Preliminary Brigatinib Results Indicate Possible Use In ALK-Positive NSCLC

The ALK inhibitor brigatinib has shown activity in patients with ALK-rearranged non-small-cell lung cancer regardless of prior crizotinib therapy

medwireNews: Phase I/II study results support further investigation into brigatinib for ALK rearrangement-positive non-small-cell lung cancer (NSCLC), including patients that have and have not previously been treated with crizotinib .

The findings indicate that the novel ALK inhibitor has “durable responses and promising activity in patients with brain metastases, and that it has a clinically acceptable safety profile at the phase 2 doses tested in this trial”, the authors write in The Lancet Oncology.

The open-label study included 137 patients, 79 of whom had ALK-rearranged NSCLC and the remainder had other types of advanced malignancies refractory to treatment, explain Scott Gettinger, from Yale Cancer Center in New Haven, Connecticut, USA, and team.

Dose-limiting toxicities of grade 3 alanine aminotransferase elevation (240 mg/day) and grade 4 dyspnoea (300 mg/day) in the dose-escalation phase led to a recommended phase II brigatinib dose of 180 mg/day, with alternative regimens of 90 mg/day or twice daily, or a 7-day lead-in dose of 90 mg/day followed by 180 mg/day.

All four of the patients with ALK inhibitor-naive ALK-rearranged NSCLC treated with brigatinib 180 mg/day or 90 to 180 mg/day achieved an objective response, as did 74% of the 42 patients who had previously been treated with crizotinib and received 90 mg/day or twice daily, 90 to 180 mg/day or 180 mg/day.

In addition, five (83%) of six patients with crizotinib-naive or crizotinib-treated ALK-rearranged NSCLC with active and measurable central nervous system (CNS) metastases achieved an objective response to brigatinib. Three of these six patients also had an intracranial response.

“The activity of brigatinib in the CNS was particularly encouraging, considering that the brain is a common site of progression with crizotinib treatment, although the number of patients is small and the results must be interpreted cautiously”, the researchers comment.

And while 17% of the 18 patients with other solid advanced malignancies with a brigatinib target – mainly ALK rearrangement or ROS1 mutation – achieved an objective response to  treatment, the patient with EGFR T790M mutation-positive NSCLC resistant to at least one tyrosine kinase inhibitor did not.

The authors emphasise that all eight patients with ALK-rearranged NSCLC who were naïve to crizotinib had a confirmed objective response to brigatinib therapy, including three complete responses.

Median progression-free survival was 13.2 months in patients who had previously received crizotinib and was not reached in the crizotinib-naïve group, they add.

The majority of side effects reported in the trial were grade 1 or 2, including nausea (53%), fatigue (43%) and diarrhoea (41%); the most common grade 3–4 treatment-emergent events were elevated lipase (9%), dyspnoea (6%) and hypertension (5%). Serious events other than disease progression included dyspnoea (7%), pneumonia (7%) and hypoxia (5%).

In all, 15% of the 98 patients given a phase II dose of brigatinib required a dose reduction due to adverse events. One case of sudden death, one death from hypoxia and one unknown cause of death were considered possibly related to treatment.

The author of a linked comment on the study notes that brigatinib did cause “unique pulmonary toxicity” in 8% of patients and that while this was “mitigated” by limiting the dose to 180 mg/day and using a 90 mg/day run in, “the cause of the toxicity, the patients most likely to develop it, and its appropriate management remain unclear.”

Shirish Gadgeel, from Wayne State University in Detroit, Michigan, USA, also points out that with the availability of several ALK inhibitors, the question of which to use and in what sequence requires solid clinical trial research.

“Availability of several ALK inhibitors might lead to use of these inhibitors in a non-specific sequence”, he writes.

“Not only should the oncology community resist such temptations, but the community should further these advances in a scientifically rigorous manner so that appropriate drugs or drug combinations can be selected for patients with ALK-positive NSCLC.”

References

Gettinger SN, Bazhenova LA, Langer CJ, et al. Activity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial. Lancet Oncol; Advance online publication 7 November 2016.
DOI: http://dx.doi.org/10.1016/S1470-2045(16)30392-8

Gadgeel SM. Drug selection for anaplastic lymphoma kinase-positive non-small-cell lung cancer. Lancet Oncol; Advance online publication 7 November 2016.
DOI: http://dx.doi.org/10.1016/S1470-2045(16)30567-8  

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