Renal function-based versus standard dosing of pemetrexed: a randomized controlled trial

Our plain-English summary of Renal function-based versus standard dosing of pemetrexed: a randomized controlled trial, by N. de Rouw, R.J. Boosman, J.A. Burgers, et al (Cancer Chemotherapy and Pharmacology, 2023).

The study

• Authors: N. de Rouw, R.J. Boosman, J.A. Burgers, A.D.R. Huitema, A.C. Dingemans, H.J. Derijks, D.M. Burger, B. Piet, L.E.L. Hendriks, B. Biesma, M.A. Pruis, D.W. Dumoulin, S. Croes, R.H.J. Mathijssen, M.M. van den Heuvel, R. Ter Heine
• Journal: Cancer Chemotherapy and Pharmacology
• Published: 2023;91(1):33-42
• Type of article: Randomized trial
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: Pemetrexed is a chemotherapeutic drug in the treatment of non-small cell lung cancer and mesothelioma. Optimized dosing of pemetrexed based on renal function instead of body surface area (BSA) is hypothesized to reduce pharmacokinetic variability in systemic exposure and could therefore improve treatment outcomes. The aim of this study is to compare optimized dosing to standard BSA-based dosing.

Methods: A multicenter randomized (1:1) controlled trial was performed to assess superiority of optimized dosing versus BSA-based dosing in patients who were eligible for pemetrexed-based chemotherapy. The individual exposure to pemetrexed in terms of area under the concentration-time curve (AUC) was determined. The fraction of patients attaining to a predefined typical target AUC (164 mg × h/L ± 25%) was calculated.

Results: A total of 81 patients were included. Target attainment was not statistically significant different between both arms (89% vs. 84% (p = 0.505)). The AUC of pemetrexed was similar between the optimized dosing arm (n = 37) and the standard of care arm (n = 44) (155 mg × h/L vs 160 mg × h/L (p = 0.436).

Conclusion: We could not show superiority of optimized dosing of pemetrexed in patients with an adequate renal function does not show added value on the attainment of a pharmacokinetic endpoint, safety, nor QoL compared to standard of care dosing.

Clinical Trial Number: Clinicaltrials.gov identifier: NCT03655821.

© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

In plain English

This Dutch multicenter, open-label, randomized phase II trial (IMPROVE-II) tested whether dosing the chemotherapy drug pemetrexed by kidney function, instead of the standard dose based on body surface area, would bring more patients to a target total exposure to the drug over time (the area under the blood concentration–time curve, or AUC). It included 81 patients between March 2019 and April 2021: 62 with non-small cell lung cancer, 16 with mesothelioma and 3 with thymoma. It did not study asbestos exposure. Enrolment stopped early during the COVID-19 pandemic, at 81 of 94 planned patients. The target exposure was reached by 37 of 44 patients (84.1%) on standard dosing and 33 of 37 (89.1%) on kidney-based dosing. The difference was not statistically significant (p = 0.505). Blood-count side effects, treatment delays and dose reductions did not differ significantly between the groups, and patients' quality-of-life scores did not change significantly over the study. The authors concluded that they could not support the superiority of kidney-function-based dosing in patients with adequate kidney function. They noted that the narrow range of kidney function among their patients raised questions about the study's power.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Multicenter, open-label, randomized (1:1) phase II controlled trial (IMPROVE-II)
• Who was studied: 81 patients eligible for pemetrexed-based treatment with predicted creatinine clearance above 45 mL/min, at hospitals in the Netherlands, March 2019 to April 2021: 44 in the standard (body surface area) arm and 37 in the kidney-function arm. Diagnoses were non-small cell lung cancer (62, 77%), mesothelioma (16, 20%) and thymoma (3, 4%).
• Exposure: Not an asbestos exposure study. The comparison was pemetrexed given at the standard 500 mg/m2 dose, based on body surface area, versus a dose calculated each cycle from creatinine clearance (Cockcroft–Gault). Treatment was every 21 days for up to four cycles, alone or with carboplatin or cisplatin and/or pembrolizumab.
• Main results:
  • The share of patients reaching the target exposure (an individual AUC of 123–205 mg × h/L) did not differ significantly between arms: 37 of 44 (84.1%) in the standard arm versus 33 of 37 (89.1%) in the kidney-function arm, p = 0.505.
  • Geometric mean AUC was 159.9 mg × h/L in the standard (body surface area) arm and 154.7 mg × h/L in the kidney-function arm (p = 0.436).
  • Within the standard arm only, drug exposure differed significantly between patients with creatinine clearance below 95 mL/min and those at or above 95 mL/min (p = 0.003). No such difference was seen in the kidney-function arm (p = 0.34).
  • There were no statistically significant differences between arms in blood-count side effects. Grade III/IV events ranged from 0 to 15.9%; for example, grade 3 or higher neutropenia occurred in 7 of 44 (15.9%) on standard dosing and 4 of 36 (11.1%) on kidney-function dosing. Treatment delays and dose reductions also did not differ significantly.
  • The median pemetrexed dose per cycle was lower in the kidney-function arm (850 mg) than in the standard arm (950 mg).
  • Among the 58 patients who completed the questionnaires at both time points, quality-of-life scores at 12 weeks were not significantly different from baseline in any of the four categories. The change was not significantly different between arms.
• The authors' conclusion: The authors concluded that they could not support the superiority of renal function-based dosing of pemetrexed in patients with adequate renal function. They said further research in patients with moderate renal function is needed.
• Limitations the authors state:
  • Few patients had kidney function at the extremes of the range, so the authors said the study's power is questionable and definitive conclusions are difficult.
  • Enrolment was halted during the COVID-19 pandemic. An unplanned interim analysis was done after 81 of the 94 planned patients.
  • Most patients also received other cancer drugs with overlapping side effects, so the side effects of pemetrexed alone could not be established.
  • The small patient groups made quality of life hard to assess.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Non-Small Cell Lung Cancer, Mesothelioma, Chemotherapy.

Related studies

• Pharmacokinetically-guided dosing of pemetrexed in a patient with renal impairment and a patient requiring hemodialysis — N. de Rouw, S. Croes, et al. (2019)
• Folinic Acid Prophylaxis and Dose Adjustments Enable Safe Treatment with Pemetrexed in Patients with Renal Impairment — N. de Rouw, L.S. Otten, et al. (2025)
• Rethinking the Application of Pemetrexed for Patients with Renal Impairment: A Pharmacokinetic Analysis — N. de Rouw, R.J. Boosman, et al. (2021)
• Protocol for a Randomized Controlled Trial of Proactive Web-Based Versus Telephone-Based Information and Support: Can Electronic Platforms Deliver Effective Care for Lung Cancer Patients? — C.L. Paul, A.W. Boyes, et al. (2016)
• Simple nutritional intervention in patients with advanced cancers of the gastrointestinal tract, non-small cell lung cancers or mesothelioma and weight loss receiving chemotherapy: a randomised controlled trial — C. Baldwin, A. Spiro, et al. (2011)
• Effect of renal function on pemetrexed-induced haematotoxicity — Y. Ando, T. Hayashi, et al. (2016)

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