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Exposure-response analysis of alectinib in crizotinib-resistant ALK-positive non-small cell lung cancer.

ABSTRACT: PURPOSE:Alectinib is a selective and potent anaplastic lymphoma kinase (ALK) inhibitor that is active in the central nervous system (CNS). Alectinib demonstrated robust efficacy in a pooled analysis of two single-arm, open-label phase II studies (NP28673, NCT01801111; NP28761, NCT01871805) in crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC): median overall survival (OS) 29.1 months (95% confidence interval [CI]: 21.3-39.0) for alectinib 600 mg twice daily (BID). We investigated exposure-response relationships from final pooled phase II OS and safety data to assess alectinib dose selection. METHODS:A semi-parametric Cox proportional hazards model analyzed relationships between individual median observed steady-state trough concentrations (Ctrough,ss) for combined exposure of alectinib and its major metabolite (M4), baseline covariates (demographics and disease characteristics) and OS. Univariate logistic regression analysis analyzed relationships between Ctrough,ss and incidence of adverse events (AEs: serious and Grade???3). RESULTS:Overall, 92% of patients (n?=?207/225) had Ctrough,ss data and were included in the analysis. No statistically significant relationship was found between Ctrough,ss and OS following alectinib treatment. The only baseline covariates that statistically influenced OS were baseline tumor size and prior crizotinib treatment duration. Larger baseline tumor size and shorter prior crizotinib treatment were both associated with shorter OS. Logistic regression confirmed no significant relationship between Ctrough,ss and AEs. CONCLUSION:Alectinib 600 mg BID provides systemic exposures at plateau of response for OS while maintaining a well-tolerated safety profile. This analysis confirms alectinib 600 mg BID as the recommended global dose for patients with crizotinib-resistant ALK-positive NSCLC.

SUBMITTER: Morcos PN

PROVIDER: S-EPMC6010493 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Exposure-response analysis of alectinib in crizotinib-resistant ALK-positive non-small cell lung cancer.

Morcos Peter N PN Nueesch Eveline E Jaminion Felix F Guerini Elena E Hsu Joy C JC Bordogna Walter W Balas Bogdana B Mercier Francois F

Cancer chemotherapy and pharmacology 20180510 1

<h4>Purpose</h4>Alectinib is a selective and potent anaplastic lymphoma kinase (ALK) inhibitor that is active in the central nervous system (CNS). Alectinib demonstrated robust efficacy in a pooled analysis of two single-arm, open-label phase II studies (NP28673, NCT01801111; NP28761, NCT01871805) in crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC): median overall survival (OS) 29.1 months (95% confidence interval [CI]: 21.3-39.0) for alectinib 600 mg twice daily (BID). We in ...[more]

PMID: 29748847

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Project description:BackgroundAlectinib--a highly selective, CNS-active, ALK inhibitor-showed promising clinical activity in crizotinib-naive and crizotinib-resistant patients with ALK-rearranged (ALK-positive) non-small-cell lung cancer (NSCLC). We aimed to assess the safety and efficacy of alectinib in patients with ALK-positive NSCLC who progressed on previous crizotinib.MethodsWe did a phase 2 study at 27 centres in the USA and Canada. We enrolled patients aged 18 years or older with stage IIIB-IV, ALK-positive NSCLC who had progressed after crizotinib. Patients were treated with oral alectinib 600 mg twice daily until progression, death, or withdrawal. The primary endpoint was the proportion of patients achieving an objective response by an independent review committee using Response Evaluation Criteria in Solid Tumors, version 1.1. Response endpoints were assessed in the response-evaluable population (ie, patients with measurable disease at baseline who received at least one dose of study drug), and efficacy and safety analyses were done in the intention-to-treat population (all enrolled patients). This study is registered with ClinicalTrials.gov, number NCT01871805. The study is ongoing and patients are still receiving treatment.FindingsBetween Sept 4, 2013, and Aug 4, 2014, 87 patients were enrolled into the study (intention-to-treat population). At the time of the primary analysis (median follow-up 4·8 months [IQR 3·3-7·1]), 33 of 69 patients with measurable disease at baseline had a confirmed partial response; thus, the proportion of patients achieving an objective response by the independent review committee was 48% (95% CI 36-60). Adverse events were predominantly grade 1 or 2, most commonly constipation (31 [36%]), fatigue (29 [33%]), myalgia 21 [24%]), and peripheral oedema 20 [23%]). The most common grade 3 and 4 adverse events were changes in laboratory values, including increased blood creatine phosphokinase (seven [8%]), increased alanine aminotransferase (five [6%]), and increased aspartate aminotransferase (four [5%]). Two patients died: one had a haemorrhage (judged related to study treatment), and one had disease progression and a history of stroke (judged unrelated to treatment).InterpretationAlectinib showed clinical activity and was well tolerated in patients with ALK-positive NSCLC who had progressed on crizotinib. Therefore, alectinib could be a suitable treatment for patients with ALK-positive disease who have progressed on crizotinib.FundingF Hoffmann-La Roche.

