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An assessment of extended pembrolizumab dosing in advanced non-small-cell lung cancer in the COVID-19 pandemic.

ABSTRACT: Background: There are limited clinical data comparing extended dosing (ED) versus standard dosing (SD) of pembrolizumab for metastatic non-small-cell lung cancer. Methods: This retrospective study included patients with metastatic non-small-cell lung cancer and PD-L1 tumor proportion score ≥50% treated with one or more cycles of single-agent pembrolizumab with SD or ED from January 2018 to December 2020. Results: A higher proportion of patients were alive in the ED group (vs SD) at 6 months (94 vs 51%), 12 months (94 vs 33%) and data cutoff (94 vs 26%) (p < 0.001 for all). The rate (44 vs 32%; p = 0.407) and severity of grade ≥3 immune-related adverse events were similar (50 vs 52%); however, ED patients more frequently discontinued treatment due to toxicity (45 vs 15%; p < 0.001). Conclusion: A greater proportion of ED patients were alive at data cutoff, and the rate and severity of immune-related adverse events were similar between groups.

SUBMITTER: Moffat GT

PROVIDER: S-EPMC10340130 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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An assessment of extended pembrolizumab dosing in advanced non-small-cell lung cancer in the COVID-19 pandemic.

Moffat Gordon Taylor GT Hanna Lilian L Hopman Wilma W Fung Andrea S AS Gaudreau Pierre-Olivier PO

Immunotherapy 20230711 12

Background: There are limited clinical data comparing extended dosing (ED) versus standard dosing (SD) of pembrolizumab for metastatic non-small-cell lung cancer. Methods: This retrospective study included patients with metastatic non-small-cell lung cancer and PD-L1 tumor proportion score ≥50% treated with one or more cycles of single-agent pembrolizumab with SD or ED from January 2018 to December 2020. Results: A higher proportion of patients were alive in the ED group (vs ...[more]

PMID: 37431608

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Project description:BackgroundIn the phase I KEYNOTE-001 study, pembrolizumab demonstrated durable antitumor activity in patients with advanced non-small-cell lung cancer (NSCLC). We sought to characterize the relationship between pembrolizumab dose, exposure, and response to define an effective dose for these patients.Patients and methodsPatients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) (n = 55), 10 mg/kg Q3W (n = 238), or 10 mg/kg Q2W (n = 156). Response (RECIST v1.1) was assessed every 9 weeks. The relationship between the estimated pembrolizumab area under the concentration-time curve at steady state over 6 weeks (AUCss-6weeks) and the longitudinal change in tumor size (sum of longest diameters) was analyzed by regression and non-linear mixed effects modeling. This model was simultaneously fit to all tumor size data, then used to simulate response rates, normalizing the trial data across dose for prognostic covariates (tumor PD-L1 expression and EGFR mutation status). The exposure-safety relationship was assessed by logistic regression of pembrolizumab AUCss-6weeks versus occurrence of adverse events (AEs) of interest based on their immune etiology.ResultsOverall response rates were 15% [95% confidence interval (CI) 7%-28%] at 2 mg/kg Q3W, 25% (18%-33%) at 10 mg/kg Q3W, and 21% (95% CI 14%-30%) at 10 mg/kg Q2W. Regression analyses of percentage change from baseline in tumor size versus AUCss-6weeks indicated a flat relationship (regression slope P > 0.05). Simulations showed the exposure-response relationship to be similarly flat, thus indicating that the lowest evaluated dose of 2 mg/kg Q3W to likely be at or near the efficacy plateau. Exposure-safety analysis showed the AE incidence to be similar among the clinically tested doses.ConclusionsNo significant exposure dependency on efficacy or safety was identified for pembrolizumab across doses of 2-10 mg/kg. These results support the use of a 2 mg/kg Q3W dosage in patients with previously treated, advanced NSCLC.Clinicaltrialsgov registryNCT01295827.

