Findings from a phase III clinical trial funded by funded by F. Hoffmann-La Roche, point to a more effective initial treatment for patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC).
In the open label clinical trial (ALEX; NCT02075840), researchers randomly assigned 303 patients with stage IIIB or IV, ALK-positive NSCLC to receive alectinib or crizotinib. The patients had not received prior systemic therapy for advanced NSCLC. 
The trial was designed to evaluate the efficacy and safety of alectinib, an oral medicine created at Chugai Kamakura Research Laboratories being developed for people with NSCLC whose tumors are identified as ALK-positive, compared with crizotinib treatment in participants with treatment-naive ALK-positive advanced NSCLC. The drug has shown systemic and central nervous system (CNS) efficacy in the treatment of ALK-positive NSCLC.
Participants will be randomized in a 1:1 ratio to receive either alectinib, 600 milligrams (mg) orally twice daily (BID), or crizotinib, 250 mg orally BID. Participants received treatment until disease progression, unacceptable toxicity, consent withdrawal or death.
The study was featured at the 53rd annual meeting of the American Society of Clinical Oncology (ASCO), held June 2 – 6, 2017 in Chicago, Ill, and simultaneously published in the June 6, 2017 edition of the New England Journal of Medicine (NEJM). 
The results show that compared to the current standard of care crizotinib (Xalkori®; Pfizer Oncology / EMD Serono), the newer ALK inhibitor alectinib (Alecensa®; Genentech/Roche) halted cancer growth for a median of 15 months longer and caused fewer severe side effects.
A new standard
“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 in Boston, MA.
“Alectinib was especially beneficial in controlling and preventing brain Phmetastases, which can have a major impact on patients’ quality of life,” Shaw added.
About 5% of NSCLCs are ALK-positive, meaning they have a genetic rearrangement where the ALK gene is fused with another gene. In the United States, about 12,500 people are diagnosed with ALK-positive NSCLC each year.
Crizotinib, the first medicine to specifically target ALK, was approved by the FDA in 2011. Although the majority of patients initially benefit from crizotinib, the cancer typically starts growing again within a year. The study confirms that alectinib is a more potent, next-generation inhibitor of ALK. It was initially approved in 2015 for use in patients with advanced NSCLC that worsens despite crizotinib.
Alectinib reduced the risk of cancer progression or death by 53% compared with crizotinib when given as initial (first-line) treatment for people with ALK-positive advanced NSCLC (hazard ratio (HR)=0.47, 95% CI: 0.34-0.65, p<0.0001). 
Median progression-free survival or PFS, as reported by the investigators, shows that primary endpoint of the study was not yet reached in people who received alectinib (95% CI: 17.7-not reached) versus 11.1 months (95% CI: 9.1-13.1 months) in those who received crizotinib.
Based on independent review, alectinib extended the median time to progression by about 15 months. The median PFS was 25.7 months (95% CI: 19.9-not reached) with alectinib and 10.4 months for people who received crizotinib (95% CI: 7.7-14.6 months) (HR=0.50, 95% CI 0.36–0.70; p<0.0001).
The safety profile of alectinib was consistent with that observed in previous studies.
“Nobody imagined it would be possible to delay advanced lung cancer progression by this much. Most targeted therapies for lung cancer are associated with a median progression-free survival of roughly 12 months,” Shaw said.
While both treatments cross the blood-brain barrier, alectinib was more effective in preventing brain metastases than crizotinib, because it can better penetrate into the brain. At 12 months, the incidence of brain metastases was much lower with alectinib than with crizotinib (9% vs. 41%).
Severe Grade 3-5 adverse events (AEs) were less common with alectinib than with crizotinib, occurring in 41% vs. 50% of patients. Overall, the most common side effects of alectinib were fatigue, constipation, muscle aches, and swelling, whereas crizotinib caused gastrointestinal problems and liver enzyme abnormalities.
In numbers, in the alectinib arm, the most common Grade 3-5 AEs (≥5%) were increased liver enzymes (alanine transferase and aspartate transferase; 5%) and decreased red blood cells (anaemia; 5%). AEs leading to discontinuation (11% vs. 13%), dose reduction (16% vs. 21%) and dose interruption (19% vs. 25%) were all lower in the alectinib arm compared to the crizotinib arm.
Europe, the United States and ten other countries globally, alectinib is approved as a monotherapy for people with ALK-positive NSCLC who have progressed on or are intolerant to crizotinib. Alecensa is also approved in Japan for people whose tumors were advanced, recurrent or unresectable.
In September 2016 the United States Food and Drug Administration (FDA) granted alectinib Breakthrough Therapy Designation (BTD) for the treatment of people with advanced ALK-positive NSCLC who have not received prior treatment with an ALK inhibitor.
In the European Union (EU), alectinib was granted conditional marketing authorization in February 2017 as monotherapy for people with ALK-positive advanced NSCLC previously treated with crizotinib.
“The fact that this second-generation targeted treatment halted advanced lung cancer growth for more than two years while preventing brain metastases is a remarkable result in this difficult disease,” noted John Heymach, MD, PhD, an ASCO Expert not involved with the study.
“Thanks to this advance, we are on the road to helping these patients live longer and better,” Heymach added.
The researchers will continue to follow patients on this study to see if those treated with alectinib live longer than those treated with crizotinib. Meanwhile, several ongoing clinical trials are comparing other next-generation ALK inhibitors to crizotinib in the first-line setting.
Last editorial review: June 6, 2017
Featured Image: Attendees during the day at the American Society of Clinical Oncology (ASCO) Annual Meeting here today, Friday June 2, 2017 . Courtesy: © 2017 ASCO/Scott Morgan. Used with permission. Photo 1.0: Alice T. Shaw, MD, PhD, Massachusetts General Hospital. Courtesy: © 2017 ASCO/Scott Morgan. © 2017 ASCO/Scott Morgan.
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