Project description:ObjectiveTo systematically evaluate the efficacy and safety of alectinib versus crizotinib in the treatment of anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer.MethodsStudies about the efficacy of alectinib versus crizotinib in the treatment of ALK-positive non-small cell lung cancer were searched in PubMed, Scopus, Embase and the Cocharane Library from inception to February 15, 2020. Two reviewers independently screened these studies, extracted the data, assessed the risk of bias in the included studies by using the Cochrane risk assessment tool, and then used review manager 5.3 software for meta-analysis.ResultsThree studies comprising a total of 697 patients with ALK-positive non-small cell lung cancer were included, 380 in the alectinib group and 317 in the crizotinib group. The dose of alectinib (300 mg) in J-ALEX were lower than the approved dose (600 mg), however the crizotinib group in all three studies received the recommended dose (250 mg). Performance bias was high in all three studies whereas, and the attrition bias was high in two studies (Toyoaki Hida 2017 and Solange peters 2017). The results of meta-analysis showed that: the overall response rate [OR = 2.07, 95% CI (1.41, 3.06), P = 0.0002], the progression free survival [HR = 0.34, 95% CI (0.21, 0.55), P <0.0001], the partial response [OR = 1.71, 95% CI (1.19, 2.46), P = 0.003], P = 0.001], in alectinib group were higher than that of crizotinib group. Though the total number of events in complete response and the disease control rate were more in alectinib group than that of crizotinib group, the meta-analysis results shows no significant differences between two drugs in the disease control rate [OR = 2.24, 95% CI (0.56, 8.88), P = 0.25], the complete response [OR = 1.82, 95% CI (0.75, 4.45), P = 0.19]. In addition, the number of events in the stable disease [OR = 0.45, 95% CI (0.28, O.74), P = 0.001], and the adverse events [OR = 0.50, 95% CI (0.23, 0.81), P = <0.0001] in alectinib group were lower than that of crizotinib group.ConclusionAlectinib in terms of overall response rate, progression-free survival and partial response is superior to crizotinib in the treatment of ALK-positive non-small cell lung cancer and is well tolerated. Compared with crizotinib, alectinib is more effective than crizotinib and has a lower incidence of total adverse reactions. Meta-analysis results confirm the strong base for alectinib as a first-line treatment for ALK-positive NSCLC.

Project description:BackgroundThe 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 methodsOverall, 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.ResultsIn 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.ConclusionAlectinib 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 registrationClinicalTrials.gov NCT02075840.

Project description:BackgroundThis 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 methodsALUR (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).ResultsAltogether, 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).ConclusionAlectinib significantly improved systemic and CNS efficacy versus chemotherapy for crizotinib-pretreated ALK-positive NSCLC patients, with a favorable safety profile.Trial registrationClinicalTrials.gov NCT02604342; Roche study MO29750.

Dataset Information

Exposure-response analysis of alectinib in crizotinib-resistant ALK-positive non-small cell lung cancer.

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Exposure-response analysis of alectinib in crizotinib-resistant ALK-positive non-small cell lung cancer.

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