Long-Term Outcomes and Retreatment Among Patients With Previously Treated, Programmed Death-Ligand 1‒Positive, Advanced Non‒Small-Cell Lung Cancer in the KEYNOTE-010 Study

Abstract

PURPOSE In the KEYNOTE-010 study, pembrolizumab improved overall survival (OS) versus docetaxel in previously treated, programmed death-ligand 1 (PD-L1)‒expressing advanced non‒small-cell lung cancer (NSCLC) in patients with a tumor proportion score (TPS) ≥ 50% and ≥ 1%. We report KEYNOTE-010 long-term outcomes, including after 35 cycles/2 years or second-course pembrolizumab. METHODS Of 1,033 patients randomly assigned (intention to treat), 690 received up to 35 cycles/2 years of pembrolizumab 2 mg/kg (n = 344) or 10 mg/kg (n = 346) every 3 weeks, and 343 received docetaxel 75 mg/m2 every 3 weeks. Eligible patients with disease progression after 35 cycles/2 years of pembrolizumab could receive second-course treatment (up to 17 cycles). Pembrolizumab doses were pooled because no between-dose difference was observed at primary analysis. RESULTS Pembrolizumab continued to improve OS over docetaxel in the PD-L1 TPS ≥ 50% and ≥ 1% groups (hazard ratio [HR], 0.53; 95% CI, 0.42 to 0.66; P < .00001; and HR, 0.69; 95% CI, 0.60 to 0.80; P < .00001, respectively) after a 42.6-month (range, 35.2-53.2 months) median follow-up. Estimated 36-month OS rates were 34.5% versus 12.7% and 22.9% versus 11.0%, respectively. Grade 3-5 treatment-related adverse events occurred in 16% versus 37% of patients, respectively. Seventy-nine of 690 patients completed 35 cycles/2 years of pembrolizumab; 12-month OS and progression-free survival rates after completing treatment were 98.7% (95% CI, 91.1% to 99.8%) and 72.5% (95% CI, 59.9% to 81.8%), respectively. Seventy-five patients (95%) had objective response (RECIST v1.1, blinded independent central review) and 48 (64%) had ongoing response. Grade 3-5 treatment-related adverse events occurred in 17.7% of patients. Fourteen patients received second-course pembrolizumab: 5 completed 17 cycles, 6 (43%) had partial response, and 5 (36%) had stable disease. CONCLUSION Pembrolizumab provided long-term OS benefit over docetaxel, with manageable safety, durable responses among patients receiving 2 years of treatment, and disease control with second-course treatment, further supporting pembrolizumab for previously treated, PD-L1‒expressing advanced NSCLC.

<p>Toll-Like Receptor 9 Agonists in Cancer</p>

“…Anti-PD(L)1 immune checkpoint inhibitors (ICI) singly or in combination with anti-CTLA-4 or other agents are approved across multiple indications in sixteen separate diseases including a histology-agnostic indication in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors. 1,2 The hallmark of ICI therapy is the durability of responses in a subset of patients as evidenced by progression-free survival (PFS) rates of 21-29% in melanoma and 22% in non-small cell lung cancer (NSCLC) with anti-PD(L)1 singly; [3][4][5][6][7] and up to 36% with anti-PD-1/anti-CTLA-4 dual ICI in melanoma. 8 However, the majority of patients do relapse and the question of how to improve outcomes in these patients remains a vexing problem for the field.…”

Comprehensive analysis of prognostic immune-related genes in the tumor microenvironment of lung adenocarcinoma

“…Consistent with these results, previous studies have shown that the biological processes of the immune system are critical to the formation of a complicated LUAD tumor microenvironment 10,30,[37][38][39] . In the past few years, the understanding of the immunological characteristics of LUAD has increased, and the development of effective LUAD immunotherapy strategies has drawn wide attention [40][41][42][43][44] .…”

Re-biopsy after first line treatment in advanced NSCLC can reveal changes in PD-L1 expression

“…Despite the imperfection of PD-L1 TPS due to heterogeneity, it has proven to be an independent predictive biomarker of response to immune-checkpoint inhibitors in guidance of first and second line treatment in advanced NSCLC [2][3][4][27][28][29][30][31]. Improvement in median PFS from 6.0 months (95% CI, 4.2− 6.2) with chemotherapy to 10.3 months (95% CI, 6.7-NR) with pembrolizumab has changed first line treatment algorithm in advanced NSCLC patients with PD-L1 TPS ≥50% [27,28].…”

“…Second line treatment of advanced NSCLC is largely independent of PD-L1 TPS, according to European Society of Medical Oncology (ESMO) Clinical Practice Living Guidelines of Metastatic Non-Small-Cell Lung [32], although the type of immune-checkpoint inhibitor therapy can be affected. Hence, second line pembrolizumab is only recommended if PD-L1 TPS is ≥1% according to results of the KEYNOTE-010 study [29,30], and atezolizumab/nivolumab can be administered regardless of PD-L1 TPS according to results of the CHECKMATE 017/057 [2,3] and OAK trials [4,31]. These guidelines are primarily based on studies with no mandatory new biopsy for PD-L1 TPS analyses, although in KEYNOTE-010 (including patients with PD-L1 TPS ≥ 1%), a protocol amendment required a new biopsy for PD-L1 TPS, except when it risked patient safety.…”