Brigatinib in Advanced Crizotinib-Refractory ALK-Positive NSCLC

Key Points

  • In patients with advanced crizotinib-refractory NSCLC, brigatinib was associated with high response rates.
  • The intracranial response rate was high among patients with measurable disease.

As reported by Kim et al in the Journal of Clinical Oncology, the phase II ALTA trial showed that the next-generation oral ALK inhibitor brigatinib produced a high response rate, including intracranial responses, in patients with advanced crizotinib-refractory non–small cell lung cancer (NSCLC). The study supported the recent accelerated approval of brigatinib in this setting, with recommended dosing of 90 mg/d for 7 days followed by an increase to 180 mg if 90 mg is tolerated.

Study Details

In the open-label study, 222 patients with locally advanced or metastatic disease from 71 sites in 18 countries were randomized between June 2014 and September 2015 to receive brigatinib at 90 mg once daily (n = 112) or 180 mg once daily following a 7-day lead-in at 90 mg (n = 110). Randomization was stratified by the presence of brain metastases and best response to crizotinib (Xalkori). Investigator-assessed confirmed objective response rate was the primary endpoint.

Among all patients, median age was 54 years, 57% were women, 67% were white and 31% Asian, 93% had an Eastern Cooperative Oncology Group performance status of 0 or 1, 39% had a history of smoking, 97% had adenocarcinoma histology, 69% had brain metastases at baseline, and 74% had received prior chemotherapy. The best response to prior crizotinib was partial or complete in 65%, stable disease in 22%, and progressive disease in 6%. The median cumulative duration of prior crizotinib was 12.6 months.

Response Rates

As of data cutoff in February 2016, 64 patients (57%) in the 90-mg group and 76 patients (69%) in the 180-mg group remained on study treatment, with a median follow-up of 7.8 and 8.3 months, respectively. Investigator-assessed confirmed objective response rates were 45% (97.5% confidence interval [CI] = 34%–56%) in the 90-mg group, including 1 complete response and 54% (97.5% CI = 43%–65%) in the 180-mg group, including 4 complete responses. Response rates were 42% vs 54% among patients with prior chemotherapy and 52% vs 52% in those without prior chemotherapy. Median time to response was 1.8 months vs 1.9 months. At data cutoff, median duration of response was 13.8 months vs 11.1 months. Median progression-free survival was 9.2 months vs 12.9 months (post hoc hazard ratio = 0.55, 95% CI = 0.35–0.86). Estimated overall survival at 1 year was 71% vs 80%.

On independent review committee assessment, the objective response rates were 48% (4 complete responses) vs 53% (5 complete responses), the median response duration was 13.8 vs 13.8 months, and the median progression-free survival was 9.2 vs 15.6 months.

Intracranial Response Rates

A total of 217 patients had an independent review committee–evaluated baseline brain image, with 153 having baseline brain metastases and 44 having measurable lesions. Independent review committee–assessed intracranial objective responses in patients with measurable lesions occurred in 11 of 26 patients (42%) in the 90-mg group vs 12 of 18 patients (67%) in the 180-mg group. Among those with nonmeasurable lesions, response rates were 7% vs 18%. The median duration of intracranial response was not reached in either group. The median intracranial progression-free survival was 15.6 vs 12.8 months.

Adverse Events

The most common adverse events of any grade included gastrointestinal symptoms (nausea in 33% vs 40%, diarrhea in 19% vs 38%), headache (28% vs 27%), and cough (18% vs 34%). The most common grade ≥ 3 adverse events were hypertension (6% vs 6%), increased creatine phosphokinase (CPK; 3% vs 9%), pneumonia (3% vs 5%), and increased lipase (4% vs 3%).

A subset of pulmonary adverse events with early onset (median time to onset = 2 days, range = 1–9 days), including dyspnea, hypoxia, cough, pneumonia, or pneumonitis, occurred in 14 patients (6%), with grade ≥ 3 events occurring in 7 patients (3%). The adverse events occurred during 90-mg dosing in both groups. The events were managed with dose interruption and successful reintroduction of treatment in 6 patients and an additional patient continued treatment with resolution of symptoms without interruption after dose reduction to 60 mg once daily. Seven patients discontinued treatment, including one patient who died on day 7 after experiencing dyspnea, cough, and pneumonia. Analysis indicated that risk factors for early onset of pulmonary adverse events were older age and an interval of < 7 days between the last crizotinib dose and the first brigatinib dose.

Adverse events led to dose reductions in 7% and 20%, with the most common causes being increased CPK, pneumonitis, and rash, and dose interruption for any reason occurred in 18% vs 36%. Death for reasons other than disease progression occurred in 8 patients (4%) within 30 days of the last dose, with causes consisting of pneumonia in 2 patients (including the patient with an early pulmonary adverse event) and bacterial meningitis, dyspnea, pulmonary embolism, respiratory failure, sudden death, and urosepsis in 1 patient each.

The investigators concluded: “Brigatinib yielded substantial whole-body and intracranial responses as well as robust progression-free survival; 180 mg (with lead-in) showed consistently better efficacy than 90 mg, with acceptable safety.”

The study was supported by Ariad Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Dong-Wan Kim, MD, PhD, of Seoul National University Hospital, is the corresponding author of the Journal of Clinical Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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