RNA-customized adjuvant chemotherapy for patients with completely resected stage II-IIIA NSCLC: lower toxicity and a numerical survival benefit

Customized adjuvant chemotherapy based on the expression level of ERCC1 and TS results in a numerically longer median overall (OS) and recurrence-free survival (RFS) compared to standard adjuvant chemotherapy in patients with completely resected stage II-IIIA NSCLC. However, these differences did not cross the border for statistical significance. Interestingly, the tailored treatment strategy did significantly improve the toxicity profile without compromising the activity of adjuvant chemotherapy.

Introduction

Adjuvant platinum-based chemotherapy in early-stage NSCLC confers a modest 5% benefit in OS. A better definition of patients who are most likely to derive a survival benefit from adjuvant therapy and spare patients who do not need adjuvant chemotherapy due to the toxicity of such a treatment would be welcome. In this respect, the phase III ITACA study aimed to evaluate the predictive utility of the mRNA expression levels of molecular markers Excision Repair Cross Complementation 1 (ERCC1) and Thymidylate synthase (TS). The choice for these two markers is based on reports linking cisplatin, carboplatin, and oxaliplatin resistance to high ERCC1 mRNA levels and the fact that a lower TS expression in lung adenocarcinoma was found to be associated with a higher efficacy of cisplatin plus pemetrexed.

Study design

The presented open label, randomized, phase III study (EudraCT 2008-001764-36) enrolled adult patients (aged > 18 years), with an ECOG performance status of 0 or 1 and with a completely resected stage II-III NSCLC (TNM edition 6). Patients in the study came from 17 Italian centers and 13 German centers and were included within 6-12 weeks after undergoing radical surgery. Genomic analyses were performed soon after surgery after which patients in each of the 4 genomic subgroups were randomly assigned to investigator’s choice of platinum-based chemotherapy (C1-2-3-4) or chemotherapy defined by the molecular markers. In the tailored arm patients with tumors that had high ERCC1 and high TS received single-agent docetaxel (T1, patients with high ERCC1 and low TS received single-agent pemetrexed (T2), patients with low ERCC1 and high TS received cisplatin and gemcitabine (T3) and finally low ERCC1 and low TS patients received cisplatin and pemetrexed (T4). The primary end point of the study was overall survival (OS), with recurrence free survival 9RFS), toxicity and therapeutic compliance as key secondary objectives. For the final statistical analysis all the control arms were grouped in one (control arm) and all tailored chemotherapies in another one (experimental arm).

Numerical, but non-significant benefit in OS and RFS from tailored adjuvant chemotherapy

Patient and disease characteristics were fairly similar between the control and experimental arm. Patients had a median age of 65 years, 70% was male and about 10% were never-smokers. Three quarters of patients in the study had an ECOG performance status of 0 and 60% had stage II disease. About four out of five patients underwent a lobectomy, while the remaining 20% was treated with a pneumonectomy. The median OS in patients treated with tailored adjuvant chemotherapy was 96.4 months, while this was reported at 83.5 for patients in the control arm (HR[95%CI]: 0.76[0.55-1.04]). Unfortunately, this 13 months OS difference did not prove to be statistically significant. Also when looking at the individual tailored regimens, no significant OS benefit was observed vs. the control arm. While the median RFS with tailored chemotherapy was numerically longer compared to the control arm, this difference did not meet the criteria for statistical significance (median RFS: 64.4 vs. 41.5 months; HR[95%CI]: 0.94[0.74-1.20]). A closer look into the data in function of age, sex, smoking habit, disease stage, tumor histology and the type of surgery did not identify a subgroup of patients in whom the RFS or OS were significantly better with the tailored adjuvant therapy approach. Treatment customization did lead to significantly less toxicity. In fact, the odds ratio of at least one toxicity with grade 3-4 for the tailored vs. the control arm was reported at 0.57 in favor of the tailored strategy (95%CI: 0.42-0.78; p< 0.001).

Conclusion

Adjuvant chemotherapy customization based on the primary tumor tissue mRNA expression of ERCC1 and TS did not significantly improve OS and RFS. However, a non-statistically significant trend was seen for a better OS in patients treated in the customized arm. Unfortunately, when the final analysis was performed the study proved to be underpowered with only 46% of collected events. When sticking to the same HR point estimate and assuming that the expected 336 events did occur, the HR estimates would be 0.76 with a 95% confidence interval of 0.61-0.94 (p= 0.012). Interestingly, treatment customization did significantly improve the toxicity profile without compromising the activity of adjuvant chemotherapy.

Reference

Novello S, et al. International Tailored Chemotherapy Adjuvant (ITACA) Phase III study of Pharmacogenomic-Driven versus Standard Adjuvant Chemotherapy in completely Resected Stage II-IIIA Non-Small Cell Lung Cancer. Presented at WCLC 2020; Abstract PS01.04.