Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase–Positive Non–Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial

Abstract

Most crizotinib-treated patients with anaplastic lymphoma kinase gene (ALK)-rearranged non-smallcell lung cancer (ALK-positive NSCLC) eventually experience disease progression. We evaluated two regimens of brigatinib, an investigational next-generation ALK inhibitor, in crizotinib-refractory ALK-positive NSCLC. Patients and MethodsPatients were stratified by brain metastases and best response to crizotinib. They were randomly assigned (1:1) to oral brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg (180 mg once daily [with lead-in]; arm B). Investigator-assessed confirmed objective response rate (ORR) was the primary end point. ResultsOf 222 patients enrolled (arm A: n = 112, 109 treated; arm B: n = 110, 110 treated), 154 (69%) had baseline brain metastases and 164 of 222 (74%) had received prior chemotherapy. With 8.0-month median follow-up, investigator-assessed confirmed ORR was 45% (97.5% CI, 34% to 56%) in arm A and 54% (97.5% CI, 43% to 65%) in arm B. Investigator-assessed median progression-free survival was 9.2 months (95% CI, 7.4 to 15.6) and 12.9 months (95% CI, 11.1 to not reached) in arms A and B, respectively. Independent review committee-assessed intracranial ORR in patients with measurable brain metastases at baseline was 42% (11 of 26 patients) in arm A and 67% (12 of 18 patients) in arm B. Common treatment-emergent adverse events were nausea (arm A/B, 33%/ 40%), diarrhea (arm A/B, 19%/38%), headache (arm A/B, 28%/27%), and cough (arm A/B, 18%/ 34%), and were mainly grades 1 to 2. A subset of pulmonary adverse events with early onset (median onset: day 2) occurred in 14 of 219 treated patients (all grades, 6%; grade $ 3, 3%); none occurred after escalation to 180 mg in arm B. Seven of 14 patients were successfully retreated with brigatinib. ConclusionBrigatinib yielded substantial whole-body and intracranial responses as well as robust progressionfree survival; 180 mg (with lead-in) showed consistently better efficacy than 90 mg, with acceptable safety.

The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions

“…The phase II ALTA trial therefore looked at two different dosing schedules at either 90 mg daily (group A) or 90 mg daily with escalation to 180 mg daily after 7 days (group B). The ORR was 45% in group A and 54% in group B [27]. The median duration of response was 13.8 months in group A and 11.1 months in group B.…”

Moving more potent and less toxic options to the frontline in the management of advanced lung cancer

“…Clinical data from the brigatinib phase II ALTA clinical trial (NCT02094573) showed ORRs of 45% and 54% for doses of 90 and 180 mg daily, respectively (14). The most noticeable adverse event associated with brigatinib is early pulmonary toxicity.…”

“…Subsequent study schema have therefore incorporated a dose escalation phase with a starting dose of 90 mg orally daily for 7 days, then increasing to 180 mg daily. Outside of pulmonary concerns, the drug is otherwise well tolerated and with serious gastrointestinal side effects and headaches occurring in a minority of cases (14). Brigatinib received regulatory approval for use in crizotinibresistant or intolerant patients in 2017.…”

“…In turn, the identification and delineation of these oncogenic events has led to the successful development of nearly ten different oral targeted therapies now approved for use in routine clinical practice for advanced NSCLCs (2)(3)(4)(5)(6). These are directed against: mutations in the epidermal growth factor receptor (EGFR) (7)(8)(9)(10), anaplastic lymphoma kinase (ALK) (11)(12)(13)(14) gene rearrangements, ROS proto-oncogene 1 (ROS1) (15) gene rearrangements, and B-Raf protooncogene, serine/threonine kinase (BRAF) mutations (16) (Figure 1). These well vetted targeted therapies have demonstrated superior and more durable clinical outcomes and quality of life in patients with genotype-defined advanced NSCLC, as compared to the efficacy and toxicity profiles associated with cytotoxic chemotherapies in this disease.…”

ALK Inhibitors in NSCLC- Crizotinib and Beyond

“…Additional ALK inhibitor approved in April 2017 was Brigatinib [12] (Table 1), which demonstrated PFS of 8.8 months with the daily dose 90 mg, and 11.1 months with the 180 mg dose, although the starting dose will be 90 mg. The overall RR was 46% and 54% in each arm, respectively.…”