Abstract 1300P
Background
BRG, a next-generation ALK tyrosine kinase inhibitor (TKI), has robust overall and intracranial efficacy in CRZ-resistant ALK+ NSCLC. At first ALTA-1L interim analysis (IA) in patients (pts) with TKI-naive ALK+ NSCLC, the primary endpoint, blinded independent review committee (BIRC)-assessed PFS, was met (HR, 0.49; P<0.001; NCT02737501). Similarly, intracranial PFS (iPFS) in the ITT population was significantly improved with BRG vs CRZ (HR, 0.42; P=0.0006). Here we report updated intracranial efficacy from the second IA.
Methods
This open-label, multicenter study enrolled pts with TKI-naive stage IIIB/IV ALK+ NSCLC. Pts were stratified by presence of baseline (BL) brain metastases and history of chemotherapy for advanced disease and randomized 1:1 to BRG 180 mg qd with 7-day lead-in at 90 mg or CRZ 250 mg bid. Primary endpoint was BIRC-assessed PFS (RECIST v1.1). Secondary endpoints included intracranial ORR (iORR) and iPFS. The second IA was planned at ∼75% of 198 expected PFS events.
Results
Of 275 randomized pts (BRG/CRZ, n=137/138), 34%/36% had BL brain metastases (BIRC-assessed). 13%/14% had prior brain radiotherapy, with whole brain radiation and stereotactic radiosurgery balanced across arms. At data cutoff (28 June 2019; median follow-up [BRG/CRZ], 24.9/15.2 mo, 150 events), iPFS in the ITT population remained significantly improved with BRG (HR, 0.45 [95% CI, 0.29–0.69]; log-rank P=0.0001). Additional intracranial efficacy results are presented in the table. Radiological overall disease progression occurred in (BRG vs CRZ) 54 (39%) vs 74 (54%) pts as assessed by BIRC and 50 (36%) vs 84 (61%) pts as assessed by investigator; of these, brain was the first site of disease progression more frequently in pts treated with CRZ: (CRZ vs BRG) 31 (42%) vs 17 (31%) pts by BIRC and 22 (26%) vs 7 (14%) pts by investigator. Table: 1300P
| BIRC-Assessed Endpoint | BRG | CRZ | P Value |
| All patients (ITT), n | 137 | 138 | |
| iPFS events, n (%) | 40 (29) | 51 (37) | |
| Median iPFS, mo | 32 (30–NRa) | 24 (13–NRa) | |
| 2-yr iPFS, % | 65 (55–73a) | 50 (38–60a) | |
| iPFS HR | 0.45 (0.29–0.69a) | 0.0001b | |
| Any baseline brain metastases by BIRC, n | 47 | 49 | |
| iPFS events, n (%) | 21 (45) | 32 (65) | |
| Median iPFS, mo | 24 (13–NRa) | 6 (4–8a) | |
| 2-yr iPFS, % | 48 (30–63a) | 15 (5–32a) | |
| iPFS HR | 0.31 (0.17–0.56a) | <0.0001b | |
| Confirmed iORR, % | 66 (51–79a) | 16 (7–30a) | <0.0001c |
| Measurable brain metastases, n | 18 | 23 | |
| Confirmed iORR, % | 78 (52–94a) | 26 (10–48a) | 0.0014c |
NR, not reached a95% CI; bLog-rank; cCochran-Mantel-Haenszel test.
Conclusions
BRG demonstrated superior intracranial activity vs CRZ in pts with ALK TKI-naive ALK+ NSCLC in ALTA-1L.
Clinical trial identification
NCT02737501. Release date: March 30, 2016.
Editorial acknowledgement
Professional medical writing assistance was provided by Lauren Gallagher, RPh, PhD, of Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, and funded by Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
Legal entity responsible for the study
ARIAD Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
Funding
ARIAD Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
Disclosure
S. Popat: Research grant/Funding (institution): Boehringer Ingelheim, Epizyme, BMS, Clovis Oncology, Roche, Lilly, Takeda; Honoraria (self): Boehringer Ingelheim, AstraZeneca, Roche, Takeda, Chugai Pharma; Advisory/Consultancy: Boehringer Ingelheim, Roche, Novartis, Pfizer, AstraZeneca, BMS, MSD, Guardant Health, AbbVie; Travel/Accommodation/Expenses: Boehringer Ingelheim, BMS, Merck Sharp & Dohme. H.R. Kim: Honoraria (self), Advisory/Consultancy: AstraZeneca, Roche, Boehringer Ingelheim. M-J. Ahn: Honoraria (self): AstraZeneca, BMS, Boehringer Ingelheim, MSD, Novartis; Advisory/Consultancy: AstraZeneca, BMS, Boehringer Ingelheim, MSD, Novartis. J.C-H. Yang: Honoraria (self), Advisory/Consultancy: Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech/Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono Pharmaceutical, Daiichi Sankyo, Takeda, AstraZeneca, Hansoh Pharmaceuticals. J-Y. Han: Research grant/Funding (self): Roche. M.J. Hochmair: Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Roche, Takeda; Advisory/Consultancy: Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, Roche, Takeda. K.H. Lee: Honoraria (self), Advisory/Consultancy: AstraZeneca, Eli Lilly, Boehringer Ingelheim. A. Delmonte: Advisory/Consultancy: AstraZeneca, Boehringer Ingelheim. M.R. Garcia Campelo: Honoraria (self): ARIAD, AstraZeneca, Roche, Pfizer, BMS, Boehringer Ingelheim; Advisory/Consultancy, Speaker Bureau/Expert testimony: ARIAD, AstraZeneca, Roche, Pfizer, BMS, Boehringer Ingelheim. D-W. Kim: Research grant/Funding (institution): Alpha Biopharma, AstraZeneca/ MedImmune, Boehringer Ingelheim, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan; Travel/Accommodation/Expenses: Amgen, Daiichi Sankyo. F. Griesinger: Advisory/Consultancy: AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, ARIAD, Takeda, Roche, Novartis, Pfizer, AbbVie, Siemens, Tesaro, Amgen, Bayer. E. Felip: Advisory/Consultancy: AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Eli Lilly, Guardant Health, MSD, Novartis, Pfizer, Roche, Takeda, Merck. R. Califano: Honoraria (self), Advisory/Consultancy: AstraZeneca, BMS, Roche, MSD, Boehringer Ingelheim, Takeda, Novartis. A. Spira: Advisory/Consultancy: ARIAD, AstraZeneca, Clovis Oncology, Roche; Speaker Bureau/Expert testimony: Roche. S. Gettinger: Advisory/Consultancy: ARIAD, BMS, Janssen; Research grant/Funding (institution): ARIAD, AstraZeneca/MedImmune, BMS, Boehringer Ingelheim, Incyte, Pfizer, Roche/Genentech. M. Tiseo: Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Otsuka, Pfizer, Pierre Fabre, Roche. Q. Ni: Full/Part-time employment: Takeda. P. Zhang: Full/Part-time employment: Takeda. D.R. Camidge: Honoraria (self): AstraZeneca, Takeda, Arrys/Kyn, Genoptix, G1 Therapeutics (DSMB), Mersana Therapeutics, Roche/Genentech, Ignyta, Daiichi Sankyo (ILD adjudication committee), Hansoh SRC, Bio-Thera DSMB, Lycera, Revolution Med, Orion, Clovis, Celgene, Novartis; Research grant/Funding (self): ARIAD/Takeda.