Adjuvant alectinib represents an efficacious new treatment strategy for patients with resected ALK-positive NSCLC, according to the findings of a global study led by senior investigator Professor Ben Solomon from the Peter MacCallum Cancer Centre, Melbourne.
The open-label ALINA trial, published in the NEJM [link here], randomised 257 patients from 26 countries including Australia to either oral alectinib for 24 months or IV platinum-based chemotherapy in four 21-day cycles.
Participants had diagnoses of either stage IB (10.8%), stage II (36.2%) or stage III disease (53.1%) and were randomised a median of 1.7 months after tumour resection.
The study found the disease-free survival among patients with stage II or IIIA disease at two years was 93.8% in the alectinib group and 63.0% in the chemotherapy group while disease-free survival at three years was 88.3% and 53.3% respectively.
“The hazard ratio for disease recurrence or death was 0.24 (95% confidence interval [CI], 0.13 to 0.45; P<0.001), which corresponds to a 76% lower risk with adjuvant alectinib than with chemotherapy.”
It found the disease-free survival benefit was generally consistent across all subgroups defined according to disease stage, race, sex, and smoking status.
Disease recurrence was most common in the brain – reported in 4 patients in the alectinib group and 14 in the chemotherapy group (HR 0.22).
“An exploratory analysis showed a clinically meaningful prolongation of CNS disease-free survival with alectinib … consistent with the intracranial efficacy of alectinib in advanced NSCLC,” the study authors reported.
Regarding safety, the most common AEs were grade 1 or 2 events.
“The most commonly reported adverse events were increased creatine kinase levels (43.0%) and constipation (42.2%) in the alectinib group and nausea (72.5%) and decreased appetite (29.2%) in the chemotherapy group,” the study authors said.
Grade 3 or 4 treatment-related adverse events occurred more frequently with chemo – 18.0% in the alectinib group and 27.5% in the chemotherapy group.
In contrast, serious adverse events (13.3% v 8.3%) and adverse events leading to dose reduction (25.8% v 10.0%) or dose interruption (27.3% v 18.3%) were more common with the second-generation ALK TKI.
AEs leading to dose discontinuation were reported in 5.5% of the alectinib group and 12.5% of the chemotherapy group.
“Chemotherapy-free regimens have potential benefits with respect to adverse-event profile, could allow chemotherapy to be reserved as a treatment option after disease recurrence, and may be preferred by patients and their families,” the investigators said.
“However, our trial does not address the potential additional usefulness of adding chemotherapy to alectinib. This approach could allow intensification of therapy in selected groups of patients and should be investigated in future clinical trials.”
The study noted the importance of testing for ALK alterations across all stages of NSCLC.
“Currently, biomarker testing for ALK alterations in resectable NSCLC is mainly performed to exclude patients from receiving immunotherapy, but routine ALK testing should also support identification of patients who are likely to benefit from adjuvant alectinib.”
An accompanying editorial in the journal [link here] said the study’s findings were highly meaningful especially given the magnitude of the benefit reported.
“The effect of alectinib on the risk of CNS disease recurrence positions it as a therapeutic breakthrough,” it said.
“Although more mature data on overall survival (a critical end point after curative-intent surgery and adjuvant treatments) are still expected, there is little hesitation in assuming it will be positively affected.”
However there were remaining considerations such as the feasibility of incorporating additional biologic therapies in the adjuvant context, the potential of TKIs as a sufficient stand-alone treatment, the most effective duration of TKI therapy, and the need for molecular profiling for all patients with resected NSCLC.
There was also a need for long term evaluation of the safety profiles of TKI in the adjuvant context “in which treatment is given to patients with no evidence of active disease.”
The study was sponsored by Hoffmann-La Roche.