Brigatinib Elicits Responses in ALK+ NSCLC Following Next-Generation TKIs

Thomas E. Stinchcombe, MD

Brigatinib (Alunbrig) demonstrated promising response rates in patients with ALK-positive non—small cell lung cancer (NSCLC) who have progressed on treatment with another next-generation ALK TKI, according to preliminary phase II results presented at the 2019 ASCO Annual Meeting.¹

Results of the single-arm study showed that the ALK TKI was associated with a 40% ORR (95% CI, 19%-62%) and a median progression-free survival (PFS) of 6.4 months (95% CI, 4.6-not evaluable [NE]).

“Brigatinib has clinically relevant activity after next-generation ALK TKIs,” said lead study author Thomas E. Stinchcombe, MD, professor of medicine, Duke Cancer Institute in a poster presentation of the data.

Previously, brigatinib demonstrated a significant benefit in patients with metastatic ALK-positive NSCLC and was initially approved in 2017 for the treatment of patients who have progressed on or are intolerant to the first-generation ALK TKI crizotinib (Xalkori).² Evidence of efficacy has also been seen with brigatinib in treatment-naïve patients with ALK rearrangements.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 ALK-positive NSCLC, based on an FDA-approved test and had an ECOG performance status of 0 to 2 were eligible for enrollment.

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. Treatment with brigatinib continued until disease progression, unacceptable toxicity, or withdrawal of consent.

The primary endpoint of the trial 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 of ALK mutations, 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.

Moreover, 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.

Regarding safety, 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).

References

1. Stinchcombe T, Doebele RC, Wang XF, et al. Preliminary results of single arm phase 2 trial of brigatinib in patients (pts) with progression disease (PD) after next-generation (NG) Anaplastic Lymphoma Kinase (ALK) tyrosine kinase inhibitors (TKIs) in ALK + non-small cell lung cancer (NSCLC). J Clin Oncol. 2019;37(suppl; abstr 9027). meetinglibrary.asco.org/record/174623/abstract.
2. Kim DW, Tiseo M, Ahn MJ, et al. Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial. J Clin Oncol. 2017;35(2:2490-2498. doi: 10.1200/JCO.2016.71.5904.
3. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer. N Engl J Med. 2018;379(21):2027-2039. doi: 10.1056/NEJMoa1810171.