Phase I and pharmacologic study of olaparib in combination with high-dose radiotherapy with and without concurrent cisplatin for non-small cell lung cancer

Rosemarie de Haan, Michel M. van den Heuvel, Judi van Diessen, Heike M. U. Peulen, Erik van Werkhoven, Adrianus J. de Langen, Ferry Lalezari, Dick Pluim, Manon Verwijs-Janssen, Conchita Vens, Jan H. M. Schellens, Neeltje Steeghs, Marcel Verheij, Baukelien van Triest

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Abstract

Purpose: To identify an MTD of olaparib, a PARP inhibitor, in combination with loco-regional radiotherapy with/without cisplatin for the treatment of non-small cell lung cancer (NSCLC). Patients and Methods: Olaparib dose was escalated in two groups: radiotherapy (66 Gy/24 fractions in 2.75 Gy/fraction) with and without daily cisplatin (6 mg/m 2), using time-to-event continual reassessment method with a 1-year dose-limiting toxicity (DLT) period. The highest dose level with a DLT probability <15% was defined as MTD. Poly ADP-ribose (PAR) inhibition and radiation-induced PAR-ribosylation (PARylation) were determined in peripheral blood mononuclear cells. Results: Twenty-eight patients with loco-regional or oligometastatic disease (39%) were treated: 11 at olaparib 25 mg twice daily and 17 at 25 mg once daily. The lowest dose level with cisplatin was above the MTD due to hematologic and late esophageal DLT. The MTD without cisplatin was olaparib 25 mg once daily. At a latency of 1-2.8 years, severe pulmonary adverse events (AE) were observed in 5 patients across all dose levels, resulting in 18% grade 5 pulmonary AEs. Exploratory analyses indicate an association with the radiation dose to the lungs. At the MTD, olaparib reduced PAR levels by more than 95% and abolished radiation-induced PARylation. Median follow-up of survivors was 4.1 years. Two-year loco-regional control was 84%, median overall survival in patients with locally advanced NSCLC was 28 months. Conclusions: Combined mildly hypofractionated radiotherapy and low-dose daily cisplatin and olaparib was not tolerable due to esophageal and hematologic toxicity. Severe pulmonary toxicity was observed as well, even without cisplatin. More conformal radiotherapy schedules with improved pulmonary and esophageal sparing should be explored.

Original languageEnglish
Pages (from-to)1256-1266
Number of pages11
JournalClinical cancer research
Volume27
Issue number5
DOIs
Publication statusPublished - 1 Mar 2021

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