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Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: A
Dong-Wan Kim1, Marcello Tiseo1, Myung-Ju Ahn1
1Dong-Wan Kim, Seoul National University Hospital; Myung-Ju Ahn, Samsung Medical Center; Sang-We Kim, Asan Medical Center, Seoul, South Korea; Marcello Tiseo, University Hospital of Parma, Parma, Italy; Karen L. Reckamp, City of Hope, Duarte, CA; Karin Holmskov Hansen, Odense University Hospital, Odense, Denmark; Rudolf M. Huber, University Hospital of Munich, German Centre for Lung Research, Munich, Germany; Howard L. West, Swedish Cancer Institute, Seattle, WA; Harry J.M. Groen, University of Groningen, University Medical Center Groningen, Groningen; Egbert F. Smit, VU University Medical Center, Amsterdam, the Netherlands; Maximilian J. Hochmair, Otto Wagner Hospital, Vienna, Austria; Natasha B. Leighl, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Scott N. Gettinger, Yale Cancer Center, New Haven, CT; Corey J. Langer, University of Pennsylvania Abramson Cancer Center, Philadelphia, PA; Luis G. Paz-Ares Rodríguez, Hospital Universitario 12 de Octubre, Madrid, Spain; Edward S. Kim, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC; William Reichmann, Frank G. Haluska, and David Kerstein, ARIAD Pharmaceuticals, Cambridge, MA; and D. Ross Camidge, University of Colorado Cancer Center, Aurora, CO.
Abstract:
Purpose Most crizotinib-treated patients with anaplastic lymphoma kinase gene ( ALK)-rearranged non-small-cell 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 Methods Patients 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. Results Of 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. Conclusion 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.
Insights
Brigatinib demonstrated significant efficacy in treating anaplastic lymphoma kinase-positive non-small-cell lung cancer that progressed after crizotinib. The 180 mg regimen with a lead-in showed superior outcomes compared to 90 mg daily, with manageable safety.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Anaplastic lymphoma kinase (ALK) gene rearrangements drive a subset of non-small-cell lung cancer (NSCLC).
- Crizotinib resistance is a common challenge in ALK-positive NSCLC treatment.
- Next-generation ALK inhibitors are crucial for overcoming treatment resistance.
Purpose of the Study:
- To evaluate the efficacy and safety of two brigatinib dosing regimens in patients with ALK-positive NSCLC refractory to crizotinib.
- To compare brigatinib 90 mg once daily versus 180 mg once daily with a 7-day lead-in at 90 mg.
Main Methods:
- A randomized clinical trial involving 222 patients with crizotinib-refractory ALK-positive NSCLC.
- Patients were stratified based on brain metastases and prior crizotinib response.
- Primary endpoint was investigator-assessed objective response rate (ORR).
Main Results:
- The 180 mg (with lead-in) regimen showed a higher ORR (54%) compared to 90 mg (45%).
- Median progression-free survival was longer with the 180 mg regimen (12.9 months) versus 90 mg (9.2 months).
- Intracranial ORR was notably higher in the 180 mg arm (67%) compared to the 90 mg arm (42%) for patients with brain metastases.
Conclusions:
- Brigatinib provides substantial whole-body and intracranial responses in crizotinib-refractory ALK-positive NSCLC.
- The 180 mg daily dose with a 7-day lead-in demonstrated superior efficacy over the 90 mg daily dose.
- Brigatinib exhibited an acceptable safety profile, with most adverse events being low-grade.
