Brigatinib in patients with ALK‐positive anaplastic large cell lymphoma who have failed brentuximab vedotin

Abstract

ALK-positive anaplastic large cell lymphoma (ALK+ ALCL) patients (pts) who have failed brentuximab vedotin (BV) have a poor prognosis with a median OS after BV failure of 2.9 months and 2-year OS of 27.1% (Chihara D, 2019). ALK-inhibitors have shown interesting results in relapsed ALK+ ALCL, but in these studies, most pts had not received prior BV, which does not correspond to current standards of treatment in adults. Furthermore, there are currently several ALK-inhibitors, but too few pts available to test them in this rare and difficult-to-treat population. It is therefore important to evaluate these ALK-inhibitors in preclinical studies, before selecting one for a clinical study. We carried out a preclinical study and then a real-life clinical study. We generated a patient-derived xenograft (PDX) model from a fresh lymph node biopsy of a 41-year-old man newly diagnosed with ALK+ ALCL. Our PDX closely mimicked the patient’s primary tumor, as assessed by pathology, FISH, TCR gene rearrangement, WES and RNA-seq. We used this model to assess 8 ALK-inhibitors (alectinib, brigatinib, ceritinib, crizotinib, ensartinib, entrectinib, lorlatinib, gilteritinib). We selected and recommended brigatinib for clinical off-label use based on our preclinical results and the safety profile in pts with ALK-positive non-small cell lung cancer (NSCLC). Between Jan 2020 and Oct 2022, 15 French adults who have failed BV started brigatinib. At brigatinib initiation, the median age was 35 y (19–73; 2 pts > 60 y), 8/15 were male, the median number of prior treatment lines was 2 (1–8), 4/15 (27%) had received prior crizotinib, including 3 crizotinib-resistant (crizo-R) and 1 crizotinib-sensitive (crizo-S) who relapsed after discontinuation of the drug. 4 pts had previously undergone stem cell transplantation (3 autoSCT, 1 alloSCT). ALCL was refractory to the last treatment in 10/15 pts. 10/11 pts had detectable ALK transcript in blood by RT-PCR. Pts received brigatinib at a dose of 180 mg once daily (with a 7-day lead-in period at 90 mg), as recommended in ALK-positive NSCLC. The best ORR was 93% (14/15) with 73% (11/15) CR according to Lugano response criteria. 2 crizo-R and the crizo-S pts achieved CR, and 1 crizo-R pt reached PR. Time to achieve CR ranged from 8 to 325 days. 9 pts were monitored for ALK transcript in blood over time and kinetics correlated with response. 5 CR pts were bridged to alloSCT. There were 4 progressions/relapses after brigatinib initiation, all occurring within the first 6 months. After a median follow-up of 1.3 years, 1-year PFS and OS were 72% and 85%, respectively. There was no permanent discontinuation of brigatinib related to adverse event (AE), and 3 pts had dose reduction for moderate AE (1 dyspnea and 2 cramps), with complete resolution. Keywords: Aggressive T-cell non-Hodgkin lymphoma, Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. D. Sibon Consultant or advisory role: Takeda, AbbVie, Janssen, Roche