Preliminary results from a phase II trial demonstrated promising activity for brigatinib in patients with non–small cell lung cancer with an <em>ALK </em>rearrangement who have progressed on treatment with another next-generation ALK tyrosine kinase inhibitor.
Thomas E. Stinchcombe, MD
Preliminary results from a phase II trial demonstrated promising activity for brigatinib (Alunbrig) in patients with nonsmall cell lung cancer (NSCLC) with anALKrearrangement who have progressed on treatment with another next-generation ALK tyrosine kinase inhibitor (TKI).1
The overall response rate (ORR) was 40% (95% CI, 19%-62%) and the median progression-free survival (PFS) was 6.4 months (95% CI, 4.6-not evaluable [NE]), according to results presented in a poster at the 2019 ASCO Annual Meeting.
“Brigatinib has clinically relevant activity after next-generation ALK TKIs,” lead study author Thomas E. Stinchcombe, MD, professor of medicine, Duke Cancer Institute, commented.
Brigatinib has previously demonstrated a significant benefit in patients with metastatic NSCLC with anALKrearrangement and was approved in 2017 for the treatment of patients who have progressed on or are intolerant to the first-generation ALK TKI crizotinib (Xalkori).2Evidence of efficacy has also been seen with brigatinib in patients withALKrearrangements who are treatment naïve.3
The investigators of the phase II trial determined the efficacy of brigatinib in patients who experience disease progression on a next-generation ALK TKI. Patients with stage IIIB or IV NSCLC who wereALK-positive based on an FDA-approved test and had an ECOG performance status of 0 to 2 were eligible for inclusion in the study.
Patients were treated with a dose of 90 mg daily for 7 days followed by a dose escalation to 180 mg daily. Disease was assessed every 2 cycles (28 days each) using RECIST 1.1 criteria as assessed by an investigator. Treatment with brigatinib continued until disease progression, unacceptable toxicity, or withdrawal of consent.
The primary endpoint of the study was ORR and secondary endpoints included PFS, duration of response, intracranial and extracranial PFS, and overall survival (OS). An exploratory analysis will also be performed to focus on the presence or absence ofALKmutations, as detected by circulating tumor DNA, and their effects on ORR and PFS.
According to the study design, which incorporated a Simon 2-stage design, a response rate of ≥20% would be considered worthy of further investigation and an ORR of ≤5% would be considered not worthy. If ≥2 patients among 20 achieved a response in the first stage of the trial, the study would proceed to stage 2 and enroll an additional 20 patients.
Twenty-two patients were enrolled in the first stage of the trial between March 2017 and November 2018 across 4 US academic centers, but only 20 patients were eligible for treatment. The patients had a median age of 55.5 years (range, 32-71) and 60% were male. All patients had adenocarcinoma histology and 55% had brain metastases at baseline.
The median number of prior systemic therapies was 3 (range, 1-6), with 35% of patients having received ≥4 prior regimens. Prior ALK TKIs included crizotinib in 75% of patients, alectinib (Alecensa) in 80%, ceritinib (Zykadia) in 30%, and an investigational agent in 15%. Forty percent of patients also had prior whole brain radiation therapy or stereotactic radiosurgery.
Patients most commonly (90%) had prior disease progression outside of the central nervous system (CNS), but 30% had both CNS and extra-CNS disease progression.
The median PFS for patients with brain metastases (n = 11) was 7.8 months (95% CI, 5.4-9.2) and was 10.1 months (95% CI, 3.8-NE) for patients without brain metastases. The median OS was not evaluable at the time of data cutoff.
Grade ≥3 treatment-related adverse events included 2 cases of pneumonitis and 1 case each of hypoxemic respiratory failure, acute renal failure, grade 4 sepsis, headache, hypertension, and grade 4 creatine phosphokinase elevation. One patient experienced pneumonitis, hypoxemic respiratory failure, acute renal failure, and sepsis in 1 clinical event, the study authors noted.
The investigators added that enrollment is ongoing for the second stage of the trial, and the exploratory analyses are currently underway. The trial has since been expanded to include additional cohorts of patients to test the efficacy of brigatinib in patients with disease progression after frontline alectinib (cohort B, 40 patients) and for the dose escalation of brigatinib to 240 mg daily in patients who experienced progression on the 180-mg dose and had acceptable toxicity (cohort C, 40 patients).