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Adjuvant Chemotherapy Customisation Based on ERCC1 and TS mRNA Levels Does Not Improve Efficacy in Resected NSCLC

Findings from the ITACA study in patients with completely resected, stage II-IIIA non-small cell lung cancer
06 Oct 2021
Anticancer agents & Biologic therapy;  Lung and other thoracic tumours;  Personalised medicine

The International Tailored Chemotherapy Adjuvant Therapy (ITACA) study was open-label, randomised, investigator-initiated study to evaluate the predictive utility of ERCC1 and TS mRNA expression levels in completely resected stage II-IIIA non-small cell lung cancer (NSCLC). The results indicate that adjuvant chemotherapy customisation based on ERCC1 and TS mRNA levels did not improve efficacy. However, in terms of safety, the pharmacogenomic-driven arm was associated with better efficacy/toxicity ratio. The findings are reported by Prof. Silvia Novello of the University of Torino, Department of Oncology at S. Luigi Hospital Regione Gonzole in Orbassano, Turin, Italy and colleagues in an article published on 4 October 2021 in the Annals of Oncology

The study investigators included in the analysis adult patients with ECOG performance status of 0 or 1 and completely resected pathological stage II-IIIA NSCLC. High and low ERCC1 or TS mRNA expression was defined as the value ≥ or < the median values for these 2 markers as assessed in a preliminary study performed at the University of Torino in 50 consecutive cases of surgically resected NSCLC. For ERCC1 the cut–off value was set at 3.90 unitless ratio and for TS at 3.50 unitless ratio. The ERCC1 and TS primers were designed to detect the entire genes and they were not detecting any specific isoforms.

Eligible patients were stratified by disease stage (stage II versus IIIA), smoking status (never/former versus current), genomic profile and allocated 1:1 to tailored or standard adjuvant chemotherapy. Patients were randomly assigned to investigator’s choice of platinum-based chemotherapy or chemotherapy defined by the molecular markers. In the tailored arm patients with tumours that had high ERCC1 and high TS received single-agent paclitaxel, patients with high ERCC1 and low TS received single-agent pemetrexed, patients with low ERCC1 and high TS received cisplatin and gemcitabine, patients with low ERCC1 and low TS received cisplatin and pemetrexed.

In total, 773 completely resected stage II-IIIA NSCLC patients were enroled and randomly assigned to investigator’s choice of platinum-based chemotherapy (n=389) or tailored chemotherapy (n=384). All anticancer drugs were administered according to standard doses and schedules. The study primary endpoint was overall survival (OS).

In the primary analysis, 690 patients were included. At a median follow-up of 45.9 months, 85 patients (24.6%) died in the investigator’s choice of platinum-based chemotherapy and 70 patients (20.3%) died in tailored chemotherapy arm.

Five-year OS for patients in the investigator’s choice of platinum-based chemotherapy arm was of 65.4% (95% confidence interval [CI] 58.5-71.4%) and 72.9% (95% CI 66.5-78.3%) in tailored chemotherapy arm, respectively. The estimated hazard ratio (HR) was 0.77 (95% CI 0.56-1.06, p = 0.109) for tailored arm versus investigator’s choice of chemotherapy arm.

HR for recurrence-free survival (RFS) was 0.89 (95% CI 0.69-1.14, p = 0.341) for tailored arm versus investigator’s choice of chemotherapy arm.

Grade 3-5 toxicities were more frequently reported in the investigator’s choice of platinum-based chemotherapy arm than in tailored chemotherapy arm.

The study results indicate that adjuvant chemotherapy customisation based on the primary tumour tissue mRNA expression of two molecular markers associated with cytotoxic drug metabolism did not significantly improve efficacy outcomes in terms of OS and RFS. Treatment customisation significantly improved toxicity profile of the adjuvant therapy without compromising the activity. However, it should be noted that at the time of the analysis only 155 events of the 336 (46.1%) expected events were reported. Therefore, the failure to reach the statistical significance can clearly be attributed to the lack of power of the study.

The authors wrote that several strategies are investigated to improve the 4% survival advantage of adjuvant chemotherapy in early-stage NSCLC. In a future therapeutic landscape, where immune-checkpoint inhibitors and targeted therapies will play a relevant role also in the early disease therapeutic strategy, the role of chemotherapy will remain critical in maximising the therapeutic benefit as already demonstrated in the advanced disease setting. Consequently, any attempt to improve its therapeutic ratio should be carefully considered.

The study was funded by an unrestricted educational grant by Eli Lilly and Co. (Indianapolis, US) with no role in study design, data collection, data analysis, data interpretation or writing of the report. 

Reference

Novello S, Torri V, Grohe C, et al. International Tailored Chemotherapy Adjuvant (ITACA) Trial, a Phase III Multicenter Randomized Trial Comparing Adjuvant Pharmacogenomic-Driven Chemotherapy versus Standard Adjuvant Chemotherapy in completely Resected Stage II-IIIA Non-Small Cell Lung Cancer. Annals of Oncology; Published online 4 October 2021.  DOI: https://doi.org/10.1016/j.annonc.2021.09.017

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