MADRID, Spain — Impressive activity against central nervous system (CNS) metastases has been shown again with the targeted agent alectinib (Alecensa, Roche/Genentech) in patients with anaplastic lymphoma kinase–positive (ALK+) non-small cell lung cancer (NSCLC).
The data come from two studies — ALUR (NCT02604342) and ALEX (NCT02075840) — that will be reported here at the European Society for Medical Oncology (ESMO) 2017 Congress.
Both are phase 3 studies in advanced ALK+ NSCLC. ALEX uses alectinib in the first-line setting and ALUR uses it in the second-line.
ALUR showed that in patients with measurable central nervous system (CNS) disease at baseline, CNS overall responses rate (ORR) was 54.2% for patients receiving alectinib and 0% for patients receiving chemotherapy. A subanalysis of ALEX showed that patients with measureable CNS disease at baseline were at a 40% reduced risk for progression with alectinib compared with crizotinib (Xalkori, Pfizer).
“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+ lung cancers,” Fiona Blackhall, MD, PhD, from the University of Manchester and The Christie Hospital, United Kingdom, said in a statement.
Alectinib is approved for second-line use to treat ALK+ NSCLC that has progressed on crizotinib. But the data from ALEX, which were presented at the American Society of Clinical Oncology (ASCO) 2017 annual meeting, showed impressive findings in the first-line setting. ASCO expert John V. Heymach, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston, called it “a watershed moment for the treatment of ALK+ lung cancer” and agreed with the study investigators that alectinib presented a new standard for first-line ALK+ NSCLC.
ALUR in ALK+ Previously Treated Advanced NSCLC
ALUR randomly assigned previously treated patients with ALK+ NSCLC to alectinib, 600 mg twice daily (n = 72), or chemotherapy (pemetrexed or docetaxel; n = 35) until disease progression, death, or withdrawal.
Median follow-up was 6.5 months for patients receiving alectinib and 5.8 months for patients receiving chemotherapy. Investigator-assessed median progression-free survival (PFS) — the primary endpoint — was 9.6 months for patients receiving alectinib and 1.7 months for patients receiving chemotherapy, and alectinib was associated with a significant 85% reduced risk for progression. Median PFS was 7.1 months for alectinib and 1.6 months for chemotherapy based on independent review committee determination, and alectinib was associated with a 68% reduced risk for progression —again significant.
Overall response rates (independent review committee) were 36.1% and 11.4% for patients receiving alectinib and chemotherapy, respectively. The disease control rate (overall response rate + stable disease) was also significant for patients receiving alectinib: 80.6% vs 28.6% for patients receiving chemotherapy.
Adverse events occurred with a lower frequency in the alectinib group even though patients were taking alectinib for a longer time (20 weeks vs 6 weeks for chemotherapy).
Study investigator Silvia Novella, MD, from the University of Turin, Italy, noted that the brain is a frequent site of metastasis for patients with ALK+ NSCLC. “These results are important because if we’re aiming to prolong survival we must preserve [patients’] neurocognitive capacity. A drug that has this activity on brain metastases can allow us to modify treatment and reduce the need for whole-brain radiotherapy,” he said.
Subanalysis of ALEX in Treatment-Naive ALK+ Advanced NSCLC
In the original cohort of 303 treatment-naive patients with ALK+ advanced NSCLC, median PFS was 25.7 months with alectinib vs 10.4 months with crizotinib.
At the ESMO 2017 Congress, new data will be presented from a subanalysis of patients who did (n = 122 [64 for alectinib and 58 for crizotinib]) and did not (n = 181 [88 for alectinib and 93 for crizotinib]) present with CNS metastases at baseline.
For patients who did not present with CNS metastases at baseline, median PFS was 14.8 months for those receiving crizotinib and was not reached for those receiving alectinib.
For patients with CNS metastases at baseline, median PFS was 7.4 months for crizotinib recipients and was not reached for alectinib recipients.
Because radiation therapy is used to treat brain metastases, the ALEX investigators also report PFS data based on whether patients with CNS metastases at baseline had received prior radiation therapy (RT). For patients who had not received prior RT, median PFS was 12.7 months for patients taking crizotinib and was not reached for those taking alectinib. For patients with prior RT, median PFS was 7.2 months and 14.0 months for crizotinib and alectinib, respectively.
Another salient point of the analyses was the site of first disease progression. For patients receiving crizotinib, first disease progression was more common in CNS than in non-CNS sites. For example, of patients without CNS metastases at baseline, 38% and 20% showed CNS vs non-CNS disease progression. However, for alectinib, first disease progression was more frequent in non-CNS sites for patients without baseline CNS metastases: 6.8% CNS disease progression vs 28% non-CNS disease progression.
But for patients receiving alectinib with CNS metastases at baseline, first disease progression in CNS and non-CNS sites was similar, but not so for patients on crizotinib, with 57% of patients showing CNS disease progression and 24% showing non-CNS disease progression.
In all cohorts analyzed, the 12-month cumulative incidence rate for CNS disease progression was lower in patients receiving alectinib. In patients with no CNS metastases at baseline, rates of CNS disease progression were 4.6% for patients receiving alectinib and 31.5% for patients receiving crizotinib. Corresponding rates in patients with CNS metastases at baseline were 16.0% and 58.3%, respectively.
Alectinib controls existing CNS metastases and inhibits the formation of new metastases better than crizotinib.
This analysis suggests that “alectinib controls existing CNS metastases and inhibits the formation of new metastases better than crizotinib,” commented presenter Shirish Gadgeel, MD, from the University of Ann Arbor, Michigan. He further noted that the superiority against CNS metastases contributes to the overall efficacy of alectinib. Echoing the sentiments of Dr Novella, he said in a statement: “By its superior efficacy in the CNS, alectinib limits the morbidity both from these metastases but also from treatments such as whole brain radiation.”
“Patients with NSCLC have a high risk of CNS and brain metastases. These trials provide an important evidence base for the CNS efficacy of alectinib that can be translated to routine clinical care,” Dr Blackhall said in a statement.
Financial relationships for study authors are found at the end of the abstracts.
European Society for Medical Oncology (ESMO) 2017 Congress. To be presented September 11. Abstracts 1298O and 1299O.
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