Folinic Acid Prophylaxis and Dose Adjustments Enable Safe Treatment with Pemetrexed in Patients with Renal Impairment

Our plain-English summary of Folinic Acid Prophylaxis and Dose Adjustments Enable Safe Treatment with Pemetrexed in Patients with Renal Impairment, by N. de Rouw, L.S. Otten, M.P. Kicken, et al (Clinical Pharmacology and Therapeutics, 2025).

The study

• Authors: N. de Rouw, L.S. Otten, M.P. Kicken, B. Piet, B. Biesma, B. van Veggel, C.M.J. Steendam, B. van den Borne, L.E.L. Hendriks, S. Croes, A.C. Dingemans, D.W. Dumoulin, R.H.J. Mathijssen, J.A. Burgers, A.D.R. Huitema, H.J. Derijks, M.J. Deenen, M.M. van den Heuvel, R. Ter Heine
• Journal: Clinical Pharmacology and Therapeutics
• Published: 2025;118(3):715-722
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Pemetrexed is a cornerstone in chemo(immunotherapy) of non-small cell lung cancer and mesothelioma; however, it is contraindicated in patients with renal impairment due to severe toxicity concerns. Therefore, a large proportion of patients is withheld from effective chemo(immunotherapy). We performed an intra-patient 3 + 3 dose escalation renal impairment study (eGFR < 45 mL/min). The pemetrexed dose was calculated based on renal function to reach a target AUC, and patients received oral folinic acid prophylaxis 45 mg four times daily on Days 2-15 of each cycle. Endpoints included safety (incidence of hematological and non-hematological toxicity, treatment delays) and pharmacokinetics in line with regulatory guidance for renal impairment trials. Six patients with an estimated glomerular filtration rate (eGFR) between 26 and 41 mL/min were included. All patients were successfully escalated to the full dose. Adverse event patterns and pharmacokinetics were comparable to those in patients with normal renal function. Grade I/II anemia occurred in five patients (already present at baseline). One occurrence of grade IV neutropenia was observed, which resolved without intervention. Moreover, in three patients, a 1-week treatment delay occurred. Treatment resulted in a response in four patients (n = 1 complete response, n = 2 partial response, n = 1 stable disease). Pemetrexed can be safely administered in patients with impaired renal function when the dose is calculated based on renal function and folinic acid prophylaxis is administered, thereby enabling an effective treatment modality for patients that, thus far, could not be treated.

© 2025 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

In plain English

This small dose-escalation study, done at three Dutch hospitals, tested the cancer drug pemetrexed in people with reduced kidney function (eGFR below 45 mL/min), for whom the drug is normally contraindicated. It did not study asbestos, and all six evaluable patients had non-small cell lung cancer, not mesothelioma. Eight patients were enrolled; six were evaluable, with eGFR of 26 to 41 mL/min. Doses were calculated from kidney function to reach a target exposure, and patients took oral folinic acid 45 mg four times daily on Days 2 to 15 of each cycle. All six reached the full dose, with drug exposure inside the predefined target range (geometric mean AUC 170 mg*h/L, 90% CI 152 to 190). One patient had one grade IV low neutrophil count that resolved within a week; another was briefly admitted for rehydration, graded as a grade III toxicity. One patient had a complete response, two a partial response, one stable disease and two progressive disease. The authors concluded the strategy resulted in safe treatment, while acknowledging the small sample size.

