Adaptive De-escalation TKI Therapy in Advanced NSCLC Shows Feasibility

The results of the trial showed that at least 75% of patients with NSCLC harboring driver gene alterations may benefit from this treatment.

Investigators found that an adaptive de-escalation tyrosine kinase inhibitor (TKI) strategy may be feasible for patients with advanced non–small cell lung cancer (NSCLC) with no lesions after local consolidative therapy (LCT) and a negative circulating tumor DNA (ctDNA) test, according to findings from a nonrandomized, exploratory proof of concept study (NCT03046316) published in JAMA Oncology.

The results of the study found that at least 75% of patients with NSCLC harboring driver gene alterations could benefit from this treatment. The median progression-free survival (PFS) was 18.4 months (95% CI, 12.6-24.2). Additionally, PFS rates at 12 and 24 months were 67.7% (95% CI, 53.3%-78.5%) and 40.2% (95% CI, 24.3%-55.6%), respectively.

Among 60 patients diagnosed with lung adenocarcinoma with driver gene-sensitive variations, all had received TKI before enrollment. Fifty received first-line TKI treatment, and 10 received second-line treatment.

All patients had received at least 1 treatment break by the cut-off date of November 30, 2022. Median follow-up time after treatment cessation was 19.2 months (range, 3.8-29.7), and data analyses were performed from December 15, 2022 to May 10, 2023 using IBM SPSS Statistics.

The primary end point of the study was PFS. Secondary end points included objective response rate (ORR), time to next treatment (TTNT), and overall survival (OS).

The median total treatment break duration was 9.1 months (range, 1.5-28.1). Three outcome groups were observed based on triggers of first retreatment; group A was composed of 14 patients who remained in treatment break, group B was composed of 31 patients who began retreatment after displaying positive molecular indicators before progressive disease, and group C was composed of 15 patients who experienced confirmed disease progression and reinitiated treatment.

Group A had a median treatment break of 20.3 months (range, 6.8-28.1). Of the 31 patients in group B, 12 experienced progression in subsequent retreatment (n = 3) or break intervals (n = 9), and median PFS was 20.2 months (95% CI, 12.9-27.4). The median PFS was 5.5 months (95% CI, 1.5-7.2) in Group C; among the 15 patients, ctDNA was undetectable in 9, with 6 patients exclusively having brain metastases.

By the end of the study period, 27 patients had experienced disease progression. Of these patients, 24 had a response to retreatment following prior TKIs. Twelve achieved a complete response, 11 achieved a partial response, and 1 had stable disease, yielding an ORR of 96% (95% CI, 87.7%-100%).

Twelve patients experienced disease progression while receiving TKI retreatment and received physician-administered next-line treatment. The median TTNT from the initiation of the first treatment break was 29.3 months (95% CI, 25.3-35.2). TNTT rates at 12 and 24 months were 92.2% (95% CI, 80.2%-97.0%) and 74.1% (95% CI, 56.2%-85.5%), respectively.

Although no patient died during treatment discontinuation, median OS data were immature. Twelve of 24 patients who achieved sufficient tumor regression opted to discontinue TKI treatment. In group B, ctDNA was undetectable in 96% of patients (n = 25), and carcinoembryonic antigens (CEA) reached a normal level in 3 of 5 patients after 3-month retreatment with prior TKI agents.

Grade 1 to 2 adverse effects (AEs) included rash (n = 7), paronychia (n = 2) and arrhythmia (n = 1). No grade 3 or worse events occurred.

Of those who experienced progressive disease (n = 27), 9 developed intrathoracic metastases, 11 had extrathoracic metastases, and 7 developed both. Three patients underwent a second wedge resection for growing oligometastatic nodules in the lungs, and another patient received rib radiotherapy locally. Twelve patients eventually experienced progression while receiving retreatment with prior TKIs and were instructed to initiate next-line treatment; 7 received third-generation EGFR TKIs, 4 received chemotherapy, and 1 received erlotinib (Tarceva) in combination with bevacizumab (Avastin).

Reference

Dong S, Wang Z, Zhang JT, et al. Circulating tumor DNA-guided de-escalation targeted therapy for advanced non−small cell lung cancer: a nonrandomized clinical trial. JAMA Oncol. Published online June 13, 2024. doi:10.1001/jamaoncol.2024.1779