Adjuvant Pembrolizumab Provides Sustained DFS Benefit in Resected Stage IB, II, or IIIA NSCLC

Adjuvant treatment with pembrolizumab (Keytruda) continued to induce a disease-free survival (DFS) benefit vs placebo in patients with resected early-stage non–small cell lung cancer (NSCLC), and a benefit with pembrolizumab compared with placebo was also observed in patients who received adjuvant chemotherapy prior to initiating study treatment, according to findings from the phase 3 PEARLS/KEYNOTE-091 trial (NCT02504372).¹

Data from the final DFS analysis were presented during the 2023 ESMO Immuno-Oncology Congress, showing that at a median follow-up of 51.7 months (range, 32.7-84.2) in the intention-to-treat (ITT) population, pembrolizumab (n = 590) elicited a median DFS of 53.8 months (95% CI, 46.2-67.0) vs 43.0 months (95% CI, 35.0-51.6) with placebo (n = 587; HR, 0.81; 95% CI, 0.68-0.96). The respective 4-year DFS rates in the pembrolizumab and placebo arms were 52.4% (95% CI, 47.8%-56.9%) and 45.7% (95% CI, 41.1%-50.3%).

“Patients with high PD-L1 NSCLC did not have a benefit from pembrolizumab,” Benjamin Besse, MD, PhD, of Paris Saclay University at the Institut Gustave Roussy in Villejuif, France, said in a presentation of the data.

PEARLS/KEYNOTE-091 enrolled patients with confirmed stage IB (T ≥ 4 cm), II, or IIIA NSCLC per AJCC v7 criteria. To be eligible for enrollment, patients needed to have complete surgical resection of their tumor with negative margins and have provisional tumor tissue for PD-L1 testing. Eligible patients were stratified by disease stage (IB vs II vs IIIA), PD-L1 tumor proportion score (TPS; > 1% vs 1%-49% vs ≥ 50%), receipt of adjuvant chemotherapy (yes or no), and geographic region (Asia vs Eastern Europe vs Western Europe vs rest of the world).

To be eligible for random assignment, patients needed to have no evidence of disease and an ECOG performance status of 0 or 1. Patients were considered for adjuvant chemotherapy if they had stage IB disease, and adjuvant chemotherapy was strongly recommended for those with stage II or IIIA disease. Notably, adjuvant chemotherapy was limited to a maximum of 4 cycles.

Upon central PD-L1 testing per immunohistochemistry 22C3 pharmDx, patients were randomly assigned 1:1 to receive either placebo or 200 mg pembrolizumab every 3 weeks for a maximum of 18 administrations.

The dual primary end points of the investigation were DFS in the overall population and DFS in the PD-L1 TPS of 50% or greater population. Secondary end points included DFS in the PD-L1 greater than 1% population; overall survival in the overall, PD-L1 TPS of 50% or greater, and PD-L1 TPS greater than 1% populations; lung cancer–specific survival in the overall population; and safety.

At the second interim analysis of PEARLS/KEYNOTE-091, pembrolizumab led to a significant DFS improvement compared with placebo in the ITT population (HR, 0.76; 95% CI, 0.63-0.91; P = .0014). However, the DFS improvement with pembrolizumab vs placebo in the population with a TPS of at least 50% was not significant (HR, 0.82; 95% CI, 0.57-1.18; P = .14).² Based on these data, in January 2023, adjuvant pembrolizumab received FDA approval for patients with completely resected NSCLC who have received platinum-based chemotherapy for stage IB (T2a ≥4 cm), II, or IIIA.³

In the third interim analysis of PEARLS/KEYNOTE-091, the statistical significance of DFS in the overall population was not tested because the trial met the success criterion for this end point at the second interim analysis.1 The statistical significance of DFS in the PD-L1 TPS of 50% or greater population was tested at the nominal alpha level of 0.01038 (overall α = 0.0125).

Besse noted in the presentation that the baseline characteristics were similar between the ITT and PD-L1 TPS of 50% or greater populations. In the ITT population, 67.5% and 61.8% of patients in the pembrolizumab and placebo arms had nonsquamous histology, respectively, compared with respective rates of 61.3% and 63.6% of those in the PD-L1 TPS of 50% or greater population.

In the ITT population, 14.4%, 55.9%, and 29.7% of patients in the pembrolizumab arm and 14.8%, 57.6%, and 27.3% of those in the placebo arm had pathologic stage IB, II, or IIIA disease, respectively. In the PD-L1 TPS of 50% or greater population, these respective rates were 13.1%, 56.0%, and 31.0% in the pembrolizumab arm and 13.3%, 57.0%, and 29.7% in the placebo arm. A total of 85.8% of patients in the pembrolizumab arm of the ITT population had received adjuvant chemotherapy before study treatment, compared with 85.9% of those in the placebo arm. In the PD-L1 TPS of 50% or greater population, these respective rates were 85.1% and 85.5%.

