Evaluation of changes in renal function in PARAMOUNT: a phase III study of maintenance pemetrexed plus best supportive care versus placebo plus best supportive care after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer

Abstract

Objectives: To assess the effect of long-term pemetrexed maintenance therapy on patients’ renal function.

Methods: In the PARAMOUNT phase III trial (NCT 00789373), pemetrexed was compared with placebo as maintenance treatment in advanced nonsquamous non-small-cell lung cancer patients who completed 4 cycles of pemetrexed plus cisplatin induction therapy. To evaluate changes in renal function during pemetrexed continuation maintenance treatment, we retrospectively analyzed changes in serum creatinine (sCr), treatment-emergent adverse events, dose delays and treatment discontinuations associated with impaired renal function.

Results: Creatinine clearance ≥45 mL/min was required before the start of any cycle. Patients on pemetrexed maintenance had a significantly higher percentage maximum increase in sCr over baseline versus placebo for the range of ≥10% to ≥90% increase (p < .05). The risk of experiencing renal events leading to dose delays and discontinuations was higher with higher increases in sCr but reversible in most patients. sCr increases of ≥30% and ≥40% were associated with gender (female), age (<70 years) and longer exposure to pemetrexed compared with placebo. Sixteen (4%) pemetrexed patients and 1 (1%) placebo patient discontinued treatment due to drug-related renal events; 13/16 (81%) of those pemetrexed patients had sCr increases ≥30% and 7/13 (54%) had pre-existing conditions and/or were receiving nephrotoxic drugs.

Conclusions: The appearance of renal events leading to dose delays and/or treatment discontinuations was associated with sCr increase of at least 30%. However, it was difficult to identify patients at a higher risk of treatment discontinuation due to a drug-related renal event based only on changes in pre-maintenance laboratory values.

Keywords:

• Creatinine clearance
• maintenance therapy
• non-small-cell-lung cancer
• pemetrexed
• serum creatinine
• renal toxicity

Transparency

Declaration of funding

This work was sponsored and funded by Eli Lilly and Company, Indianapolis, IN, USA, and/or any of its subsidiaries. Eli Lilly and Company was responsible for the study design; the collection, analysis, and interpretation of data; and the decision to submit this report for publication.

Author contributions: All authors have contributed to the conception and design of this manuscript, drafted and critically revised the manuscript for intellectual content, and approved the final version of the manuscript. All authors have agreed to be accountable for all aspects of the work.

Declaration of financial/other relationships

C.M.V.-G., B.S.A., W.J.J., A.H.Z. and N.C. have disclosed that they are employees of Eli Lilly and Company. C.G. has disclosed that he has received honoraria as a speakers bureau member and held an advisory role for Eli Lilly and Company. G.M. has disclosed that he has received honoraria as a speakers bureau member and held an advisory role for Eli Lilly and Company. L.P.-A. has disclosed that he received honoraria and participated in a speakers bureau for Eli Lilly and Company. J.-L.P. has disclosed that he served as a consultant for Eli Lilly and Company. M.R. has disclosed that he served as a consultant (compensated) for Eli Lilly and Company and received honoraria for lectures from Eli Lilly and Company, Hoffmann-La Roche, Bristol-Myers Squibb, Merck Sharp & Dohme (MSD), AstraZeneca, Boehringer-Ingelheim, Novartis and Pfizer. F.D.M., B.P., T.P. and R.R. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article.

CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgements

We thank all of the patients, their families, and clinical personnel who participated in this clinical trial. The authors also thank Michael Ossipov, Ira Ayene, and Sarah Becker-Marrero for assistance with writing and editorial services. Eli Lilly and Company contracted inVentiv Health Clinical LLC for writing and editorial services.