A Phase I/II Study of Neoadjuvant Cisplatin, Docetaxel, and Nintedanib for Resectable Non-Small Cell Lung Cancer
- 18 March 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 26 (14), 3525-3536
- https://doi.org/10.1158/1078-0432.CCR-19-4180
Abstract
Purpose: Nintedanib enhances the activity of chemotherapy in metastatic non-small cell lung cancer (NSCLC). In this phase I/II study, we assessed safety and efficacy of nintedanib plus neoadjuvant chemotherapy, using major pathologic response (MPR) as primary endpoint. Patients andMethods: Eligible patients had stage IB (>= 4 cm)-IIIA resectableNSCLC. Asafety run-in phase was followed by an expansion phase with nintedanib 200 mg orally twice a day (28 days), followed by three cycles of cisplatin (75 mg/m(2)), docetaxel (75 mg/m(2)) every 21 days plus nintedanib, followed by surgery. With 33 planned patients, the study had 90% power to detect an MPR increase from 15% to 35%. Results: Twenty-one patients (stages I/II/III, N = 1/8/12) were treated. One of 15 patients treated with nintedanib 200 mg achieved MPR [7%, 95% confidence interval (CI), 0.2%-32%]. Best ORR in 20 evaluable patients was 30% (6/20, 95% CI, 12%-54%). Twelve-month recurrence-free survival and overall survival were 66% (95% CI, 47%-93%) and 91% (95% CI, 79%-100%), respectively. Most frequent treatment-related grade 3-4 toxicities were transaminitis and electrolyte abnormalities. On the basis of an interim analysis the study was discontinued for futility. Higher levels of CD3(+) and cytotoxic CD3(+)CD8(+) T cells were found in treated tumors of patients who were alive than in those who died (652.8 vs. 213.4 cells/mm(2), P = 0.048; 142.3 vs. 35.6 cells/mm(2), P = 0.018). Conclusions: Although tolerated, neoadjuvant nintedanib plus chemotherapy did not increase MPR rate compared with chemotherapy historical controls. Additional studies of the combination in this setting are not recommended. Posttreatment levels of tumor-infiltrating T cells were associated with patient survival. Use of MPR facilitates the rapid evaluation of neoadjuvant therapies.Other Versions
Funding Information
- Boehringer Ingelheim
- Lung SPORE grant 5 (P50 CA070907)
- Cancer Center Support Grant (P30 CA016672)
- American Society of Clinical Oncology (12895)
- The University of Texas MD Anderson Cancer Center Lung Cancer Moon Shot Program
- The University of Texas MD Anderson Cancer Center CG Johnson Foundation Advanced Scholar Program
- The University of Texas MD Anderson Cancer Center Khalifa Scholar Program
- The University of Texas MD Anderson Cancer Center Physician Scientist Program
- T.J. Martell Foundation
- Bruton Endowed Chair in Tumor Biology Funds
- The Bob Mayberry Foundation
This publication has 33 references indexed in Scilit:
- Histopathologic Response Criteria Predict Survival of Patients with Resected Lung Cancer After Neoadjuvant ChemotherapyJournal of Thoracic Oncology, 2012
- Principles and mechanisms of vessel normalization for cancer and other angiogenic diseasesNature Reviews Drug Discovery, 2011
- Surgery With or Without Preoperative Paclitaxel and Carboplatin in Early-Stage Non–Small-Cell Lung Cancer: Southwest Oncology Group Trial S9900, an Intergroup, Randomized, Phase III TrialJournal of Clinical Oncology, 2010
- A Novel Histopathological Evaluation Method Predicting the Outcome of Non-small Cell Lung Cancer Treated by Neoadjuvant Therapy: The Prognostic Importance of the Area of Residual TumorJournal of Thoracic Oncology, 2010
- Lung Adjuvant Cisplatin Evaluation: A Pooled Analysis by the LACE Collaborative GroupJournal of Clinical Oncology, 2008
- The IASLC Lung Cancer Staging Project: Proposals for the Revision of the TNM Stage Groupings in the Forthcoming (Seventh) Edition of the TNM Classification of Malignant TumoursJournal of Thoracic Oncology, 2007
- C7-03: Efficacy of BIBF 1120, a potent triple angiokinase inhibitor, in models of human non-small cell lung cancer is augmented by chemotherapyJournal of Thoracic Oncology, 2007
- Histologic Assessment of Non–Small Cell Lung Carcinoma after Neoadjuvant TherapyLaboratory Investigation, 2003
- Tumour regression in non-small-cell lung cancer following neoadjuvant therapy. Histological assessmentZeitschrift für Krebsforschung und Klinische Onkologie, 1997
- Nonparametric Estimation from Incomplete ObservationsJournal of the American Statistical Association, 1958