Updated KEYNOTE-042 Data Show Sustained Survival Benefit at 4 Years in Chinese Patients With Frontline NSCLC

Four-year overall survival results of the phase 3 KEYNOTE-042 trial (NCT02220894) and phase 3 China extension KEYNOTE-042 trial (NCT03850444) continue to show superiority of pembrolizumab (Keytruda) vs standard-of-care chemotherapy in Chinese patients with treatment-naïve advanced or metastatic non–small cell lung cancer (NSCLC) that expresses PD-L1 and does not harbor sensitizing EGFR or ALK mutations, according to data made available during the American Association for Cancer Research (AACR) 2022 Annual Meeting.¹

Results showed that patients with PD-L1 tumor proportion score (TPS) of at least 50% achieved a 4-year OS rate of 23.4% and a median OS of 24.5 months (95% CI, 17.4-34.3) with pembrolizumab, compared with 13.6% and 13.8 months (95% CI, 10.1-18.3) with chemotherapy (HR, 0.66; 95% CI, 0.45-0.95). Additionally, patients with a PD-L1 TPS of at least 20% demonstrated a 4-year OS of 22.5% and a median OS of 21.9 months (95% CI, 17.4-27.0) with pembrolizumab, vs 14.4% and 13.5 months (95% CI, 10.1-17.9) for chemotherapy (HR, 0.68; 95% CI, 0.49-0.93).

Moreover, pembrolizumab generated a 4-year OS of 21.3% and a median OS of 20.2 months (95% CI, 17.4-25.3) in patients with a PD-L1 TPS of at least 1%, vs 12.7% and 13.5 months (95% CI, 10.1-17.9) with chemotherapy (HR, 0.67; 95% CI, 0.51-0.89). Finally, in patients with PD-L1 TPS between 1% and 49%, pembrolizumab produced a 4-year OS of 19.3% and a median OS of 18.6 months (95% CI, 13.5-20.7), compared with 11.2% and 10.4 months (95% CI, 8.2-18.6) with chemotherapy (HR, 0.69; 95% CI 0.45-1.05).

“Pembrolizumab monotherapy remains a standard of care treatment for Chinese patients with previously untreated, locally advanced or metastatic NSCLC with PD-L1 TPS greater than or equal to 1 and without sensitizing EGFR or ALK alterations,” lead study author, Yi-Long Wu, MD, said in the poster presentation.

Prior data from KEYNOTE-042 trial at a median follow-up of 33 months (range, 25.6-41.9) showed pembrolizumab elicited significantly improved OS rates vs chemotherapy in the patients with a PD-L1 TPS of at least 50% (HR, 0.63; 95% CI, 0.43- 0.94), at least 20% (HR, 0.66; 95% CI, 0.47- 0.92), and at least 1% (HR, 0.67; 95% CI, 0.50-0.89).²

In addition to providing updated safety and efficacy outcomes of the KEYNOTE-042 China trial, study authors aimed to provide updated efficacy and safety outcomes of patients with additional 14 months of follow up of Chinese patients.

Key eligibility criteria for patients on the study included untreated locally advanced or metastatic NSCLC of any histology and a PD-L1 TPS at least 1%. Moreover, patients could not have sensitizing EGFR or ALK alterations and must have had ECOG performance status of 0 or 1. Exclusion criteria included untreated or unstable central nervous system metastases and a histology of pneumonitis that required corticosteroids.

Patients were stratified by ECOG performance status, squamous vs non-squamous disease, and PD-L1 TPS of 1%-49% or ≥ 50%.

In China, 262 eligible patients were randomized 1:1 to receive either 200 mg pembrolizumab for no more than to 35 cycles (n = 128); or carboplatin area under the curve (AUC) 5 or 6 and paclitaxel 200 mg/m2 or carboplatin AUC 5 or 6 and pemetrexed 500 mg/m2 every 3 weeks for up to 6 cycles (n = 134). Patients who completed 35 cycles of pembrolizumab were also eligible to receive a second course of 200 mg pembrolizumab every 3 weeks for up to 1 year.

The primary end point of the trial was OS, and secondary end points included progression-free survival (PFS) and overall response rate (ORR) as assessed by RECIST v 1.1, plus safety and tolerability of patients with a PD-L1 TPS of at least to 50%, 20%, and 1%.

Tumor response was assessed per RECIST v 1.1 by blinded independent central review and was assessed by tumor imaging at baseline every 9 weeks for 45 weeks, followed by every 12 weeks thereafter.

Among patients treated with pembrolizumab, the ORRs were 41.7% (95% CI, 30.2%-53.9%), 34.7% (95% CI, 25.5%-44.8%), and 32.0% (95% CI, 24.1%-40.9%) in the PD-L1 TPS ≥ 50%, ≥ 20%, and ≥ 1% groups, respectively, compared with 24.3% (95% CI, 15.1%-35.7%), 24.3% (95% CI, 16.4%-33.7%), and 24.6% (95% CI, 17.6%-32.8%) in the chemotherapy groups, respectively.

Pembrolizumab elicited a median PFS of 8.3 months (95% CI, 4.2-13.1), 6.3 months (95% CI, 4.2-9.0), and 6.4 months (95% CI, 4.2-8.3) in the PD-L1 TPS ≥ 50%, ≥ 20%, and ≥ 1% groups, respectively, vs 6.5 months (95% CI, 4.4-10.4), 7.2 months (95% CI, 6.0-9.7), and 6.7 months (95% CI, 6.0-9.1), respectively.

Among 22 patients who completed the 35 cycles of pembrolizumab, 7 patients (31.8%) were still alive without progressive disease or subsequent treatment at data cutoff. Moreover, median OS of patients who completed 35 cycles of pembrolizumab was 69.1 months (95% CI, 42.7-85.1) with an ORR of 81.8% (95% CI, 59.7%-94.8%).

Treatment-related adverse effects (TRAEs) of any grade were reported in 82.8% and 92.0% of patients who received pembrolizumab and chemotherapy, respectively. Grade 3 or higher TRAEs were observed in 19.5% and 68.8% of patients in the pembrolizumab and chemotherapy arms, respectively. Notable TRAEs of any grade in the patients who received pembrolizumab were increase ALT (17.2%); anemia (8.6%); decreased appetite (5.5%); decreased platelet count (3.1%); decreased neutrophil count (2.3%); decreased white blood cells (1.6%); and alopecia (0.8%).

Immune-related AEs of any grade occurred in 26.6% and 5.6% of patients who received pembrolizumab and chemotherapy respectively. Notable immune-related AEs in the pembrolizumab group were hypothyroidism (11.7%); pneumonitis (7.8%); hyperthyroidism (5.5%); infusion reactions (3.1%); severe skin reactions (1.6%); thyroiditis (1.6%); hepatitis (1.6%); and colitis (0.8%).

References

1. Wu YL, Fan Y, Zhou JY, et al. Pembrolizumab vs chemotherapy in Chinese patients with PD-L1-positive NSCLC: 4-year update from KEYNOTE-042 China study. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, Louisiana. Accessed April 8, 2022. Poster CT555.
2. Mok TS, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019;393(10183):1819-1830. doi:10.1016/S0140-6736(18)32409-7