Customized Adjuvant Chemo Falls Short in Early Lung Cancer

A pharmacogenomic-driven approach for adjuvant chemotherapy in early-stage non-small cell lung cancer (NSCLC) significantly reduced treatment-related toxicity but failed to improve survival in the international, phase III ITACA trial.

Among nearly 800 patients with stage II-IIIA disease who achieved a complete resection, median overall survival (OS) reached 96.4 months in the tailored chemotherapy arm versus 83.5 months with a standard cisplatin-based doublet (HR 0.76, 95% CI 0.55-1.04), reported Silvia Novello, MD, PhD, of the University of Torino at San Luigi Gonzaga Hospital in Italy.

Recurrence-free survival (RFS) reached 64.4 months in the tailored arm, where patients received one of four different treatments based on their mRNA expression levels of excision repair cross complementation 1 (ERCC1) and thymidylate synthase (TS), as compared with 41.5 months in the control arm (HR 0.94, 95% CI 0.74-1.20).

“Adjuvant chemotherapy customization based on the primary tumor tissue and based on the mRNA level of ERCC1 and TS did not significantly improve OS and [RFS], but as you have seen, there was a non-statistically significant trend for overall survival favoring the customized arm,” Novello said during a presentation at the virtual World Conference on Lung Cancer.

“Unfortunately, when the final analysis was performed the study was underpowered and we were only able to reach 46% of the expected events,” she said. “It is important to underline that the treatment customization significantly improved the toxicity profile without compromising the efficacy.”

In the tailored arm, grade 3/4 toxicities occurred in 32.6% of patients, as compared to 45.9% of those in the standard chemotherapy arm (odds ratio 0.57, 95% CI 0.42-0.78, P<0.001).

“The ITACA study is the largest adjuvant study tailored to ERCC1/TS status, and the results have been long-awaited,” Tetsuya Mitsudomi, MD, president of the International Association for the Study of Lung Cancer, said in a statement. “This trial confirmed that there is no biomarker strong enough to predict the efficacy of cytotoxic chemotherapy; however, the concept of customizing adjuvant therapy according to the genomic status of patients’ tumors is valid, leading to the recent demonstration in the ADAURA study of the superiority of osimertinib [Tagrisso] in delaying the postoperative recurrence of disease in patients with EGFR-mutated NSCLC.”

Cisplatin-based chemotherapy is standard of care for patients with completely resected NSCLC, but there remains a need to better identify those who truly benefit from this approach in terms of both outcomes and safety, said Novello. Previous studies have shown mRNA expression levels of ERCC1 and TS to be correlated with sensitivity or resistance to certain chemotherapeutic agents, which led to the design of the current trial.

From 2008 to 2014, ITACA (International Tailored Chemotherapy Adjuvant) randomized 773 patients with completely resected stage II-IIIA NSCLC at 30 centers in Germany and Italy to either a cisplatin-doublet of the investigators’ choice (control) or one of four tailored regimens based on patients’ mRNA expression levels of ERCC1 and TS:

• ERCC1 high/TS high: docetaxel alone
• ERCC1 high/TS low: pemetrexed (Alimta) alone
• ERCC1 low/TS high: cisplatin-gemcitabine (Gemzar)
• ERCC1 low/TS low: cisplatin-pemetrexed

Arms were well balanced, said Novello. Two-thirds of patients had stage II disease, 11% were never smokers, and a lobectomy was the resection method in the vast majority of cases. For the OS, RFS, and toxicity analyses, all tailored arms were grouped together and compared against all control arms.

Common grade 3/4 adverse events between the tailored and standard arms, respectively, included neutropenia (13.4% vs 18.9%), leucopenia (3.9% vs 13.3%), thrombocytopenia (3.3% vs 7.7%), nausea (3.9% vs 4.4%), vomiting (2.1% vs 1.8%), and fatigue (2.7% vs 1.5%).