A Phase I/II Study of Neoadjuvant Cisplatin, Docetaxel and Nintedanib for Resectable Non-Small Cell Lung Cancer
Mené sur 21 patients atteints d’un cancer du poumon non à petites cellules et résécable, cet essai de phase I/II évalue l’efficacité, du point de vue de la réponse histologique majeure, et la toxicité de l’ajout du nintédanib à une chimiothérapie néoadjuvante à base de cisplatine et de docétaxel
Purpose: Nintedanib enhances the activity of chemotherapy in metastatic 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. Experimental Design: Eligible patients had stage IB (?4 cm)-IIIA resectable NSCLC. A safety run-in phase was followed by an expansion phase with nintedanib 200 mg PO bid (28 days), followed by 3 cycles of cisplatin (75 mg/m2), docetaxel (75 mg/m2) q21 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: 21 patients (stages I/II/III, N=1/8/12) were treated. One of 15 patients treated with nintedanib 200 mg achieved MPR (7%, 95% CI 0.2%-32%). Best ORR in 20 evaluable patients was 30% (6/20, 95% CI 12%-54%). 12-month RFS and OS were 66% (95% CI 47%-93%) and 91% (95% CI, 79%-100%), respectively. Most frequent treatment-related G3-4 toxicities were transaminitis and electrolyte abnormalities. Based on 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/mm2, P=0.048; 142.3 vs. 35.6 cells/mm2, P=0.018). Conclusions: Although tolerated, neoadjuvant nintedanib plus chemotherapy did not increase MPR rate compared to chemotherapy historical controls. Additional studies of the combination in this setting are not recommended. Post-treatment levels of tumor infiltrating T cells were associated with patient survival. Use of MPR facilitates the rapid evaluation of neoadjuvant therapies.