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Anaplastic Lymphoma Kinase Mutation (ALK F1174C) in Small Cell Carcinoma of the Prostate and Molecular Response to Alectinib.

ABSTRACT: Purpose: Small cell carcinoma of the prostate (SCCP) is an aggressive disease that can arise de novo or by transdifferentiation from prostate adenocarcinoma. Alterations in anaplastic lymphoma kinase (ALK) gene are involved in neuroblastoma, lung cancer, and other malignancies, but its role in SCCP has not been documented. We describe a patient with refractory de novo SCCP with ALK F1174C-activating mutation who obtained clinical benefit from treatment with ALK inhibitor.Experimental Design: Next-generation sequencing (NGS) was used to analyze primary and circulating tumor DNA (ctDNA). Prostate cancer databases were queried for alterations in ALK gene, mRNA, and its impact in clinical outcomes. In vitro prostate cell line/organoid models were generated by lentiviral-mediated expression of ALK and ALK F1174C and assessed for response to ALK inhibitors crizotinib and alectinib.Results: NGS analysis of the primary tumor and ctDNA of a 39-year-old patient with refractory SSCP identified ALK F1174C mutation. Treatment with second-generation ALK inhibitor alectinib resulted in radiographic stable disease for over 6 months, symptomatic improvement, and significant molecular response as reflected by declining ctDNA allele fraction. Analysis of prostate cancer datasets showed that ALK amplification was associated with poor outcome. In prostate cancer cells and organoids, ALK F1174C expression enhanced growth and induced expression of the neuroendocrine marker neuron-specific enolase. Alectinib was more effective than crizotinib in inhibiting ALK F1174C-expressing cell growth.Conclusions: These findings implicate ALK-activating mutations in SCCP pathogenesis and suggest the therapeutic potential of targeting ALK molecular alterations in some patients with SCCP. Clin Cancer Res; 24(12); 2732-9. ©2018 AACR.

SUBMITTER: Carneiro BA

PROVIDER: S-EPMC6715284 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Anaplastic Lymphoma Kinase Mutation (ALK F1174C) in Small Cell Carcinoma of the Prostate and Molecular Response to Alectinib.

Carneiro Benedito A BA Pamarthy Sahithi S Shah Ami N AN Sagar Vinay V Unno Kenji K Han HuiYing H Yang Ximing J XJ Costa Rubens B RB Nagy Rebecca J RJ Lanman Richard B RB Kuzel Timothy M TM Ross Jeffrey S JS Gay Laurie L Elvin Julia A JA Ali Siraj M SM Cristofanilli Massimo M Chae Young K YK Giles Francis J FJ Abdulkadir Sarki A SA

Clinical cancer research : an official journal of the American Association for Cancer Research 20180320 12

Purpose: Small cell carcinoma of the prostate (SCCP) is an aggressive disease that can arise de novo or by transdifferentiation from prostate adenocarcinoma. Alterations in anaplastic lymphoma kinase (ALK) gene are involved in neuroblastoma, lung cancer, and other malignancies, but its role in SCCP has not been documented. We describe a patient with refractory de novo SCCP with ALK F1174C-activating mutation who obtained clinical benefit from treatment with ALK ...[more]

PMID: 29559559

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Project description:Background:The phase III ALEX study in patients with treatment-naive advanced anaplastic lymphoma kinase mutation-positive (ALK+) non-small-cell lung cancer (NSCLC) met its primary end point of improved progression-free survival (PFS) with alectinib versus crizotinib. Here, we present detailed central nervous system (CNS) efficacy data from ALEX. Patients and methods:Overall, 303 patients aged ?18?years underwent 1:1 randomization to receive twice-daily doses of alectinib 600?mg or crizotinib 250?mg. Brain imaging was conducted in all patients at baseline and every subsequent 8?weeks. End points (analyzed by subgroup: patients with/without baseline CNS metastases; patients with/without prior radiotherapy) included PFS, CNS objective response rate (ORR), and time to CNS progression. Results:In total, 122 patients had Independent Review Committee-assessed baseline CNS metastases (alectinib, n?=?64; crizotinib, n?=?58), 43 had measurable lesions (alectinib, n?=?21; crizotinib, n?=?22), and 46 had received prior radiotherapy (alectinib, n?=?25; crizotinib, n?=?21). Investigator-assessed PFS with alectinib was consistent between patients with baseline CNS metastases [hazard ratio (HR) 0.40, 95% confidence interval (CI): 0.25-0.64] and those without (HR 0.51, 95% CI: 0.33-0.80, P interaction = 0.36). Similar results were seen in patients regardless of prior radiotherapy. Time to CNS progression was significantly longer with alectinib versus crizotinib and comparable between patients with and without baseline CNS metastases (P?<?0.0001). CNS ORR was 85.7% with alectinib versus 71.4% with crizotinib in patients who received prior radiotherapy and 78.6% versus 40.0%, respectively, in those who had not. Conclusion:Alectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advanced ALK+ NSCLC, irrespective of prior CNS disease or radiotherapy. Clinical trial registration:ClinicalTrials.gov NCT02075840.

Project description:Background:This is the first trial to directly compare efficacy and safety of alectinib versus standard chemotherapy in advanced/metastatic anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) patients who have progressed on, or were intolerant to, crizotinib. Patients and methods:ALUR (MO29750; NCT02604342) was a randomized, multicenter, open-label, phase III trial of alectinib versus chemotherapy in advanced/metastatic ALK-positive NSCLC patients previously treated with platinum-based doublet chemotherapy and crizotinib. Patients were randomized 2 : 1 to receive alectinib 600?mg twice daily or chemotherapy (pemetrexed 500?mg/m2 or docetaxel 75?mg/m2, both every 3?weeks) until disease progression, death, or withdrawal. Primary end point was investigator-assessed progression-free survival (PFS). Results:Altogether, 107 patients were randomized (alectinib, n?=?72; chemotherapy, n?=?35) in 13 countries across Europe and Asia. Median investigator-assessed PFS was 9.6?months [95% confidence interval (CI): 6.9-12.2] with alectinib and 1.4?months (95% CI: 1.3-1.6) with chemotherapy [hazard ratio (HR) 0.15 (95% CI: 0.08-0.29); P?<?0.001]. Independent Review Committee-assessed PFS was also significantly longer with alectinib [HR 0.32 (95% CI: 0.17-0.59); median PFS was 7.1?months (95% CI: 6.3-10.8) with alectinib and 1.6?months (95% CI: 1.3-4.1) with chemotherapy]. In patients with measurable baseline central nervous system (CNS) disease (alectinib, n?=?24; chemotherapy, n?=?16), CNS objective response rate was significantly higher with alectinib (54.2%) versus chemotherapy (0%; P?<?0.001). Grade ?3 adverse events were more common with chemotherapy (41.2%) than alectinib (27.1%). Incidence of AEs leading to study-drug discontinuation was lower with alectinib (5.7%) than chemotherapy (8.8%), despite alectinib treatment duration being longer (20.1?weeks versus 6.0?weeks). Conclusion:Alectinib significantly improved systemic and CNS efficacy versus chemotherapy for crizotinib-pretreated ALK-positive NSCLC patients, with a favorable safety profile. Trial registration:ClinicalTrials.gov NCT02604342; Roche study MO29750.

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Anaplastic Lymphoma Kinase Mutation (ALK F1174C) in Small Cell Carcinoma of the Prostate and Molecular Response to Alectinib.

Publications

Anaplastic Lymphoma Kinase Mutation (<i>ALK</i> F1174C) in Small Cell Carcinoma of the Prostate and Molecular Response to Alectinib.

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