Alectinib Improved PFS by 15 Months Over Crizotinib in ALK+ NSCLC in ALEX Trial

Alice T. Shaw, MD, PhD

Second-generation ALK inhibitor alectinib (Alecensa) demonstrated a 15-month improvement in progression-free survival (PFS) compared with crizotinib (Xalkori), the first-generation ALK inhibitor and standard of care, in patients withALK-positive non—small cell lung cancer (NSCLC). Phase III results from the ALEX study presented at the 2017 ASCO Annual Meeting showed that alectinib was associated with a median PFS of 25.7 months (95% CI, 19.9-not reached) compared with 10.4 months for crizotinib (95% CI, 7.7-14.6), based on independent review.¹The drug also reduced the risk of death by 53% (HR, 0.47; 95% CI, 0.34—0.65;P<.0001).

In addition, the study found that alectinib demonstrated superior ability to penetrate the central nervous system (CNS) and control tumor growth in the brain. At 12 months, the incidence of brain metastases was 9.4% with alectinib (95% CI, 5.4-14.7) versus 41.4% with crizotinib (95% CI, 33.2-49.4).

&ldquo;One of the most common sites of worsening disease is the brain or central nervous system,&rdquo; said lead study author Alice T. Shaw, MD, PhD, director of Thoracic Oncology at Massachusetts General Hospital Cancer Center. &ldquo;These findings show that alectinib can significantly delay disease progression in the brain compared with crizotinib.&rdquo;

Crizotinib has been the standard of care inALK-positive NSCLC since it was approved in 2011 as the first treatment to target theALKmutation. Shaw said the results show alectinib should be the treatment choice for this patient population.

&ldquo;Taken together, both the efficacy and safety results of this study establish alectinib as the new standard-of-care for patients with advanced, previously untreatedALK-positive lung cancer,&rdquo; she said. In October 2016, Alectinib received an FDA breakthrough therapy designation as a frontline treatment for patients withALK-positive NSCLC.

About 5% of NSCLCs areALK-positive, and roughly 12,500 people in the United States are diagnosed with the disease each year.

ALEX is an open-label randomized multicenter phase III study comparing the safety and efficacy of alectinib with crizotinib in patients with stage IIIB/IVALK-positive NSCLC. Patients were randomly assigned to receive daily dosages of 600 mg of alectinib (n = 152) or 250 mg of crizotinib (n = 151).

Severe adverse events (AEs) also were lower with alectinib. Fifty percent of patients assigned to crizotinib experienced grade 3/4 AEs compared with 41% of the alectinib group, and alectnib was associated with a lower incidence of fatal AEs, 3% versus 5%. Patients assigned to alectinib were also less likely to experience AEs leading to discontinuation (13% versus 11%), dose reduction (21% versus 16%) or interruption (25% versus 19%).

The objective response rate was 83% (95% CI, 76—89) for alectinib versus 76% (95% CI, 68&ndash;82) for crizotinib (P= .09).

The ALEX results update previous findings from the Japanese open-label phase III J-ALEX study presented at last year&rsquo;s ASCO Annual Meeting. J-ALEX showed that alectinib improved PFS by 66% versus crizotinib.²

Apar Kishor Ganti, MD, a professor in the division of oncology/hematology at the University of Nebraska Medical Center, said he was impressed with the findings.

&ldquo;The results are pretty amazing and I believe will change standard of care for first-line treatment forALK-positive lung cancer,&rdquo; he said. &ldquo;ALKtranslocation accounts for a small proportion of patients, but for these patients, this is pretty dramatic. In the past, anything more than about 15% [decreased risk for progression] was considered good. Now we&rsquo;re looking at 53%. That&rsquo;s as good as it has gotten in the lung cancer world. The more important thing is that not only did alectinib have these efficacy benefits, but even in terms of safety the drug did well.&rdquo;

References:

1. Shaw AT, Peters S, Mok T, et al. Alectinib versus crizotinib in treatment-naive advanced ALK-positive non—small cell lung cancer (NSCLC): primary results of the global phase III ALEX study.J Clin Oncol.2017;35 (suppl; abstr LBA9008).
2. Nokihara H, Hida T, Kondo M, et al. Alectinib (ALC) versus crizotinib (CRZ) in ALK-inhibitor na&iuml;ve ALK-positive non-small cell lung cancer (ALK+ NSCLC): Primary results from the J-ALEX study.J Clin Oncol.2016;34 (suppl; abstr 9008).