br Disclosures br Introduction Survivals of advanced anaplas
Introduction Survivals of advanced anaplastic lymphoma kinase (ALK-positive) non-small cell lung cancer (NSCLC) patients have dramatically changed since the development of efficient ALK tyrosine kinase inhibitors (TKi). However, ALK-positive patients seem to relapse more commonly in the central nervous system (CNS), considered as a sanctuary site. Whether ML-210 metastases (BM) or lepto-meningeal disease (LMD), both are associated with very poor prognosis . Though there is evidence of intracranial activity of 1st generation ALK TKi - crizontib to 2nd and next-generations TKi alectinib, ceretinib against BM, few cases report their activity on LMD. We present the case of a patient who developed LMD under crizotinib and ceritinib and achieved intracranial response >14 months, with brigatinib, a second-generation ALK TKi, given under expanded access program.
Case presentation He was started on crizotinib in December 2015 and achieved a 10-month progression-free survival (PFS). In October 2016, he presented with mild confusion. Brain MRI confirmed intra-cranial relapse with multiple parenchymal lesions and diffused leptomeningeal enhancement, whereas cerebrospinal fluid cytology did not find malignant cells. Body-scanner showed extra-cranial stable disease. He was started on ceritinib at 750 mg/d. However, three months later, the patient worsened neurologically. Imagery revealed parenchymal and leptomeningeal progression, without extra-cranial involvement. Thus, platin-based chemotherapy with bevacizumab was prescribed resulting in a partial response after 4 cycles. During maintenance regimen, a follow-up CT-scan revealed local thoracic relapse on the right lower lobe. Brain MRI demonstrated stable intra-cranial disease, with parenchymal and leptomeningeal enhancement (Fig. 1A). Lung biopsy for updated mutational status showed ALK 2 + IHC staining and negativity by FISH. Additional NGS testing on lung tissue and plasma samples did not find resistance mutations to ALK inhibitors. After multi-disciplinary discussion, brigatinib was started under expanded access program, in July 2017, at 180 mg once daily with a 7-day lead-in period at 90 mg. After 2 months treatment, the patient showed neurological signs of improvement. Brain MRI (Fig. 1B) and CT-scan evaluation showed both intra- and extra-cranial favorable response, which is currently maintained, more than 14 months from drug-initiation. The drug is well tolerated and quality of life significantly improved.
Discussion Brigatinib (AP26113) is a second-generation ALK TKi, with a broader spectra of activity, specifically on acquired resistance mutations . Brigatinib has demonstrated significant improvement of PFS and response rate (RR), both in crizotinib-refractory ALK-positive NSCLC patients  (Phase II ALTA trial) and in 1st line treatment  (Phase III ALTA-1 L Trial), compared with the 1st ALK-TKi crizotinib. Consequently, it received FDA approval in crizotinib-pretreated patients in April 2017. Furthermore, recent studies also suggested the benefit of brigatinib against BM in crizotinib-refractory ALK-positive patients [5,6]. In the phase II ALTA trial, patients in the arm B (patients receiving 180 mg daily with a 7-day lead-in at 90 mg; n = 18) showed intracranial objective response rate (IC ORR) up to 67%. Considering all patients with CNS involvement at baseline, the median CNS PFS was of 18.4 months. IC ORRs were similar in subsets without prior radiation or progression post-radiation. Similarly, in ALK inhibitor naïve patients, brigatinib also suggested intracranial efficacy . In the ALTA-1 L trial, 90/275 patients had BM at baseline. Among them, 39 had measurable BM. The IC ORR was of 78% (95% CI, 52–94) against 29% (95% CI, 11–52) with crizotinib. The 12-month survival rate was estimated at 67% in the brigatinib group against 21% in the crizotinib group.