From the Journals

ALEX: Alectinib showed superior CNS efficacy in ALK+ NSCLC

Key clinical point: Alectinib showed superior CNS activity and significantly delayed CNS progression over crizotinib in patients with treatment-naive anaplastic lymphoma kinase–positive non–small cell lung cancer.

Major finding: Time to CNS progression was significantly longer with alectinib versus crizotinib (hazard ratio, 0.18; 95% confidence interval, 0.09-0.36) and was comparable among patients with and without baseline CNS metastases or prior radiotherapy.

Study details: A phase 3 trial of 303 patients receiving alectinib (600 mg) or crizotinib (250 mg) twice daily.

Disclosures: F. Hoffman-La Roche funded the study. Dr. Gadgeel disclosed honoraria and consultancy fees from Roche/Genentech, ARIAD Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, and Pfizer.

Source: Gadgeel SM et al. Ann Oncol. 2018 Sep 12. doi: 10.1093/annonc/mdy405.

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Findings justify first-line alectinib in ALK+ NSCLC

The results of the phase 3 ALEX trial provide strong rationale for the first-line use of alectinib in patients with non–small cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements.

Alectinib showed robust evidence of intracranial and extracranial efficacy, not only eliciting responses in existing brain metastases but also helping prevent new ones. These results likely translate into significant improvements in quality of life, function, and survival for patients, and reduce the well-documented health economic burden associated with the development of CNS metastases.

Newer-generation ALK inhibitors, such as brigatinib and lorlatinib, also show CNS activity and are currently in phase 3 trials. It will be important to assess their effects on brain metastases to help determine their role in managing patients with ALK-positive NSCLC.

Alesha A. Thai, MD, is with the Peter MacCallum Cancer Centre in Melbourne and Benjamin J. Solomon, MD, is with the University of Melbourne. Dr. Thai disclosed no conflicts of interest. Dr. Solomon disclosed advisory board relationships with Roche-Genentech, Pfizer, Novartis, AstraZeneca, Merck, and Bristol-Myers Squibb. These comments are from their editorial (Ann Oncol. 2018 Sep 18. doi: 10.1093/annonc/mdy415).


 

FROM ANNALS OF ONCOLOGY

For patients with treatment-naive anaplastic lymphoma kinase–positive (ALK+) non–small cell lung cancer (NSCLC), twice-daily oral treatment with alectinib (600 mg) was associated with significantly greater activity in the CNS and significantly delayed CNS progression, compared with crizotinib (200 mg), based on secondary analyses from the pivotal phase 3 ALEX trial.

Time to CNS progression was significantly longer with alectinib versus crizotinib (hazard ratio, 0.18; 95% confidence interval, 0.09-0.36) regardless of whether patients had asymptomatic baseline CNS metastases or a prior history of radiotherapy. For patients with baseline asymptomatic CNS metastases, the 12-month cumulative incidence of CNS progression was 16% with alectinib versus 58.3% with crizotinib. Among patients without asymptomatic CNS metastases at baseline, these rates were 4.6% versus 31.5%, respectively.

The findings “consolidate alectinib as the standard of care for untreated, advanced ALK+ NSCLC, irrespective of the presence or absence of baseline CNS metastases,” Shirish M. Gadgeel, MD, of the University of Michigan, Ann Arbor, and his associates wrote in Annals of Oncology.

ALEX was the first study of an ALK inhibitor to include a prospective, standardized intention-to-treat analysis of CNS lesions, regardless of whether patients had these lesions at baseline. All patients underwent brain imaging at baseline and every 8 weeks thereafter. In the primary analysis of 303 patients, alectinib significantly improved progression-free survival in patients with and without baseline CNS disease and showed a significantly higher intracranial overall response rate, irrespective of whether patients had previously received radiotherapy.

Based on these results, National Comprehensive Cancer Network guidelines were updated to include a category 1 recommendation for the first-line use of alectinib in patients with ALK+ NSCLC.

The current analysis focused on CNS efficacy. In all, 122 patients had CNS metastases at baseline. Progression-free survival was similar regardless of whether patients had these lesions (HR, 0.40; 95% CI, 0.25-0.64) or not (HR, 0.51; 95% CI, 0.33-0.80; P = .36). History of radiotherapy also did not significantly affect overall CNS response or progression-free survival.

“Our data are in agreement with a pooled analysis of alectinib phase 2 trials, which demonstrated that central nervous system efficacy of alectinib is maintained regardless of radiotherapy history in crizotinib-pretreated patients,” the investigators wrote.

Because ALEX excluded patients with symptomatic CNS disease, its effects in this population remain unclear, they noted. “ALEX data strongly suggest that in asymptomatic patients, treating CNS metastases with alectinib alone may result in a reduced or delayed need for local CNS treatment.”

F. Hoffman-La Roche funded the study. Dr. Gadgeel reported honoraria and consultancy fees from Roche/Genentech, ARIAD Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, and Pfizer.

SOURCE: Gadgeel SM et al. Ann Oncol. 2018 Sep 12. doi: 10.1093/annonc/mdy405.

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