The ORR was 45.2% among a cohort of patients with high PD-L1—expressing NSCLC.

“These results have the potential to substantively change the way that lung cancer is treated,” lead author, Edward Garon, MD, said at the AACR conference. “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 495-patient KEYNOTE-001 study 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, is currently approved for patients with advanced melanoma. Merck, which manufactures pembrolizumab, is hoping that the drug will become the second PD-1 inhibitor approved in lung cancer, and first across all NSCLC histologies. The PD-1 agent nivolumab (Opdivo) was approved in March 2015 for patients with NSCLC who have progressed on or after platinum-based chemotherapy; however, the indication is limited to individuals with squamous histology. Positive data were presented at ASCO 2015 for nivolumab in nonsquamous NSCLC, so its indication will likely be expanded in the future.

Commenting in a press release on the pembrolizumab priority review, Roger M. Perlmutter, MD, president of Merck Research, said, “Today’s announcement reflects our commitment to accelerate the development of immunotherapeutic approaches to treat lung cancer, one of the most deadly malignancies. We believe that data submitted to the FDA illustrate the significant potential of Keytruda to treat advanced non—small cell lung cancer and we look forward to working with the FDA to bring our anti–PD-1 therapy to patients afflicted with this devastating cancer.”