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Alectinib better prevents NSCLC growth compared with crizotinib
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CHICAGO — Alectinib stalled cancer growth for a median 15 months longer than crizotinib in patients with ALK–positive non–small cell lung cancer, according to data from the phase 3 ALEX clinical trial presented at ASCO annual meeting.
“The ALEX study is the first global, head-to-head trial comparing two ALK inhibitors in the first-line treatment setting,” Alice T. Shaw, MD, PhD, director of thoracic oncology at Massachusetts General Hospital Cancer Center, said during a press conference.
Approximately 5% of NSCLCs are ALK positive and more than 12,000 individuals are diagnosed with ALK–positive NSCLC annually. The FDA approved crizotinib (Xalkori, Pfizer) in 2011. Although most patients initially benefit from this treatment, cancer growth typically continues within 1 year.
“One of the most common sites of worsening disease is the brain or central nervous system, which likely reflects the drugs poor penetration into the brain,” Shaw said.
The FDA approved alectinib (Alecensa, Genentech) — an oral, small molecule, ATP–competitive tyrosine kinase inhibitor of ALK — in 2015 for the treatment of advanced NSCLC that progressed despite therapy with crizotinib.
“Based on [previous] data, we hypothesized that alectinib would be more effective than crizotinib for [first-line treatment of] patients with advanced ALK–positive cancer,” Shaw said.
Shaw and colleagues randomly assigned 303 patients with stage IIIB or stage IV ALK–positive NSCLC to 600 mg alectinib (n = 152) or 250 mg crizotinib (n = 151) twice daily.
PFS determined by systematic CNS imaging served as the primary endpoint. Secondary endpoints included independent review committee–assessed PFS and time to CNS progression, objective response rate, OS and safety.
At the primary data cutoff, alectinib reduced risk for progression and mortality by 53% (HR = 0.47; 95% CI, 0.34-0.65).
The median PFS was not reached (95% CI, 17.7 to not estimable) for alectinib compared with 11.1 months (95% CI, 9.1-13.1) for crizotinib.
Alectinib also exhibited superior results in terms of independent review committee PFS (median, 25.7 months vs. 10.4 months; HR = 0.5; 95% CI, 0.36-0.7), CNS progression (HR for cause-specific CNS progression = 0.16; 95% CI, 0.1-0.28), ORR (83% vs. 76%), and OS based on 25% of events (HR = 0.76; 95% CI, 0.48-1.2).
These results corresponded to an 84% reduction in risk for CNS progression, Shaw said.
Alectinib more effectively prevented brain metastases than crizotinib. At 1 year, brain metastases occurred in 9% of the alectinib-treated group compared with 41% in the crizotinib-treated group.
“These finding show that alectinib can significantly delay disease progression in the brain compared with crizotinib,” Shaw said.
Grade 3 to grade 5 adverse events occurred less frequently among patients treated with alectinib than crizotinib (41% vs. 50%); 3% of patients treated with alectinib and 5% treated with crizotinib died of adverse events.
Fewer patients treated with alectinib discontinued treatment (11% vs. 13%), had dose reduction (16% vs. 21%) and treatment interruption (19% vs. 25%) than patients treated with crizotinib. – by Melinda Stevens
Reference:
Shaw AT, et al. Abstract LBA9008. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.
Disclosure: Shaw reports honoraria from Novartis, Pfizer and Roche; consultant/advisory roles with ARIAD, Blueprint Medicines, Daiichi Sankyo, EMD Serono, Ignyta, KSQ Therapeutics, Loxo, Novartis, Pfizer, Roche/Genentech and Taiho Pharmaceutical; and research funding to her institution from Novartis, Pfizer and Roche. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
Perspective
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Yanis Boumber, MD, PhD
In the United States, about 12,500 people are diagnosed with ALKpositive nonsmall cell lung cancer each year. The majority of these patients are nonsmokers. Although crizotinib (Xalkori, Pfizer) is an effective drug in this category of NSCLC, resistance occurs within 1 year, and brain metastases occur in up to 50% of these patients.
At this ASCO Annual Meeting, researchers of a large phase 3 trial compared crizotinib with alectinib (Alecensa, Genentech) for ALKpositive patients who did not receive prior therapy. It showed that alectinib worked more than twice as long as crizotinib on average 15 months longer and only a few patients developed brain metastasis. Side effects also appeared less common with alectinib.
The results of this new study are exceptional, as upfront alectinib prevents brain metastasis in a majority of patients, and makes them live longer and better. Upfront use of alectinib may soon become a new standard in patients with newly diagnosed ALKpositive NSCLC.
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John V. Heymach, MD, PhD
I view this as a watershed moment for the treatment of ALK mutation–positive lung cancer. Often, studies preparing different similar-type agents will show incremental improvements. This study shows dramatic difference in efficacy — treatment more than doubled the time for cancer progression or death, accompanied by improved tolerability. The drug also is better tolerated by patients who require dose reductions.
As Shaw pointed out [during her presentation], brain metastases are one of most debilitating things that occur in these patients with ALK disease. This is the most common site for progression. The dramatic 84% reduction in the risk for brain metastases is an absolutely striking result.
Further, advances come often at the cost of decreased tolerability. Here, in terms of efficacy and tolerability, it is a clear win on all fronts.
Prior to this moment, the biggest advance in the field involving the comparison of crizotinib (Xalkori, Pfizer) — the current standard for first-line ALK disease — with chemotherapy. The difference in PFS in that study was 7 months vs. 11.9 months, representing a little more than 4-month improvement in the time to cancer progression or death.
Here, now we see this more than doubling, to over 25 months. It gives us an idea of what a dramatic advancement this is. I firmly agree with the researchers’ conclusion that this is a new standard for first-line ALK fusion in lung cancer.
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