In the PD-L1 TPS of 50% or greater population, patients who received pembrolizumab (n = 168) achieved a median DFS of 67.0 months (95% CI, 47.8-NR) vs 47.6 months (95% CI, 36.4-NR) with placebo (n = 165; HR, 0.83; 95% CI, 0.59-1.16; P = .13). The 4-year DFS rates in the pembrolizumab and placebo arms were 57.0% (95% CI, 47.9%-65.1%) and 49.1% (95% CI, 39.8%-57.8%), respectively.

Among the patients who received adjuvant chemotherapy, across PD-L1 TPS populations, patients on the pembrolizumab arm achieved a median DFS of 53.8 months (95% CI, 46.2-70.4) vs 40.5 months (95% CI, 32.9-47.4) in the placebo arm (HR, 0.80; 95% CI, 0.67-0.96). The respective 4-year DFS rates in the pembrolizumab and placebo arms were 52.5% (95% CI, 47.4%-57.3%) and 44.7% (95% CI, 39.7%-49.5%).

Regarding DFS in key subgroups of the ITT population, Besse stated in the presentation that the benefit with pembrolizumab vs placebo was greater for patients who had received adjuvant chemotherapy (HR, 0.80; 95% CI, 0.67-0.96). Furthermore, the HRs favored pembrolizumab in the patients with negative or intermediate PD-L1 expression, at 0.74 (95% CI, 0.55-0.98), and 0.84 (95% CI, 0.64-1.09), respectively.

In the as-treated population, any-grade adverse effects (AEs) occurred in 95.9% of patients in the pembrolizumab arm (n = 580) and 91.0% of those in the placebo arm (n = 581). Grade 3-5 AEs were reported in 34.1% and 25.8% of patients in each arm, respectively. Any-grade AEs leading to treatment discontinuation or death occurred in 20.0% and 1.9% of patients in the pembrolizumab arm, respectively, as well as 5.9% and 1.0% of those in the placebo arm, respectively.

Treatment-related AEs (TRAEs) were observed in 75.2% of patients in the pembrolizumab arm and 52.5% of those in the placebo arm, and grade 3-5 TRAEs occurred in 15.3% and 4.3% of patients in the pembrolizumab and placebo arms, respectively. Any-cause AEs occurring in at least 15% of patients in either arm included increased weight (pembrolizumab arm, 22.8%; placebo arm, 28.9%), pruritus (21.6%; 12.7%), hypothyroidism (20.7%; 4.6%), arthralgia (18.4%; 12.4%), diarrhea (18.3%; 14.3%), fatigue (16.6%; 15.3%), and cough (15.0%; 16.9%).

Any-grade immune-mediated AEs and infusion reactions occurred in 39.1% of patients in the pembrolizumab arm and 13.1% of those in the placebo arm, and grade 3-5 immune-mediated AEs and infusion reactions were reported in 7.9% and 1.9% of patients in these arms, respectively. Any-grade immune-mediated AEs and infusion reactions occurring in at least 1% of patients in either arm included hypothyroidism (pembrolizumab arm, 20.7%; placebo arm, 4.6%), hyperthyroidism (10.7%; 2.9%), pneumonitis (6.9%; 2.9%), severe skin reactions (2.8%; 0.7%), colitis (2.4%; 0.9%), adrenal insufficiency (1.7%; 0%), hepatitis (1.6%; 0.7%), hypophysitis (1.2%; 0%), and thyroiditis (1.0%; 0.2%).

“Adjuvant pembrolizumab had a manageable safety profile; there were no new safety signals with additional follow-up,” Besse and colleagues concluded in the presentation.

Editor’s Note: Dr Besse has disclosed conducting research at Gustave Roussy Cancer Center sponsored by AbbVie, Amgen, AstraZeneca, Chugai pharmaceutical, Daiichi-Sankyo, Ellipse pharma, EISAI, Genmab, Genzyme Corporation, Hedera Dx, Inivata, IPSEN, Janssen, MSD, Pharmamar, Roche-Genentech, Sanofi, Socar research, Taiho Oncology, and Turning Point Therapeutics.

Funding for the PEARLS/KEYNOTE-091 trial was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. Medical writing assistance for this presentation was provided by Christabel Wilson, MSc, of ICON plc (Blue Bell, PA, USA) and was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.

References

1. Besse B, Havel L, Peters S, et al. Adjuvant pembrolizumab versus placebo for early-stage NSCLC after resection and optional chemotherapy: updated results from PEARLS/KEYNOTE-091. Ann Oncol. 2023;20(suppl 1):100589. doi:10.1016/iotech/iotech100589
2. O’Brien M, Paz-Ares L, Marreaud S, et al. 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 randomised, triple-blind, phase 3 trial.Lancet Oncol. 2022;23(10):1274-1286. doi:10.1016/S1470-2045(22)00518-6
3. FDA approves pembrolizumab as adjuvant treatment for non-small cell lung cancer. FDA. January 26, 2023. Accessed January 4, 2024. https://www.fda.gov/drugs