ALEX Phase III Trial Suggests Alectinib Should Be First-Line Treatment for Patients With ALK-Positive Lung Cancer

ALEX Phase III Trial Suggests Alectinib Should Be First-Line Treatment for Patients With ALK-Positive Lung Cancer

Dr. Alice T. Shaw presents LBA9008.
The results of ALEX, a global phase III trial, suggest that alectinib, an anaplastic lymphoma kinase (ALK) tyrosine-kinase inhibitor (TKI), leads to greater progression-free survival (PFS) and longer duration until central nervous system (CNS) progression in patients with untreated, advanced ALK-positive non–small cell lung cancer (NSCLC) compared with crizotinib, which is currently the first-line treatment for this disease.

“Our results establish alectinib as a new standard of care for patients with previously untreated, advanced ALK-positive lung cancer,” Alice Tsang Shaw, MD, PhD, of the Massachusetts General Hospital, said. Dr. Shaw presented the findings in an Oral Abstract Session (Abstract LBA9008) on June 6.

According to Dr. Shaw, alectinib is already standard therapy for patients with ALK-positive NSCLC who were previously treated with crizotinib because alectinib demonstrates robust clinical activity in patients with crizotinib resistance.

The trial enrolled 303 treatment-naive patients from 29 countries. Patients were randomly assigned to receive crizotinib or alectinib, a next-generation ALK TKI that is structurally distinct from crizotinib but, unlike crizotinib, is CNS penetrant.1 Approximately 40% of the patients in each treatment arm had asymptomatic CNS metastases; among those, approximately 40% had received treatment, such as whole-brain radiation therapy, for CNS metastases.

Patients who received alectinib had significantly longer PFS than those who received crizotinib. According to investigator assessment, PFS was not reached in the alectinib treatment arm, whereas PFS was 11.1 months in the crizotinib arm (hazard ratio [HR] 0.47; p < 0.0001). An independent review committee determined that the median PFS in the alectinib group was 25.7 months compared with 10.4 months in the crizotinib group (HR 0.50; p < 0.0001). Alectinib was associated with improved PFS in patients with and without CNS metastases at baseline.

Dr. Sanjay Popat discusses LBA9008.
Conclusions about overall survival, which was a secondary endpoint of the trial, cannot be made at this time. Another analysis will be performed when the data are more mature, Dr. Shaw said.

An important secondary endpoint of the trial was CNS progression. Alectinib was found to significantly delay CNS progression; 12% of patients in the alectinib group had an event of CNS progression compared with 45% in the crizotinib group (HR 0.16; p < 0.0001). The cumulative incidence rates of 12-month CNS progression were 9.4% (95% CI [5.4%, 14.7%]) in the alectinib group and 41.4% (95% CI [33.2%, 49.4%]) in the crizotinib group.

An analysis of adverse events (AEs) found more gastrointestinal AEs in the crizotinib group than in the alectinib group, but patients in the alectinib group had higher rates of other AEs, such as increased bilirubin, myalgia, anemia, and weight gain. “These side effects were all consistent with the known safety profiles of both drugs,” Dr. Shaw said.

“ALEX firmly places alectinib as the optimal first-line ALK [TKI] of choice for patients with CNS metastases … but also for patients without CNS metastases, where it is neuroprotective,” said discussant Sanjay Popat, PhD, MBBS, of the Royal Marsden Hospital in London.

The results of the ALEX trial agree with the findings of J-ALEX,2 a recently reported phase III trial of Japanese patients with ALK-positive NSCLC that compared alectinib and crizotinib, Dr. Popat noted. Alectinib also appears superior to ceritinib, another ALK TKI, both in overall and intracranial response rates and in median PFS comparisons, on the basis of ASCEND4 trial results with ceritinib, he added.

These trials raise several questions, Dr. Popat said. For one, given the neuroprotective activity of alectinib, what should now be the role of radiotherapy in patients with CNS metastases at presentation?  He added that it is unclear how doctors should treat patients who develop resistance to alectinib.

Several ongoing phase III trials are comparing other ALK inhibitors with different toxicity profiles against crizotinib. “Will there be one dominant ALK inhibitor? Time will tell,” Dr. Popat said.

–Carina Storrs, PhD