Project description:BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but come with high costs. Alternative ICI dosing strategies could reduce costs without losing efficacy. However, clinical efficacy data are lacking.MethodsIn this retrospective cohort trial, consecutive patients with advanced non-small cell lung cancer (NSCLC) who received ≥1 cycle pembrolizumab±chemotherapy at two tertiary institutions were included. Hybrid dosed patients received either 100, 150 or 200 mg pembrolizumab every 3 weeks or double every 6 weeks depending on their weight: <65 kg, 65-90 kg or >90 kg, respectively. Standard-of-care flat dosed patients received 200 mg every 3 weeks or 400 mg every 6 weeks. Overall survival (OS) and progression-free survival (PFS) were assessed by Kaplan-Meier estimation, compared by log-rank test and HRs were calculated with the Cox proportional hazards model in both unweighted and inverse probability of treatment weighted (IPTW) cohorts. Non-inferiority margin was set at an HR of 1.15.ResultsIn total, 375 patients and 391 patients were included and median follow-up was 43.1 and 61.0 months in the hybrid and flat dose cohort, respectively. OS was non-inferior in the hybrid dose cohort compared with the flat dose cohort: median 17.7 months (95% CI 14.9 to 20.9) vs 11.8 months (95% CI 9.3 to 13.8, HR 0.76, 95% CI 0.65 to 0.90, p<0.0001 for non-inferiority). After correcting for confounders by IPTW, OS remained non-inferior (HR 0.76, 95% CI 0.63 to 0.91, p<0.0001 for non-inferiority). PFS in the hybrid cohort was also non-inferior to the flat dose cohort with a median of 6.4 months (95% CI 5.7 to 7.7) vs 4.6 months (95% CI 3.9 to 5.5, HR 0.82, 95% CI 0.70 to 0.96, p<0.0001 for non-inferiority). In total, 26.2% (or 52.5 mg per cycle, p<0.0001) pembrolizumab was saved in the hybrid dose cohort accounting to US$36 331.36 per patient.ConclusionsIn this retrospective analysis of a large cohort of advanced NSCLC patients treated with pembrolizumab±chemotherapy, OS of hybrid dosed patients was non-inferior to flat dosed patients. OS remained non-inferior after correcting for possible confounding factors. This hybrid regimen resulted in significant savings of pembrolizumab and costs.

Project description:BACKGROUNDThe anti-programmed cell death 1 (anti-PD-1) antibody pembrolizumab is clinically active against non-small cell lung cancer (NSCLC). In addition to T cells, human natural killer (NK) cells, reported to have the potential to prolong the survival of patients with advanced NSCLC, also express PD-1. This study aimed to investigate the safety and efficacy of pembrolizumab plus allogeneic NK cells in patients with previously treated advanced NSCLC.METHODSIn total, 109 enrolled patients with a programmed death ligand 1 (PD-L1) tumor proportion score (TPS) of 1% or higher were randomly allocated to group A (n = 55 patients given pembrolizumab plus NK cells) or group B (n = 54 patients given pembrolizumab alone). The patients received i.v. pembrolizumab (10 mg/kg) once every 3 weeks and continued treatment until the occurrence of tumor progression or unacceptable toxicity. The patients in group A continuously received 2 cycles of NK cell therapy as 1 course of treatment.RESULTSIn our study, patients in group A had longer survival than did patients in group B (median overall survival [OS]: 15.5 months vs. 13.3 months; median progression-free survival [PFS]: 6.5 months vs. 4.3 months; P < 0.05). In group A patients with a TPS of 50% or higher, the median OS and PFS was significantly longer. Moreover, the patients in group A treated with multiple courses of NK cell infusion had better OS (18.5 months) than did those who received a single course of NK cell infusion (13.5 months).CONCLUSIONPembrolizumab plus NK cell therapy yielded improved survival benefits in patients with previously treated PD-L1+ advanced NSCLC.TRIAL REGISTRATIONClinicalTrials.gov NCT02843204.FUNDINGThis work was supported by grants from the National Natural Science Foundation of China (NSFC) - Guangdong Joint Foundation of China (no. U1601225); the NSFC (no. 81671965); the Guangdong Provincial Key Laboratory Construction Project of China (no. 2017B030314034); and the Key Scientific and Technological Program of Guangzhou City (no. 201607020016).

Dataset Information

An assessment of extended pembrolizumab dosing in advanced non-small-cell lung cancer in the COVID-19 pandemic.

Publications

An assessment of extended pembrolizumab dosing in advanced non-small-cell lung cancer in the COVID-19 pandemic.

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