Author: By Lynda Williams, Senior medwireNews Reporter
medwireNews: Phase III trial findings point to the disease-free survival (DFS) benefit of using adjuvant pembrolizumab in patients who have undergone complete resection of stage IB–IIIA non-small-cell lung cancer (NSCLC) regardless of tumour PD-L1 expression level.
The second interim analysis of the randomised, triple-blind PEARLS/KEYNOTE-091 trial was presented at the ESMO Congress 2022 in Paris, France, and published simultaneously in The Lancet Oncology. The findings were previously reported at the ESMO Virtual Plenary in March 2022.
“Our findings support pembrolizumab as a potential new treatment option for patients with stage IB, II, or IIIA NSCLC after complete resection and, when recommended, adjuvant chemotherapy, regardless of PD-L1 expression”, write Mary O’Brien, from the Royal Marsden Hospital in Sutton, UK, and co-authors.
The study protocol advised that up to four cycles of adjuvant chemotherapy could be “considered” for patients with stage IB disease and was “strongly recommended” in those with stage II and IIIA disease, the investigators explain. Adjuvant therapy with the study agents began within 12 weeks of surgery for patients not receiving chemotherapy, or within 3–12 weeks after the last chemotherapy dose.
After a median 35.6 months of follow-up, adjuvant pembrolizumab given at a dose of 200 mg every 3 weeks achieved a median disease-free survival (DFS) of 53.6 months among the 590 treated patients versus 42.0 months for the 587 patients instead given placebo, giving a significant hazard ratio (HR) of 0.76 in favour of the PD-1 inhibitor.
In an analysis of the co-primary endpoint of DFS among participants with a PD-L1 tumour proportion score (TPS) of 50% or higher, median DFS was unreached among the 168 pembrolizumab-treated patients and the 165 placebo-treated controls, with a nonsignificant HR of 0.82.
“The absence of a disease-free survival benefit for pembrolizumab in the PD-L1 TPS of 50% or greater population at the time of this interim analysis was unexpected because the relative benefit of pembrolizumab monotherapy increases with increasing PD-L1 expression in the setting of locally advanced or metastatic NSCLC”, observe Mary O’Brien et al.
And although DFS was “numerically improved” for pembrolizumab-treated patients with PD-L1 TPS of 50% or above compared with those with a PD-L1 TPS of 1–49% or less than 1%, the researchers admit that “[u]nexpectedly” this pattern also occurred in the placebo arm of the trial.
At data cutoff median overall survival was immature and not reached in either treatment arm, and follow-up is continuing for both the primary and secondary endpoints, they say.
The pembrolizumab-treated patients received a median 17 doses over 11.7 months versus 18 doses over 11.8 months in the placebo arm, with the most common reason for discontinuation in the two groups being toxicity and disease progression, respectively.
Overall, grade 3 or more severe treatment-related adverse events (TRAEs) occurred in 15% and 4% of the pembrolizumab and placebo arms, respectively. Serious TRAEs occurred in 12% of the pembrolizumab arm, most frequently pneumonitis (2%) and diarrhoea (1%), as well as in 2% of placebo-treated patients, most commonly pneumonitis (1%) and colitis (<1%).
Four (1%) pembrolizumab-treated patients had fatal TRAEs, listed as cardiogenic shock plus myocarditis, septic shock plus myocarditis, pneumonia, and sudden death, whereas there were no fatal TRAEs among controls.
The investigators compare their current results with those for adjuvant chemotherapy followed by atezolizumab in the IMpower010 trial that showed improved DFS in patients with stage II–IIIA NSCLC with PD-L1 of 1% or higher and PD-L1 unselected stage II–IIIA disease, but not the overall population including patients with stage IB disease or those with stage II–IIIA disease and PD-L1 expression below 1%.
Mary O’Brien and co-authors observe that differences in study design, the enrolled populations, the PD-L1 assays used and the “overperformance” of the placebo arm in the PEARLS/KEYNOTE-091 trial subgroup of patients with PD-L1 TPS of 50% or above may have led to differences in the results of the two trials.
References
930MO - Peters S, Besse B, Marreaud SI, et al. PD-L1 expression and outcomes of pembrolizumab and placebo in completely resected stage IB-IIIA NSCLC: Subgroup analysis of PEARLS/KEYNOTE-091. Ann Oncol 2022; 33 (suppl_7): S427–S437. Doi: 10.1016/annonc/annonc1062
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; Advance online publication 12 September 2022. DOI:10.1016/S1470-2045(22)00518-6
medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group