Brain metastases (BM) occur in ~30-50% of ALK+ NSCLC patients, and are associated with poor outcomes. The response assessment of BM (Brain metastases) is challenge given the complexity of RANO and its unknown concordance with RECIST 1.1, and we conducted a study to assess their concordance.  

ASCEND-7 was a study dedicated to study ALK+ NSCLC with BM. It enrolled 156 ALK+NSCLC pts and all of which had BM. The primary endpoint was whole body ORR with secondary endpoints including intracranial ORR. The response assessment was performed by both local and Blinded Independent Review Committee (BIRC).

When ASCEND-7 was designed to assess the efficacy of ceritinib in ALK+ NSCLC with BM, no specific response criteria for BM were available. We decided to use RANO(Response Assessment in Neuro-Oncology) for high-grade gliomas(HGG) criteria developed to assess the response of contrast enhancing brain tumour. While RANO HGG has been reported to reduce false positive or negative progressive disease(PD) in HGG, the complexity of the criteria is a hurdle for implementation in non-brain tumour trial. In addition clinical information required from investigator may introduce bias when BIRC is involved. In contrast, RECIST 1.1,a widely accepted criteria for assessing solid tumor, is less complex and the BIRC assessment depends on the scan only,which is more objective.

In ASCEND-7, we adopted a modified RECIST 1.1(allowing five targeted lesions located in the brain) along with RANO HGG criteria to assess the intracranial response to treatment. Overall,138 patients were evaluated for overall intracranial response using both criteria. Despite difference in identifying measurable disease(mRECIST n=99 and RANO n=82), concordance between mRECIST and RANO was high for BIRC: a.One pt achieved complete response (CR) using mRECIST, none by RANO, b.Among 38 pts achieving partial response (PR) using mRECIST, 31 also had PR using RANO (31/38 -concordance 81.6%), c.Among 67 pts with either stable disease or neither CR nor PD using mRECIST, the concordance was 89.6% (60/67) d.Among 13 pts with PD using mRECIST, the concordance was 76.9% (10/13). Similar concordance was also observed from the local assessment.
We observed a high concordance between a modified RECIST 1.1 and RANO HGG response criteria in both BIRC and local assessment, suggesting that using mRECIST is reliable for assessing the objective response of BM. Modified RECIST 1.1 should now be evaluated against the BM criteria, newly developed by RANO group (Camidge DR et al, Lancet oncology 2018). 

In conclusion, ASCEND-7 intracranial efficacy data shows a high concordance between mRECIST and  RANO HGG criteria, and suggests that mRECIST is reliable for assessing BM from solid tumour response to pharmacological treatment.

Modified RECIST1.1 vs RANO HGG in assessing the intracranial efficacy of ceritinib in pts with brain metastases in ALK+ NSCLC

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