ALUR, ALEX Findings Show Alectinib Superiority For ALK-Positive NSCLC Patients

Results from the ALUR and ALEX trials consolidate alectinib as both the second- and first-line standard of care for patients with anaplastic lymphoma kinase mutation-positive non-small-cell lung cancer

medwireNews: Results from two phase III clinical trials reported at the ESMO 2017 Congress in Madrid, Spain, add evidence for the use of the anaplastic lymphoma kinase (ALK) inhibitor alectinib in patients with ALK mutation-positive non-small-cell lung cancer (NSCLC) at two different stages of disease.

Silvia Novello, from the University of Turin in Italy, presented findings for ALUR that she said “support alectinib as a new standard of care for patients with previously treated ALK-positive NSCLC”.

The study included 107 patients with disease progression after first-line treatment with platinum-based chemotherapy and the ALK inhibitor crizotinib; patients were randomly assigned to receive alectinib 600 mg twice daily or a regimen of pemetrexed or docetaxel until disease progression, death or treatment withdrawal.

Patients received alectinib for a median of 20 weeks and were followed-up for a median of 6.5 months, whereas patients given chemotherapy received treatment for 6 weeks and were followed-up for 5.8 months.

Median progression-free survival (PFS) was 9.6 and 1.4 months, respectively, with a hazard ratio (HR) of 0.15 in favour of alectinib use. And this benefit was consistently seen in subgroup analysis stratifying patients by age, gender, race, baseline central nervous system (CNS) metastases, ECOG performance status and receipt of prior radiotherapy.

The CNS objective response rate in patients with CNS metastases at baseline was 54.2% for the 24 alectinib-treated patients. This included one complete response, 12 partial responses and six cases of stable disease. By contrast, none of the 16 patients given chemotherapy achieved a response.

“The safety profile of alectinib compared favourably with that of chemotherapy”, Silvia Novello said, noting that grade 3–5 adverse events were “almost doubled” in the chemotherapy arm (41.2 vs 27.1%) despite the shorter treatment duration with chemotherapy versus with the ALK inhibitor.

Patients given alectinib were less likely to experience side effects leading to treatment discontinuation (5.7 vs 8.8%) or dose reduction (4.3 vs 11.8%) but were more likely to require dose interruptions (18.6 vs 8.8%).

Additional CNS efficacy results from the ALUR study were also presented to the meeting in poster form by Javier de Castro, from University Hospital La Paz in Madrid, Spain.

The 6-month cumulative rate of CNS progressive disease was 11% with alectinib and 48% with chemotherapy, with corresponding rates of 15% and 52% for patients with measurable CNS metastases at baseline and 0% versus 39% for those without baseline CNS involvement.

Finally, CNS efficacy findings from the ALEX study comparing alectinib versus crizotinib in patients with treatment-naïve ALK-positive NSCLC were reported to the meeting by Shirish Gadgeel, from the University of Michigan in Ann Arbor, USA.

The primary endpoint of PFS for the ALEX study was previously published in The New England Journal of Medicine, with the median value unreached for the 152 patients given alectinib 600 mg twice daily after a median of 18.6 months of follow-up. This compared with a median PFS of 11.1 months for the 151 patients given crizotinib 250 mg twice daily and followed-up for a median of 17.6 months, giving a significant HR of 0.47 in favour of alectinib.

Speaking at the ESMO 2017 Congress, Shirish Gadgeel told delegates that among patients with CNS metastases at baseline, PFS was significantly longer in the 64 patients given alectinib than the 58 patients using crizotinib, at unreached versus 7.4 months and a HR of 0.40.

Similarly, for patients free from CNS metastases at baseline, median PFS was unreached for the 88 alectinib-treated patients versus 14.8 months for the 93 patients given crizotinib, with a HR of 0.51.

“Alectinib significantly prolonged time to CNS progression both in patients with CNS metastases at baseline and in patients without CNS metastases at baseline”, the presenter reported.

Competing risk analysis gave 12-month cumulative incidence rates for CNS progression as a first event for alectinib versus crizotinib in these two patients subgroups of 16.0% versus 58.3%, and 4.6% versus 31.5%, respectively, with corresponding cause-specific HRs of 0.18 and 0.14.

“Overall, these CNS results along with the systemic results consolidate alectinib as the new standard of care for patients with previously untreated, advanced ALK+ NSCLC”, Shirish Gadgeel concluded.

References

Novello S, Mazieres J, Oh I, et al. 1299O_PR – Primary results from the phase III ALUR study of alectinib versus chemotherapy in previously treated ALK+ non-small-cell lung cancer (NSCLC). ESMO 2017 Congress; Madrid, Spain, 8–12 September.

de Castro J, Novello S, Mazieres J, et al. 1346P – CNS efficacy results from the phase III ALUR study of alectinib vs chemotherapy in previously treated ALK+ NSCLC. ESMO 2017 Congress; Madrid, Spain, 8–12 September.

Gadgeel S, Peters S, Mok T, et al. 1298O_PR – Alectinib vs crizotinib in treatment-naïve ALK+ NSCLC: CNS efficacy results from the ALEX study. ESMO 2017 Congress; Madrid, Spain, 8–12 September.

Peters S, Camidge R, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. New Engl J Med 2017;377:829–838. DOI: 10.1056/NEJMoa1704795

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