Brigatinib led to favorable intracranial and whole-body response rates and potent PFS for patients with ALK–positive, crizotinib-refractory non–small cell lung cancer, according to results of the phase 2 ALTA clinical trial.
“The ALTA trial results offer clinicians important information on the efficacy and safety of brigatinib in patients who have progressed on crizotinib, and show brigatinib to be highly effective in this setting, both systemically and in the brain,” Dong-Wan Kim, MD, PhD, head of the Cancer Clinical Trials Center at Seoul National University Hospital in South Korea, said in a press release.
The FDA granted accelerated approval to brigatinib (Alunbrig, Ariad) — a next-generation anaplastic lymphoma kinase (ALK) inhibitor — in April for the treatment of patients with metastatic ALK–positive NSCLC who progressed on or are intolerant to crizotinib (Xalkori; Pfizer, EMD Serono) based on tumor response rate and duration of response data from the ALTA trial. The FDA recommended a dose of 90 mg brigatinib orally once daily for the first 7 days, followed by an increased dose of 180 mg orally once daily, if well tolerated.
Kim and colleagues assessed the safety and efficacy of brigatinib in 222 patients with locally advanced or metastatic ALK–positive NSCLC who progressed on crizotinib (Xalkori, Pfizer). The researchers stratified patients based on the presence of brain metastases at baseline and best response to prior therapy with crizotinib.
Researchers randomly assigned patients 1:1 to 90 mg oral brigatinib once daily (n = 112) or 180 mg oral brigatinib once daily after a 7-day lead-in at 90 mg once daily (n = 110).
Objective response rate served as the primary endpoint. Secondary endpoints included confirmed ORR measured by an independent review committee, duration of response, PFS, intracranial ORR, intracranial duration of response, OS, safety and tolerability.
Median follow-up was 8 months.
Investigator-assessed results showed an ORR of 45% (95% CI, 34-56) in patients treated with 90 mg and 54% (95% CI, 43-65) in patients treated with 180 mg. Median duration of response was 13.8 months in both groups.
Researchers reported median PFS of 9.2 months (95% CI, 7.4-15.6) in patients treated with 90 mg and 12.9 months (95% CI, 11.1-not reached) in patients treated with 180 mg.
Among patients with measurable brain metastases, the intracranial ORRs were 42% (95% CI, 23-63) in patients treated with 90 mg and 67% (95% CI, 41-87) in patients treated with 180 mg.
The independent review committee found a median intracranial PFS of 15.6 months in the 90-mg group and 12.8 months in the 180-mg group.
A safety analysis with data from 219 patients showed the most common adverse events included nausea (90 mg, 33%; 180 mg, 40%), diarrhea (19%; 38%), headache (28%; 27%) and cough (18%; 34%).
The most common grade 3 or worse treatment-emergent adverse events included hypertension (6% for both groups), increased blood creatine phosphokinase (90 mg dose, 3%; 180 mg, 9%), pneumonia (3%; 5%) and increased lipase (4%; 3%).
Eight patients died within 30 days of the last dose. Investigator-reported reasons for death included pneumonia (n =2), and sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis and urosepsis (n = 1 each).
Understanding the biology of ALK–positive NSCLC is crucial to the success of ALK inhibitors over the next decade, Sai-Hong Ignatius Ou, MD, PhD, medical oncologist at University of California Irvine School of Medicine, wrote in a related editorial.
“To be able to truly personalize treatment of patients with ALK–positive NSCLC in the next decade with the advent of multiple ALK inhibitors, we must understand the biology of ALK–positive NCSCL in addition to being able to detect the presence of ALK–positive NSCLC,” Ou wrote. “We have to identify all possible resistance mechanisms to allow rational sequential and/or combination ALK inhibitor therapy rather than empirical sequencing of ALK inhibitors on the basis of the latest availability of any individual ALK inhibitor.” – by Melinda Stevens
Disclosure: Kim reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures. Ou reports honoraria and consultant/advisory roles with ARIAD, AstraZeneca, Genentech, Novartis and Pfizer; speaker roles with AstraZeneca and Genentech; and research funding to his institution from ARIAD, AstraZeneca, Boehringer Ingelheim, Genentech, Novartis and Pfizer.