Final results of the large-scale multinational trial PROFILE 1005: efficacy and safety of crizotinib in previously treated patients with advanced/metastatic ALK-positive non-small-cell lung cancer

Abstract

PurposeCrizotinib is a potent, orally administered tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC). We report final results from PROFILE 1005, the largest clinical trial to date for an ALK inhibitor in ALK-positive NSCLC.Patients and methodsPROFILE 1005 (NCT00932451) was a multicenter, single-arm phase 2 trial of the efficacy, safety and tolerability of crizotinib (250 mg twice daily; 3 week continuous treatment cycles) in patients with ALK-positive NSCLC after failure of ≥1 lines of systemic treatment for locally advanced/metastatic disease. Patients’ tumour ALK status was initially determined by a central laboratory until a protocol amendment permitted enrolment of patients based on locally determined ALK status. Co-primary endpoints were objective response rate (ORR), evaluated using Response Evaluation Criteria in Solid Tumours V.1.1 and adverse events (AEs). Cancer-specific patient-reported outcomes (PROs) were also assessed using the European Organisation for the Research and Treatment of Cancer QLQ-C30 and its lung cancer module QLQ-LC13.Results1069 patients were enrolled; 1066 received crizotinib. The as-treated population comprised 908 and 158 patients, in whom tumour positive ALK-status was determined centrally (± locally) or locally only, respectively. At baseline, a majority of patients were <65 years (84%), 66% were never smokers and 46% were Asian. Derived investigator-assessed ORR was 54% (95% CI 51 to 57) and 41% (95% CI 33 to 49) in the central-testing and local-testing subgroups, respectively. The most common treatment-related AEs in the overall population (any grade) were vision disorder (58%), nausea (51%), diarrhoea (47%) and vomiting (47%). PRO scores demonstrated clinically meaningful improvement in lung cancer symptoms and global quality of life.ConclusionThe efficacy, safety and PRO profiles of crizotinib in this cohort of 1066 patients with ALK-positive NSCLC are consistent with previous reports.Trial registration numberPhase 2 trial (NCT00932451); Results.

Tumor Resistance against ALK Targeted Therapy-Where It Comes From and Where It Goes

“…Following a number of successful in vitro studies [ 98 ] showing the efficacy of crizotinib in ALK inhibition, crizotinib entered into early phase I study (PROFILE 1001) presenting a sustained response in locally advanced or metastatic NSCLC patients carrying the EML4-ALK fusion gene [ 101 ]. Subsequently, crizotinib was evaluated in a phase II study (PROFILE 1005) with the final results published recently [ 102 ].…”

“…Other not so common TRAEs of crizotinib in patients that have been observed over the years, include interstitial lung disease (ILD), bradycardia, QTc prolongation, renal cysts and decreased total testosterone in males. Most of the TRAEs were reversible with crizotinib discontinuation or drug holiday period [ 102 ]. Altogether these results led to the approval of crizotinib by FDA for the treatment of locally advanced or metastatic ALK-positive NSCLC in 2011.…”

Acquired Resistance Mutations to ALK Inhibitors Identified by Single Circulating Tumor Cell Sequencing inALK-Rearranged Non–Small-Cell Lung Cancer

“…Selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have dramatically transformed the therapeutic landscape for patients with ALK-rearranged non-small-cell lung cancer (NSCLC). The first FDA-approved ALK inhibitor was crizotinib which produced in randomized phase III trials significant improvements in objective response rates and progression-free survival (PFS) compared with chemotherapy, but most patients relapsed within the first year of treatment (1)(2)(3). Second-generation ALK inhibitors including ceritinib, alectinib, or brigatinib have been approved for patients who progressed on crizotinib, although resistance almost always develops (4-7).…”

Drug resistance in anaplastic lymphoma kinase‐rearranged lung cancer

“…24 Similar ORR and PFS have been observed in the subsequent phase II clinical trial. 25 Based on the results of phase I and II clinical trials, the US FDA granted accelerated approval to crizotinib for the treatment of ALK-rearranged KATAYAMA | 573 NSCLC in 2011, and crizotinib was also approved in Japan in 2012.…”