A randomized, multicenter phase II study comparing efficacy, safety and tolerability of two dosing regimens of cisplatin and pemetrexed in patients with advanced or metastatic non-small-cell lung cancer.

Background: Pemetrexed and cisplatin is a first-line standard in non-squamous non-small-cell lung cancer without targetable mutations. It became the backbone of checkpoint-inhibitor-chemotherapy combinations. Single high doses of cisplatin pose toxicity risks and require hyperhydration, potentially prolonging outpatient application. The aim of this study was to compare efficacy, safety and tolerability of split-dose cisplatin with the standard schedule.
Methods: Patients with metastatic non-squamous non-small-cell lung cancer were randomly assigned to up to six 21-day cycles of pemetrexed 500 mg/m ² and cisplatin 75 mg/m ² on day 1 (arm A), or pemetrexed 500 mg/m ² (day 1) and cisplatin 40 mg/m ² (day 1 + 8, arm B), followed by pemetrexed maintenance. Primary endpoint was objective response rate. Secondary objectives were overall survival, progression-free survival, time to progression, treatment compliance, toxicity profile, and quality of life.
Results: We enrolled 130 patients (129 evaluable). Median cycle numbers in A and B were six (1-6) and five (1-6). Dose intensities were comparable between arms. More patients in A received pemetrexed maintenance (24.2% versus 11.1%). With 16 (24.2%) in A and 19 (30.2%) patients in B achieving objective responses [odds ratio 0.74 (0.34-1.62), p  = 0.55] the primary endpoint was met. Overall survival was not different between arms (median 14.4 versus 14.9 months); [HR = 1.07; (0.68-1.68), p  = 0.78]. Median progression-free survival was 7.0 months in A and 6.2 months in B [HR = 1.63; (1.17-2.38); p  = 0.01]. Adverse events of CTCAE grade ⩾3, particularly hematological, were more frequent in B. No difference in grade 4 and 5 infections between arms was noted. Treatment-related asthenia and nausea/vomiting of any grade were more frequent in A. Global health status, fatigue and constipation measured on day 1 of cycle 4 demonstrated superior scores in B.
Conclusion: Pemetrexed and split-dose cisplatin is safe and effective. Advantages of split-dose cisplatin with regard to specific toxicities allow personalization of this important chemotherapy backbone.
Trial Registration: European Clinical Trials Database (EudraCT) number 2011-001963-37.
Competing Interests: Conflict of interest statement: M.M. reports honoraria for advisory boards from MSD, BMS, Roche, Boehringer Ingelheim, Amgen, Astra Zeneca, Novartis, Pfizer and Takeda H.G.K. reports no relevant conflicts of interest F.G. reports research funding to institution from Astra Zeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Siemens, honoraria for educational lectures from Astra Zeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Ariad, Abbvie, Siemens, Tesaro/GSK, Amgen, honoraria for advisory boards from Astra Zeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Ariad, Abbvie, Tesaro/GSK, Siemens, Tesaro, Amgen N.R. received honoraria for educational lectures and advisory services from Astra Zeneca, Boehringer Ingelheim, BMS, MSD, Pfizer, Roche, and Takeda. M.S. (Sebastian) reports research funding to institution from Astra Zeneca, honoraria for advisory boards from Astra Zeneca, BMS, MSD/Merck, Roche, Pfizer, Novartis, Boehringer Ingelheim, Takeda, Abbvie, Johnson & Johnson, Amgen, Tesaro, Eli Lilly, honoraria for educational lectures rom Astra Zeneca, BMS, Novartis, Pfizer, Boehringer Ingelheim, Amgen and Eli Lilly. M.S. (Serke) reports research funding to institution from Astra Zeneca, BMS, Lilly, MSD, Roche, honoraria for educational lectures from Astra Zeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, honoraria for advisory boards from Boehringer Ingelheim, BMS, Lilly, MSD, Pfizer, Roche, Takeda, Abbvie C.F.W. Honoraria for advisory boards from Astra Zeneca, Boehringer Ingelheim, BMS, Chugai, Pfizer, Roche, Takeda: He received consultancy fees from Mylan; Alvotech; Roche and travel grants from IPSEN, BMS and Lilly. M.T. reports Honoraria for Scientific Meetings from Astra Zeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Novartis Pfizer, Roche, Takeda Advisory-Board Honoraria from Astra Zeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Lilly, MSD, Novartis, Pfizer, Roche, Takeda Travelling support from Astra Zeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Novartis, Pfizer, Roche, Takeda Research funding to institution from Astra Zeneca, Bristol-Myers Squibb, Roche, Takeda J. E. reports no conflict of interest G. S.-B. reports consultation honoraria from Eli Lilly, Boehringer Ingelheim, Roche, BMS. After completion of study temporarily employed by Eli Lilly from 2015–2017 M. H. Honoraria for advisory boards from Astra Zeneca, Boehringer Ingelheim, BMS, Chugai, Pfizer, Roche and MSD; honoraria for educational lectures from Astra Zeneca, Boehringer Ingelheim and Roche D.C.C. reports personal fees, non-financial support and other from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, MSD Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda M.K. reports no conflict of interest B.D. reports no conflict of interest S.S. reports no conflict of interest S.H. reports no conflict of interest M.S. (Schuler) reports Consultant Honoraria from Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Novartis, Roche, Takeda. Honoraria for CME presentations from Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, MSD, Novartis. Research funding to institution from Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Novartis T.H. reports no conflict of interest F.B. reports no conflict of interest W.E.E. reports research funding to institution from BMS, Astra Zeneca and Eli Lilly, honoraria for advisory boards from Astra Zeneca, BMS, MSD/Merck, Roche, Pfizer, Novartis, Boehringer Ingelheim, Takeda, Abbvie, Bayer, Johnson & Johnson, Amgen, Daichi Sankyo, Eli Lilly, honoraria for educational lectures from Astra Zeneca, BMS, MSD/Merck, Roche, Pfizer, Boehringer Ingelheim, Takeda, Amgen and Eli Lilly.
(© The Author(s), 2021.)