Nephrotoxicity Risk Factors with Use of Pemetrexed in Patients with NSCLC

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Pemetrexed is an antifolate drug approved as first-line treatment for patients with advanced nonsquamous, non–small-cell lung cancer (NSCLC) in combination with platinum-based chemotherapy.1 In patients with relapsed or refractory NSCLC after treatment with platinum-based chemotherapy it is approved as a single-use agent, and it is also used as maintenance therapy after induction chemotherapy.1 When used as maintenance therapy, it has been demonstrated to prolong both overall survival and progression-free survival. Pemetrexed is eliminated through the kidneys and can cause nephrotoxicity.1 In a clinical trial, 21% of patients treated with pemetrexed had a decline in renal function, with 8.1% opting to discontinue treatment due to nephrotoxicity. A second clinical trial demonstrated that pemetrexed maintenance treatment led to a significant increase in serum creatinine levels over baseline when compared with placebo use. This finding led to dose delays and treatment discontinuation.

To determine the risk factors associated with the development of nephrotoxicity in patients with metastatic nonsquamous NSCLC treated with maintenance pemetrexed, Kwok and colleagues conducted a retrospective single-center cohort study in 134 patients with NSCLC. The mean patient age was 63 years, 53% of the patients were female, and 48.5% of patients had EGFR mutations. The study’s primary outcome was a ≥30% reduction in creatinine clearance (CrCl) calculated by measurement of serum creatinine at baseline and at the end of therapy. The patients were on first-line chemotherapy with pemetrexed, and platinum was given every 3 weeks during induction, followed by maintenance pemetrexed every 3 to 4 weeks. All patients received daily oral folic acid and a 1-mg vitamin B12 intramuscular injection every 9 weeks. Carboplatin was the platinum choice for 89.6% of patients while 10.4% received cisplatin. The median pemetrexed cycle number was 10.

The mean CrCl at baseline was 75.9 ± 23.5 mL/min; at the end of treatment it was 69.6 ± 21.2 mL/min. Renal impairment was found in 14 patients during the course of their disease, with 4 patients experiencing a CrCl <45 mL/min. Patients with third-space fluid found at diagnosis, those with nonevacuated third-space fluid found during the course of treatment, those who received >15 cycles of pemetrexed maintenance, and those who had cisplatin during induction had more significant nephrotoxicity. Risk factors for developing nephrotoxicity with use of pemetrexed during maintenance were the use of cisplatin during induction, the presence of nonevacuated third-space fluid, and >15 cycles of maintenance pemetrexed. This risk remained even after adjusting for gender, comorbidities, Eastern Cooperative Oncology Group performance status, and age. To reduce the development of nephrotoxicity, carboplatin should be used if possible and third-space fluid should be evacuated.


Kwok WC, Chiang KY, Ho JCM, et al. Risk factors of nephrotoxicity of maintenance pemetrexed in patients with metastatic non-squamous non-small cell carcinoma of lung. Lung Cancer. 2021;162:169-174.


  1. Joerger M, Omlin A, Cerny T, Früh M. The role of pemetrexed in advanced non small-cell lung cancer: special focus on pharmacology and mechanism of action. Curr Drug Targets. 2010;11:37-47.

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