Data from ALEX, a global phase III study, suggests that alectinib, an ALK inhibitor, should be considered a first-line treatment option for patients with ALK-positive lung cancer. Presented at the 2017 ASCO Annual Meeting, the findings show that alectinib leads to an increase in progression-free survival (PFS) and longer duration until central nervous system (CNS) progression compared to crizotinib, the current standard of care (Abstract LBA9008).
“This is the first global study to compare alectinib with crizotinib in ALK-positive lung cancer and establishes alectinib as the new standard of care for initial treatment in this setting,” said lead study author Alice T. Shaw, MD, PhD, Director of Thoracic Oncology at Massachusetts General Hospital Cancer Center, Boston, in a statement. “Alectinib was especially beneficial in controlling and preventing brain metastases, which can have a major impact on patients' quality of life.”
Approved by the FDA in 2011, crizotinib was the first medicine to specifically target ALK. While most patients benefit initially from the treatment, the cancer, on average, starts growing again within a year. Alectinib, a next-generation ALK inhibitor, received initial FDA approval in 2015 for patients with advanced NSCLC that had progressed despite treatment with crizotinib.
“Alectinib is more potent and more brain penetrating than crizotinib. In early phase studies, alectinib demonstrated robust clinical activity in both crizotinib-naïve and crizotinib-resistant ALK-positive patients,” noted Shaw, during an ASCO press briefing. “Based on these prior studies, we hypothesized in a randomized, head-to-head comparison alectinib would be more effective than crizotinib for first-line treatment for patients with advanced ALK-positive lung cancer.”
The open-label clinical trial, which included 98 sites and 29 countries, enrolled 303 patients with stage IIIB or IV, ALK-positive NSCLC, determined by IHC testing, who had not received prior systemic therapy for advanced NSCLC.
Eligible patients had an ECOG performance status of 0-2. Additionally, individuals with asymptomatic CNS were allowed to participate in the study. Patients were randomized 1:1 to receive alectinib (600 mg BID) or crizotinib (250 mg BID), according to researchers.
The primary endpoint of the ALEX trial was investigator-assessed progression-free survival (PFS) (RECIST v1.1) with systematic CNS imaging in all patients. Independent review committee (IRC)-assessed PFS, IRC-assessed time to CNS progression, objective response rate, overall survival, and safety were the secondary endpoints.
“We've known the benefits of alectinib given post-crizotinib for a while. Really what we wanted to learn with this study is whether it's best to start treatment with crizotinib and then follow with alectinib as a second-line therapy when the cancer progresses, or whether using alectinib as our first-line therapy could be even better than the sequential approach,” noted D. Ross Camidge, MD, PhD, Joyce Zeff Chair in Lung Cancer Research at the University of Colorado Cancer Center and Director of Thoracic Oncology at the CU School of Medicine, in a statement. Camidge is the trial's North American Primary Investigator.
At the primary data cutoff, researchers reported that alectinib demonstrated statistically significant superiority compared to crizotinib. Treatment with alectinib reduced the risk of progression/death by 53 percent (HR 0.47, 95% CI 0.34-0.65, p<0.0001).
Based on independent review, median PFS was 10.4 months for patients treated with crizotinib compared to 25.7 months for patients receiving alectinib (HR 0.50), more than doubling PFS, according to Shaw.
“Nobody imagined it would be possible to delay advanced lung cancer progression by this much,” she emphasized, in a statement. “Most targeted therapies for lung cancer are associated with a median progression-free survival of roughly 12 months.”
Both treatments cross the blood-brain barrier; however, because alectinib can better penetrate the brain, it was proven more effective in preventing brain metastases. Researchers reported, at 12 months, the incidence of CNS progression was significantly lower with alectinib compared to crizotinib (41.4% and 9.4%, respectively).
“One of the key secondary endpoints in the ALEX study was time to progression in the CNS. Patients treated with alectinib had a significant lower incidence of CNS progression compared to those treated with crizotinib,” Shaw explained. “The cause-specific HR was 0.16 corresponding to an 84 percent reduction in the risk of having CNS progression.”
Severe side effects (grade 3/4) were less frequent among patients treated with alectinib (41%) versus crizotinib (50%), investigators reported. The most common side effects of alectinib, included fatigue, constipation, muscle aches, and swelling, while treatment with crizotinib caused gastrointestinal problems and liver enzyme abnormalities, according to researchers. Additionally, the rate of adverse events leading to discontinuation, dose reduction, and interruption were all lower in the alectinib group. Fatal adverse events occurred in 3 percent of alectinib patients compared to 5 percent in the crizotinib arm.
“Overall, there were fewer severe side effects with alectinib compared to crizotinib, as a result fewer patients required dose reduction, dose interruption, or treatment discontinuation,” Shaw emphasized.
Implications for Practice
“The ALEX study is the first, global head-to-head trial comparing a next-generation ALK inhibitor with a first-generation ALK inhibitor as a first-line therapy for advanced ALK-positive lung cancer,” Shaw said. “Taken together, both the efficacy and safety results of this study establish alectinib as the new standard of care for patients with advanced, previously untreated ALK-positive lung cancer.”
ASCO expert, John Heymach, MD, PhD, shared his own commentary on the study and its practice implications during the press briefing. “I view this as a watershed moment for the treatment of ALK-positive lung cancer,” he noted. “Often studies comparing different yet similar type agents will show incremental improvements. This [study] is really different because of the dramatic difference in efficacy, more than doubling the time to cancer progression or death.
“It is also accompanied by improved tolerability. The drug is better tolerated by patients and requires dose reductions less often. And finally, as Dr. Shaw pointed out, one of the most debilitating things that occur in these patients with ALK-mutant disease is brain metastases,” he continued. “This is the most common site for progression and what is really impressive about this [study] is the dramatic reduction in the risk of brain metastases occurrence. An 84 percent reduction in that likelihood is an absolutely striking result. So, I firmly agree with Dr. Shaw's conclusion that this is a new standard for first-line ALK-positive lung cancer.
“The fact that this second-generation targeted treatment halted advanced lung cancer growth for more than 2 years while preventing brain metastases is a remarkable result in this difficult disease,” Heymach emphasized, in a statement. “Thanks to this advance, we are on the road to helping these patients live longer and better.”
Researchers plan to continue to follow patients enrolled in the study to determine if individuals treated with alectinib live longer than those receiving crizotinib. Meanwhile, ASCO reported, there are several ongoing clinical trials comparing other next-generation ALK inhibitors to crizotinib in the first-line setting.
“Alectinib has proven the principle that going on a broader-spectrum drug first—as long as it's well-tolerated—may be a key factor in the long-term control of malignant disease,” Camidge concluded.
Catlin Nalley is associate editor.