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: Prospective intra-patient 3 + 3 dose-escalation renal impairment study (IMPROVE-I) run in two cohorts of three patients at Radboudumc Nijmegen, Catharina Hospital Eindhoven and Jeroen Bosch Hospital Den Bosch, the Netherlands; endpoints were safety and pharmacokinetics.
• Who was studied: Patients with an indication for pemetrexed-containing therapy and eGFR or creatinine clearance below 45 mL/min. Eight were enrolled and six were evaluable, with eGFR between 26 and 41 mL/min. All six had non-small cell lung cancer (five stage IV, one stage III). There were four men and two women, aged 64 to 78. Study dates are not given.
• Exposure: No asbestos exposure was studied. The exposure was the drug pemetrexed, dosed from renal function (CKD-EPI eGFR) and body weight to reach a target AUC of 164 mg*h/L, plus oral folinic acid prophylaxis 45 mg four times daily on Days 2 to 15 of each 21-day cycle. This was given alongside standard folic acid and vitamin B12, and in combination with carboplatin, with or without pembrolizumab.
• Main results:
  • Eight patients were enrolled, of whom six were evaluable; two dropped out due to rapid disease progression before pharmacokinetic evaluation.
  • All six patients had non-small cell lung cancer (NSCLC); five had stage IV and one had stage III disease.
  • All six patients escalated to the full dose and were within the predefined pharmacokinetic target range (164 mg*h/L plus or minus 25%).
  • In the six renal-impairment patients, the geometric mean AUC was 170 mg*h/L (90% CI 152 to 190 mg*h/L).
  • For comparison, the geometric mean AUC in the standard-dosing cohort with adequate renal function from the earlier IMPROVE-II study (n = 44) was 171 mg*h/L. The article prints its 90% CI as 153 to 168 mg*h/L, which does not contain 171.
  • Grade I/II anemia was already present at baseline in five of six patients.
  • Patient 6 had one measurement of grade IV decreased neutrophil count in Cycle 4, which resolved spontaneously within 1 week.
  • Patient 6 needed two cycle delays to recover from grade III pancytopenia. Patient 2 had a 1-week delay for persistent grade II thrombocytopenia. Patient 3 had a 1-week delay for elevated serum creatinine and a lower airway infection.
  • Patient 4 was briefly admitted for rehydration, which was reported as a grade III toxicity that resolved after treatment.
  • The authors reported no dose-limiting toxicities that limited pemetrexed treatment or did not resolve without intervention. In the discussion they state that one patient's ongoing grade III/IV hematological toxicity leading to treatment delay was classified as a DLT.
  • Treatment outcomes among the six patients were 1 complete response, 2 partial responses, 1 stable disease and 2 progressive disease (patients 3 and 5). The authors count stable disease among the four 'responses'.
• The authors' conclusion: The authors concluded that, in patients with moderate renal impairment, pemetrexed dosed on renal function to reach a target AUC combined with folinic acid prophylaxis resulted in safe treatment and exposure equivalent to that of the approved dose in patients with adequate renal function. They postulated, without supporting data, that it may also apply in severe renal impairment, and said real-world data should confirm this.
• Limitations the authors state:
  • Small sample size of six patients (the authors argue this follows from the 3 + 3 design).
  • Pharmacokinetics were assessed only at the 100% dose level.
  • Patients' eGFR ranged only from 26 to 41 mL/min, so validity outside that range is unknown.
  • The optimal timing for starting folinic acid was not investigated.

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), Immunotherapy, Non-Small Cell Lung Cancer, Mesothelioma, EGFR, Neutropenia.

Related studies

• Rethinking the Application of Pemetrexed for Patients with Renal Impairment: A Pharmacokinetic Analysis — N. de Rouw, R.J. Boosman, et al. (2021)
• Renal failure during chemotherapy: renal biopsy for assessing subacute nephrotoxicity of pemetrexed — M. Assayag, P. Rouvier, et al. (2017)
• Pharmacokinetically-guided dosing of pemetrexed in a patient with renal impairment and a patient requiring hemodialysis — N. de Rouw, S. Croes, et al. (2019)
• Renal function-based versus standard dosing of pemetrexed: a randomized controlled trial — N. de Rouw, R.J. Boosman, et al. (2023)
• Pemetrexed induced acute kidney injury in patients with non-small cell lung cancer: reversible and chronic renal damage — G. Rombolà, F. Vaira, et al. (2015)
• Gene and MicroRNA Perturbations of Cellular Response to Pemetrexed Implicate Biological Networks and Enable Imputation of Response in Lung Adenocarcinoma — E.R. Gamazon, M.R. Trendowski, et al. (2018)

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