Data from two separate phase 3 studies to be presented at the ESMO 2017 Congress in Madrid, show alectinib's particular central nervous system (CNS) activity in patients with advanced non-small cell lung cancer involving a mutation of the anaplastic lymphoma kinase gene (ALK-positive NSCLC).
Findings from the ALUR trial (1), as well as a secondary analysis of the ALEX trial (2) show alectinib can significantly decrease CNS progression of NSCLC, both in the first-line as well as the second-line treatment setting.
"Patients with NSCLC have a high risk of CNS and brain metastases, commented Prof. Fiona Blackhall, from the University of Manchester and The Christie Hospital, UK.
"These trials provide an important evidence base for the CNS efficacy of alectinib that can be translated to routine clinical care."
The ALUR results "support alectinib as a new standard-of-care for patients with previously treated ALK-positive NSCLC," noted that study's investigator Dr. Silvia Novello, from the University of Turin, Italy.
ALUR included 107 ALK-positive NSCLC patients whose disease had progressed after a previous first-line combination treatment of both platinum-based chemotherapy and crizotinib.
They were randomised to second-line therapy with either standard relapse chemotherapy or alectinib.
Median progression free survival (PFS) was significantly longer in the alectinib group compared to the chemotherapy group - 9.6 versus 1.4 months (hazard ratio [HR] 0.15, 95% CI 0.08-0.29; P<0.001), with a marked difference in CNS response, reported Novello.
Among patients who had measurable CNS disease at baseline, the CNS overall response rate (ORR) was 54.2% in those treated with alectinib compared to zero in the chemotherapy group (P<0.001).
The safety profile of alectinib compared favourably with chemotherapy, despite the substantially longer duration of treatment for patients on alectinib (20 weeks versus six weeks with chemotherapy).
"This is another important goal reached in the field of thoracic oncology," said Novello. "ALK- positive patients represent 4% of patients with advanced NSCLC, which is the leading cause of solid cancer deaths in men and women in several countries. CNS data are extremely relevant for these patients - the brain is a frequent site of metastasis for them - and these results are important because if we're aiming to prolong survival we must aim to preserve their neurocognitive capacity. A drug which has this activity on brain metastases can allow us to modify treatment and reduce the need for whole brain radiotherapy."
Another study to be presented at the meeting, the ALEX trial (3), previously showed significantly better PFS among treatment-naive ALK-positive NSCLC patients who were randomised to alectinib compared to crizotinib (HR for disease progression or death, 0.47, 95% CI, 0.34-0.65; P<0.001).
This new subgroup analysis, focusing specifically on 122 patients who had CNS metastases at baseline, "suggests that alectinib controls existing CNS metastases and inhibits the formation of new metastases better than crizotinib," said Dr. Shirish Gadgeel, from the University of Michigan, in Ann Arbor, Michigan, USA.
"Clearly this superiority against CNS metastases contributes to the overall efficacy of alectinib," he added. "By its superior efficacy in the CNS alectinib limits the morbidity both from these metastases but also from treatments such as whole brain radiation."
ALK-positive NSCLC was discovered only 10 years ago and progress in identifying precision medicines has been rapid, noted Prof. Blackhall. "Early on, patients were observed to be at high risk of CNS disease and after the discovery of the first-in-class ALK-inhibitor, crizotinib, there has been a focus on development of next generation ALK-inhibitors with improved CNS penetration. The results of the ALUR and ALEX trials provide proof of clinically significant CNS efficacy for alectinib and indicate that CNS staging should be routine for optimal care of patients with ALK-positive lung cancer."
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More information: Reference:
1. Abstracts 1299O_PR 'Primary results from the phase III ALUR study of alectinib versus chemotherapy in previously treated ALK+ non-small-cell lung cancer (NSCLC)' will be presented by Dr Shirish Gadgeel during Proffered Paper Session 'NSCLC, metastatic 2' on Monday, 11 September 2017, 09:30 to 10:30 (CEST) in Barcelona Auditorium.
2. Abstract 1298O_PR "Alectinib vs crizotinib in treatment-naïve ALK+ NSCLC: CNS efficacy results from the ALEX study", will be presented by Dr Silvia Novello during the Proffered Paper Session 'NSCLC, metastatic 2' on Monday, 11 September 2017, 09:30 to 10:30 (CEST) in Barcelona Auditorium.
3. N Engl J Med. 2017 Jun 6. DOI: 10.1056/NEJMoa1704795. [Epub ahead of print]