| General information |
| Database: | DB00649 |
| Objective: | Patients with non small cell lung cancer (non small cell lung cancer) and ALK rearrangements generally have a progression free survival of 811 months while on treatment with the ALK inhibitor crizotinib. however, resistance inevitably develops, with the brain a common site of progression. More potent ALK inhibitors with consistently demonstrable CNS activity and good tolerability are needed urgently. Alectinib is a novel, highly selective, and potent ALK inhibitor that has shown clinical activity in patients with crizotinibnaive ALKrearranged non small cell lung cancer. they did a phase 1/2 study of alectinib to establish the recommendedphase 2 dose of the drug and examine its activity in patients resistant or intolerant to crizotinib. |
| Authors: | Gadgeel SM, et al |
| Title: | Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinibresistant ALKrearranged non small cell lung cancer (AF002JG): results from the dosefinding portion of a phase 1/2 study. |
| Journal: | Lancet Oncol. |
| Year: | 2014 |
| PMID: | 25153538 |
| Trial Design |
| Clinical Trial Id: | NCT01588028 |
| Agent: | alectinib
|
| Target: | ALK inhibition including activity againstL1196M, G1269A, C1156Y, and F1174Lmutations
|
| Cancer Type: | advanced cancer with brain metastasis |
| Cancer Subtype: | brain metastases from crizotinibresistantALKrearranged non small cell lung cancer |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | a phase I/II, singlearm, openlabel study |
| Key Patients Feature: | Eastern Cooperative Oncology Group(ECOG) performance score of 2 or less; measurable diseaseaccording to Response Evaluation Criteria in Solid Tumors(RECIST) version 1.1;20 adequate haematological, renal, andhepatic function; resistance or intolerance to crizotinib(investigatorassessed, and reported as treatment discontinu ation because of progressive disease, adverse event, orother); and no previous treatment with ALK inhibitors other than crizotinib. they also included patients who hadasymptomatic CNS metastases at baseline¡ªincludingleptomeningeal carcino matosis¡ªand were not on steroids. |
| Biomarker: | ALKrearranged |
| Biomark Analysis: | NA |
| Control Group Info: | single arm |
| Treatment Info: | They administered various oral doses of alectinib (300900 mg twice a day) during the doseescalation portion of the study (phase 1), to ascertain the recommended dose forphase 2. They used Response Evaluation Criteria in Solid Tumors criteria (version 1.1) to investigate the activity of alectinib in all patients with a baseline scan and at least one posttreatment scan (CT or MRI), with central radiological review of individuals with brain metastases. they assessed safety in all patients who received at least one dose of alectinib. |
| Primary End Point: | the recommended phase 2 dose |
| Secondary End Point: | NA |
| Patients Number: | 47 |
| Trial Results |
| DLT_MTD: | alectinib 600 mg twice a day as the recommended dose forphase 2. |
| Objective Response Rate: | Investigatorassessed objective responses were noted in 24 (55%) patients, with a confirmed complete response in one (2%), a confirmed partial response in 14 (32%), and an unconfirmed partial response in nine (20%). 16 (36%) patients had stable disease; the remaining four (9%) had progressive disease. Of 21 patients with CNS metastases at baseline, 11 (52%) had an objective response; six (29%) had a complete response (three unconfirmed) and five (24%) had a partial response (one unconfirmed); eight (38%) patients had stable disease and the remaining two (10%) had progressive disease. |
| Disease Control Rate: | 0.7 |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | Alectinib was well tolerated, with the most common adverse events being fatigue (14 [30%]; all grade 1-2), myalgia (eight [17%]; all grade 1-2), and peripheral oedema (seven [15%] grade 1-2, one [2%] grade 3). Doselimiting toxic effects were recorded in two patients in the cohort receiving alectinib 900 mg twice a day; one individual had grade 3 headache and the other had grade 3 neutropenia. The most common grade 3-4 adverse events were increased levels of ¦Ãglutamyl transpeptidase (two [4%]), a reduction in the number of neutrophils (two [4%]), and hypophosphataemia (two [4%]). Three patients reported four grade 4 serious adverse events that were deemed unrelated to alectinib: acute renal failure; pleural eff usion and pericardial effusion; and brain metastasis. |
| Conclusions: | Alectinib was well tolerated, with promising antitumour activity in patients with ALKrearranged non small cell lung cancer resistant to crizotinib, including those with CNS metastases. On the basis of activity, tolerability, and pharmacokinetic data, they chose alectinib 600 mg twice a day as the recommended dose forphase 2. |