1364P - ctDNA analysis of SAF-189s efficacy in ALK+ advanced non-small cell lung cancer (NSCLC)

Background

SAF-189s is a next-generation inhibitor of ALK/ROS1 tyrosine kinase, which has been shown to have anti-tumor activity against ALK/ROS1 fusion-positive non-small-cell lung cancer (NSCLC), including CNS activity due to its ability to penetrate the blood-brain barrier. Here we present a circulating tumor DNA (ctDNA) biomarker analysis of patients (pts) with advanced, ALK-rearranged NSCLC treated in phase 2a study.

Methods

Tumor tissue samples were collected from all enrolled pts for ALK-fusion detection by VENTANA ALK (D5F3) IHC assay. Plasma samples were collected at baseline and disease progression. Next-generation sequencing for ctDNA was done using Lung cancer 180-gene panel (Genetron). PFS was evaluated according to ALK alteration status.

Results

By the cut-off date of Dec 13^th, 2021 (median PFS follow-up 11 mo), a total of 143 NSCLC ALK-fusion positive pts had been enrolled and treated with SAF-189s (80 mg, n=19; 120 mg, n=47, 160 mg, n=64; 210 mg, n=13), including 100 ALKi-naïve pts and 43 ALKi-refractory pts (received crizonitib and/or next-generation ALKi). ctDNA at baseline was tested in 143 pts with a ALK-fusion positivity rate of 53.8% (77/143). The main fusion partner of ALK was EML4, accounting for 93.6% (73/78). The most common fusion variants were v3 (34.5%, 27/78), v1 (28.2%, 22/78), and v2 (10.3%, 8/78). Pts with v1 variants showed a longer mPFS than v3 variants (16.5 mo vs. 13.8 mo, p=0.188). There was no significant difference in the distribution of ALK fusion variants between ALKi-naïve and ALKi-refractory groups. Of 25 pts who progressed with SAF-189s, two ALK mutations, G1202R and I1179T, were newly identified in 3 pts. I1179T has not been previously reported and is speculated to be a novel ALK-resistant mutation. TP53 co-mutations were detected in 47% pts, but it was not shown to have a significant effect on outcomes. Gene co-occurrence survival analysis showed that mPFS of pts harboring FAT3/FAT4 mutations were significantly shorter than those without FAT3/FAT4 mutations (8.9 mo vs 16.5 mo, p=0.012).

Conclusions

Clinical utility of ctDNA was demonstrated, not only at baseline by identifying fusion types and subgroups of ALK+ NSCLC pts that may benefit more from SAF-189s, but also at progression by tracking ALK-resistant mutations.

Clinical trial identification

NCT04237805.

Editorial acknowledgement

Legal entity responsible for the study

Jiangsu Wanbang Biopharmaceuticals Co., Ltd.

Funding

Shanghai Fosun Pharmaceutical (Group) Co., Ltd and Jiangsu Wanbang Biopharmaceuticals Co., Ltd.

Disclosure

All authors have declared no conflicts of interest.