Study Reports Adjuvant Pembrolizumab Improves Disease-Free Survival in Early-Stage NSCLC

Get Permission

Adjuvant pembrolizumab improves disease-free survival compared with placebo in patients with early-stage non–small cell lung cancer (NSCLC) following complete resection and adjuvant chemotherapy when indicated. These findings from the PEARLS/KEYNOTE-091 trial were reported in a European Society for Medical Oncology (ESMO) Virtual Plenary.1

The second interim analysis of the phase III study showed an increase in median disease-free survival from 42.0 months with placebo to 53.6 months with adjuvant pembrolizumab (hazard ratio [HR] = 0.76). Investigators also noted that the benefit was consistent across various levels of PD-L1 expression, including patients with a tumor proportion score (TPS) less than 1%.

“Overall, we believe that pembrolizumab has the potential to become a new adjuvant treatment option for patients with stage IB, II, and IIIA NSCLC following complete resection and adjuvant chemotherapy when recommended, regardless of PD-L1 expression,” said lead study author Luis Paz-Ares, MD, PhD, Professor of Medicine at Hospital Universitario 12 de Octubre, Madrid.

“Pembrolizumab provided benefit regardless of pathologic stage, PD-L1 expression, smoking status, or presence of an EGFR mutation.”
— Luis Paz-Ares, MD, PhD

Tweet this quote

As Dr. Paz-Ares reported, early-stage NSCLC accounts for up to 50% of all NSCLC diagnoses. For patients with stage IB (with tumors at least 4 cm) to IIIA NSCLC, standard treatment involves resection followed by adjuvant platinum-based chemotherapy. However, the absolute 5-year overall survival benefit of adjuvant chemotherapy vs observation alone is 5%.2

“These data underscore the need for more effective additional therapies in the setting,” said Dr. Paz-Ares, who noted that several regimens have been evaluated over the past few years.

Recently, the PD-L1 inhibitor atezolizumab demonstrated improved disease-free survival vs best supportive care following complete resection and adjuvant chemotherapy for patients with stage II to IIIA NSCLC that expresses PD-L1 in at least 1% of tumor cells.3 A large body of evidence also supports the role of pembrolizumab as monotherapy or in combination with chemotherapy as standard of care for locally advanced or metastatic NSCLC, regardless of histology.

Furthermore, pembrolizumab has shown efficacy when combined with concurrent radiation therapy in the setting of stage III unresectable disease regardless of PD-L1 expression or histology, said Dr. Paz-Ares. However, no data are available for pembrolizumab as adjuvant therapy for early-stage NSCLC.4

Study Methods

For the PEARLS/KEYNOTE-091 trial, investigators enrolled patients with confirmed stage IB, II, or IIIA NSCLC following complete surgical resection with negative margins (R0). Patients were required to provide tumor tissue for PD-L1 testing, which was performed centrally using the 22C3 pharmDx assay. Adjuvant chemotherapy was not mandatory, but patients with stage IB disease (with a tumor at least 4 cm) were considered for that treatment. Adjuvant chemotherapy was strongly recommended for patients with stage II or III disease according to local or national guidelines. Chemotherapy was platinum-based and limited to up to four cycles.


  • Adjuvant pembrolizumab provided a statistically significant, clinically meaningful disease-free survival improvement following complete resection and, when indicated, adjuvant chemotherapy in patients with stage IB (tumor ≥ 4 cm) to IIIA NSCLC, regardless of PD-L1 expression.
  • Overall survival data are still immature, but a nonsignificant trend was seen with the pembrolizumab treatment. The 18-month rate of overall survival was 91.7% with pembrolizumab vs 91.3% with placebo (hazard ratio = 0.87; P = .17).
  • Some experts believe there is a clear need for investigation of additional molecular confounders besides PD-L1 expression in these adjuvant trials of checkpoint inhibitors.

Patients were randomly assigned to receive pembrolizumab at 200 mg every 3 weeks for up to 18 administrations (approximately 1 year) or placebo with the same scheduling. Stratification factors included disease stage, PD-L1 tumor expression (less than 1% vs 1%–49% vs at least 50%), receipt of adjuvant chemotherapy (yes or no), and geographic region.

The trial has dual primary endpoints: disease-free survival in the global population and disease-free survival in patients with a PD-L1 TPS of at least 50%.

1-Year Improvement in Disease-Free Survival

Of the 1,177 patients randomly assigned to receive pembrolizumab or placebo, 380 completed treatment in the pembrolizumab arm and 381 completed treatment in the placebo arm. Pembrolizumab significantly improved the primary endpoint of disease-free survival in the overall population from 42 months in the placebo arm to 54 months in the pembrolizumab arm (HR = 0.76; P = .0014). The disease-free survival benefit of pembrolizumab was also observed across most of the prespecified subgroups.

“Pembrolizumab provided benefit regardless of pathologic stage, PD-L1 expression, smoking status, or the presence of an EGFR mutation,” said Dr. Paz-Ares.

Overall survival data are still immature, but a nonsignificant trend was seen with pembrolizumab. The 18-month rate of overall survival was 91.7% with pembrolizumab vs 91.3% with placebo (HR = 0.87; P = .17).

Safety Profile

The safety profile observed with pembrolizumab was as expected and was manageable, said Dr. Paz-Ares. The incidences of grade 3 or greater adverse events and adverse events leading to discontinuation of therapy were higher in the pembrolizumab arm. Treatment-related deaths occurred in four patients receiving pembrolizumab.

Immune-mediated adverse events were also recorded more frequently with pembrolizumab, including a significant incidence of thyroid disorder, hyperthyroidism, pneumonitis, and skin rash.

Disease-free survival in the PD-L1–defined populations and overall survival will be tested at future analyses according to the analysis plan, said Dr. Paz-Ares. 

DISCLOSURE: Dr. Paz-Ares reported financial relationships with Alkermes, Altum Sequencing, Daiichi Sankyo, Roche, MSD, Merck Serono, BMS, AstraZeneca, Lilly, Pfizer, PharmaMar, Bayer, Amgen, Janssen, GSK, Novartis, Ipsen, IO Biotech, Takeda, Sanofi, Tesaro, and Mirati.


1. Paz-Ares L, O’Brien MER, Mauer M, et al: Pembrolizumab versus placebo for early-stage non-small cell lung cancer following complete resection and adjuvant chemotherapy when indicated: Randomized, triple-blind, phase III EORTC-1416-LCG/ETOP 8-15 – PEARLS/KEYNOTE-091 study. ESMO Virtual Plenary. Abstract VP3-2022. Presented March 17, 2022.

2. NSCLC Meta-analyses Collaborative Group, Arriagada R, Auperin A, et al: Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: Two meta-analyses of individual patient data. Lancet 375:1267-1277, 2010.

3. Felip E, Altorki N, Zhou C, et al: Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): A randomised, multicentre, open-label, phase 3 trial. Lancet 398:1344-1357, 2021.

4. Jabbour SK, Lee KH, Frost N, et al: Pembrolizumab plus concurrent chemoradiation therapy in patients with unresectable, locally advanced, stage III non-small cell lung cancer: The phase 2 KEYNOTE-799 nonrandomized trial. JAMA Oncol 7:1-9, 2021.

Related Articles

Expert Point of View: Martin Reck, MD, PhD

The discussant of the PEARLS/KEYNOTE-091 trial, Martin Reck, MD, PhD, underscored the need to do more in the perioperative management of patients with early-stage non–small cell lung cancer (NSCLC) to improve rates of overall survival and relapse after surgery. Dr. Reck is Head of the Department of ...