Phase II clinical trial with metronomic oral vinorelbine and tri-weekly cisplatin as induction therapy, subsequently concomitant with radiotherapy (RT) in patients with locally advanced, unresectable, non-small cell lung cancer (NSCLC). Analysis of survival and value of ctDNA for patient selection. (March 2021)

• Record Type: Journal Article
• Authors: Provencio, Mariano; Majem, Margarita; Guirado, María; Massuti, Bartomeu; de las Peñas, Ramón; Ortega, Ana Laura; Dómine, Manuel; Marsé, Raquel; Sala, María Ángeles; Paredes, Alfredo; Morán, Teresa; Vázquez, Sergio; Coves, Juan; Larriba, José Luis González; Sánchez, José Miguel; Vicente, David; Farré, Núria; Fornos, Luis Fernández; Zapata, Irma; Franco, Fabio; Serna-Blasco, Roberto; Romero, Atocha; Isla, Dolores
• Is Part Of: Lung cancer. Volume 153(2021)
• Page Start: 25
• Page End: 34
• Publication Date: 2021-03
• Subjects: 3DCRT three-dimensional conformal radiation therapy -- CI confidence interval -- CR complete response -- CT computed tomography -- CTV clinical target volume -- DR duration of response -- ECOG-PS Eastern Cooperative Oncology Group-Performance Status -- EORTC European Organization for Research and Treatment of Cancer -- ESP exome sequencing project -- GPV gross tumor volume -- HR hazard ratio -- IQR interquartile range -- ITT intention-to-treat -- MAF mutant allele frequency -- MRI magnetic resonance imaging -- NCI-CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events -- NR not reached -- NS non-significant -- NSCLC non-small cells lung cancer -- ORR overall response rate -- OS overall survival -- P P-value -- PET-CT positron-emission tomography- computed tomography -- PFS progression-free survival -- PR partial response -- PTV planning target volume -- RECIST response evaluation criteria in solid tumors -- RT radiotherapy -- SD standard deviation -- SLCG Spanish Lung Cancer Group -- TRT thoracic radiotherapy -- WT wild type -- cDNA complementary DNA -- cfDNA cell-free DNA -- ctDNA circulating tumor DNA -- dPCR digital PCR -- mCT metronomic Chemotherapy -- qPCR quantitative PCR; Metronomic vinorelbine -- NSCLC -- ctDNA -- Stage III; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2021.01.005
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: New drug schemes are needed for unresectable stage III NSCLC. Metronomic chemotherapy based on oral vinorelbine and cisplatin exhibits low toxicity. ctDNA analysis can identify the subgroup of patients who might benefit from this treatment. Abstract: Background: Little progress has been achieved in non-small cell lung cancer (NSCLC) patients with unresectable stage III disease and new drug schemes are warranted. Material and methods: In this open-label, single-arm, phase II trial 65 treatment-naïve stage III NSCLC deemed surgically unresectable by a multidisciplinary team were treated with 2 cycles of induction cisplatin at 80 mg/m 2 every 21 days plus metronomic oral vinorelbine at 50 mg/day every Monday, Wednesday and Friday. During the concomitant treatment with thoracic radiotherapy cisplatin was administered in the same manner but oral vinorelbine was reduced to 30 mg/day. The objective was to administer a total radiotherapy dose of 66 Gy in 33 daily fractions of 2 Gy. The primary endpoint was progression-free survival (PFS). Correlation between circulating tumor DNA (ctDNA) levels and survival was also evaluated. Results: Fifty-five (78.5 %) patients completed treatment. Overall response rate, by RECIST criteria, was 66.2 %. Four (6.2 %) patients had complete response, 39 (60.0 %) partial response and 12 (18.5 %) stable disease. Seven patients (10.8 %) had progressive disease during the induction period. Median follow-up was 29.1 months (m), median PFS was 11.5 m (95 %CI: 9.6–15.4). PFS at 12 m in the intention-to-treat (ITT) population was 47.8 % (95 %CI: 35.1–59.4 %) and median OS was 35.6 m (95 %CI: 24.4–46.8). Grade ≥3 treatment-related adverse events occurred in 14 (21.5 %) patients during induction and in 13 (24.5 %) patients during concomitant treatment with esophagitis occurring in 3% and pneumonitis in 1.5 % of the patients. Patients with undetectable ctDNA after 3 m follow-up had median PFS and OS of 18.1 m (95 %CI: 8.8-NR) and not reached (NR) (95 %CI: 11.3-NR), respectively, compared with 8.0 m (95 %CI: 2.7-NR) and 24.7 m (95 %CI: 5.7-NR) for patients who remained ctDNA positive at that time point. Conclusions: Metronomic oral vinorelbine and cisplatin obtains similar efficacy results with significantly lower toxicity than the same chemotherapy at standard doses. ctDNA can identify populations with particularly good prognosis.