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. 2025 Sep;118(3):715-722.
doi: 10.1002/cpt.3735. Epub 2025 May 27.

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

Nikki de Rouw  1   2 , Leila-Sophie Otten  2 , Mart P Kicken  2   3 , Berber Piet  4 , Bonne Biesma  5 , Bianca van Veggel  5 , Christi M J Steendam  6 , Ben van den Borne  6 , Lizza E L Hendriks  7 , Sander Croes  8 , Anne-Marie C Dingemans  9 , Daphne W Dumoulin  9 , Ron H J Mathijssen  10 , Jacobus A Burgers  11 , Alwin D R Huitema  12   13   14 , Hieronymus J Derijks  15 , Maarten J Deenen  3   16 , Michel M van den Heuvel  4 , Rob Ter Heine  2
Affiliations

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

Nikki de Rouw et al. Clin Pharmacol Ther. 2025 Sep.

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.

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Conflict of interest statement

BP: Research funding: Amgen, Treatmeds. Advisory boards: Bristol‐Myers Squibb, Janssen, Pfizer, Takeda, Merck. Advisory/Speaker fees: AstraZeneca, Janssen, Pfizer. All fees paid to the institution/department, no personal fees. Other: Committee member Off‐label Oncological Medication (CIE‐OOM). Guideline committee: Patient counseling for genetic tumordiagnostics. Board Member Netherlands Respiratory Society. CS: Research funding: AstraZanaeca, NVALT studies, ICON Clinical Research/Arcus biosciences, VitroScan Leiden. Advisory: BMS. Other: Lilly. AD: Institutional fees from Roche, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Janssen, Chiezi, Amgen, Pfizer, Bayer, Takeda, Pharmamar, Sanofi, and Daiichi; RM: Research funding paid to the institute from Astellas, Bayer, Boehringer‐Ingelheim, Cristal Therapeutics, Novartis, Pamgene, Pfizer, Roche, Sanofi, and Servier. BvV: Advisory/Speaker fees: Astra‐Zeneca, BMS, Novartis, Lilly, Roche. LH: Research funding Roche Genentech, AstraZeneca, Boehringer Ingelheim, Takeda, Merck, Pfizer, Novartis, Gilead. Speaker educationals/webinars: AstraZeneca, Bayer, Lilly, MSD, high5oncology, Takeda, Janssen, GSK, Sanofi, Pfizer (Inst), Medtalks, Benecke, VJOncology, Medimix (self). Advisory boards: Amgen, Boehringer Ingelheim, Lilly, Novartis, Pfizer, Takeda, Merck, Janssen, MSD, Anheart, Bayer, AZ. Member guideline committees: Dutch guidelines on NSCLC, brain metastases, and leptomeningeal metastases (self), ESMO guidelines on metastatic NSCLC and SCLC (non‐financial). Other (non‐financial): secretary NVALT studies foundation, subchair EORTC metastatic NSCLC systemic therapy, vice‐chair scientific committee Dutch Thoracic Group. DD: Advisory/Speaker fees: Amgen, BMS, MSD, Novartis, Roche. MvdH: Research funding: AstraZeneca, BMS, Janssen, Treatmeds, Merck, MSD, Novartis, Pfizer, Roche, Roche diagnostics. Advisory/Speaker fees: Abbvie, AstraZeneca, BMS, Lilly, MSD, Novartis, Pfizer, Roche. Other: SON‐NVALT, NVALTstudies, Longkankernet. RtH: Research funding: Amgen. All other authors declared no competing interests for this work.

Figures

Figure 1
Figure 1
Geometric mean of the area under the concentration–time curve (AUC) plus 90% confidence intervals for patients with impaired renal function from this study (left) and patients with adequate renal function treated conform standard of care (SOC) (pemetrexed 500 mg/m2) from the IMPROVE‐II study. The dashed lines indicate the therapeutic range of 164 mg*h/L ± 25%.
Figure 2
Figure 2
Individual pharmacokinetic curves at 100% dose level.
See this image and copyright information in PMC

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