KEY TAKEAWAYS
- The phase 3 PEARLS study was a randomized, triple-blind experiment with primary objectives to evaluate overall disease-free and disease-free survival in patients with a PD-L1 TPS of 50% or above.
- Eligible participants received either pembrolizumab or a placebo intravenously once every 3 weeks for up to 18 cycles.
- The study found that pembrolizumab improved median disease-free survival compared to placebo in the ITT population (53.6 months vs 42.0 months).
- The trial involved 196 medical centers in 29 countries, with 1177 patients enrolled in the ITT population, and the median follow-up was 35.6 months.
- Pembrolizumab improves disease-free survival in resected stage IB-IIIA NSCLC, regardless of PD-L1 expression, with no new safety concerns.
Pembrolizumab is the treatment of choice for patients with advanced non-small-cell lung cancer (NSCLC). The resemblance between the two is uncanny, yet the similarities end there. Patients from 196 medical centers in 29 countries participated in this randomized, triple-blind, phase 3 experiment (PEARLS/KEYNOTE-091). Patients were aged 18 or older, had a pathologically confirmed stage IB (tumors 4 cm in diameter) or II (any histology or PD-L1 expression level), and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Adjuvant chemotherapy was to be considered for stage IB disease. It was strongly recommended for stages II and IIIA disease (7th edition). Pembrolizumab 200 mg or placebo was administered intravenously once every 3 weeks for up to 18 cycles to eligible randomly assigned participants (1:1) using a minimization technique and stratified by disease stage, prior adjuvant chemotherapy, PD-L1 expression, and geographical region using an interactive voice-response system. Treatment assignment was concealed from participants, researchers, and analysts. Overall disease-free and disease-free survival in patients with a PD-L1 tumor proportion score (TPS) of 50% or above served the study’s primary objectives. The effectiveness was evaluated in the ITT population, including all study participants randomly allocated to a treatment arm. Participants were monitored for safety after receiving at least one dosage of the treatment they were randomly assigned to receive in the trial. Researchers presented the findings from the second interim analysis, which was planned for when 118 occurrences of disease-free survival had occurred in the population with PD-L1 TPS of 50% or above. ClinicalTrials.gov identifies this trial (NCT02504372) as “Active, not recruiting.”
A total of 1177 (60%) of 1955 screened patients were enrolled in the ITT population after being randomly allocated to receive either pembrolizumab (n=590; including n=168 with PD-L1 TPS of 50%) or placebo (n=587; including n=165 with PD-L1 TPS of 50%) between January 20, 2016, and May 6, 2020. As of the data cutoff date (September 20, 2021) for this interim analysis, the median follow-up was 35.6 months (interquartile range [IQR] 27.1-45.5). Median disease-free survival in the pembrolizumab group was 53.6 months (95% confidence interval [CI]: 392 to not achieved) compared to 42.0 months (range: 31.3 to not reached) in the placebo group (hazard ratio [HR]: 0.76 [95% CI: 0.63-0.91], P=0.00014). Median disease-free survival was not obtained in the PD-L1 TPS of 50% or more significant population for either treatment arm (95% confidence interval [CI] 44.3 to not reached; HR 0.082 [95% CI 0.057-1.18]; P=0.14). 198 (34%) of 580 people who got pembrolizumab and 150 (26%) of 581 who received a placebo experienced adverse events of grade 3 or worse. Ten or more patients in either the pembrolizumab or placebo groups experienced adverse events of grade 3 or higher due to hypertension (35% [6%]) or pneumonia (12% [2%]). A total of 142 people in the pembrolizumab group (24%) and 90 people in the placebo group (15%) experienced severe adverse events, with pneumonia (13% [2%], pneumonitis (12%), and diarrhea (7% [1%]) accounting for the majority of these cases in the pembrolizumab group. 4 (1%) of the pembrolizumab-treated participants died due to treatment-related adverse events (one from cardiogenic shock and myocarditis, one from septic shock and myocarditis, one from pneumonia, and one from sudden death), while no placebo-treated participants died.
Source:https://pubmed.ncbi.nlm.nih.gov/36108662/
Clinical Trial:https://clinicaltrials.gov/ct2/show/NCT02504372
O’Brien M, Paz-Ares L, Marreaud S, Dafni U, Oselin K, Havel L, Esteban E, Isla D, Martinez-Marti A, Faehling M, Tsuboi M, Lee JS, Nakagawa K, Yang J, Samkari A, Keller SM, Mauer M, Jha N, Stahel R, Besse B, Peters S; EORTC-1416-LCG/ETOP 8-15 – PEARLS/KEYNOTE-091 Investigators. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomized, triple-blind, phase 3 trial. Lancet Oncol. 2022 Oct;23(10):1274-1286. doi: 10.1016/S1470-2045(22)00518-6. Epub 2022 Sep 12. PMID: 36108662.
