Abstract 3103
Background
The CNS is often a site of first disease progression in CRZ-treated ALK+ NSCLC pts; we report BRG efficacy and safety in pts with CRZ-refractory advanced ALK+ NSCLC in the phase 2 ALTA trial who had baseline CNS metastases.
Methods
ALTA (NCT02094573) permitted baseline CNS disease (including pts with prior whole brain radiotherapy/stereotactic radiosurgery and asymptomatic untreated pts). 222 pts stratified by presence of brain metastases and best response to prior CRZ were randomized 1:1 to receive BRG 90 mg qd (arm A, n = 112) or 180 mg qd with a 7-day lead-in at 90 mg (arm B, n = 110). This analysis included an exploratory competing risks analysis to estimate cumulative incidence of CNS progression vs non-CNS progression vs death in pts with baseline brain metastases.
Results
80 (71%)/73 (66%) pts in A/B had baseline brain metastases per independent review committee (median age, 49/55 years; 76%/74% had received chemotherapy). As of 21 Feb 2017, median follow-up for pts with brain metastases was 17.7 months; 34%/40% continued to receive BRG in A/B. Table shows intracranial efficacy. 5 pts with measurable baseline brain metastases in A had progression in the brain (≥20% growth in target lesions or new lesions) while receiving BRG 90 mg qd and escalated to 180 mg qd with ≥1 additional scan; all 5 had a reduction in measurable lesions after escalation (−14% to − 100%). While pts without baseline brain metastases did not have routine brain MRI scans, 3/32 and 1/36 pts without baseline brain metastases per investigators in A and B, respectively, had a new brain lesion identified by MRI.
Conclusions
In this update of ALTA, BRG continued to show robust intracranial efficacy in ALK+ NSCLC pts with baseline brain metastases, particularly at 180 mg (with lead-in), with a higher intracranial response rate and a numerically lower incidence of disease progression in the CNS and outside the CNS, compared to 90 mg.Table:
1345P
| Intracranial Efficacy of BRG in Pts With CRZ-Refractory ALK+ NSCLC and Baseline Brain Metastases (per IRC) | Arm A 90 mg qd | Arm B 90 mg → 180 mg qda |
|---|---|---|
| Confirmed iORR (pts with measurable brain metastases), n/N (%) | 13/26 (50) | 12/18 (67) |
| Confirmed iORR (pts with measurable, activeb brain metastases), n/N (%) | 9/19 (47) | 11/15 (73) |
| Median duration of intracranial responsec (pts with measurable brain metastases), months (95% CI) | NR (3.7–NR) n = 13 | 16.6 (3.7–16.6) n = 12 |
| Median iPFSc (pts with any baseline brain metastases), months (95% CI) | 12.8 (9.0–18.3) n = 80 | 18.4 (12.6–NR) n = 73 |
| Competing risks analysis | n = 80 | n = 73 |
| CIR of first disease progression in CNS, % (95% CI) | ||
| By 6 months | 20 (12–29) | 15 (8–25) |
| By 12 months | 33 (23–44) | 27 (17–37) |
| By 18 months | 41 (30–52) | 34 (23–45) |
| CIR of first disease progression at non-CNS site, % (95% CI) | ||
| By 6 months | 14 (7–23) | 11 (5–20) |
| By 12 months | 21 (13–31) | 20 (11–30) |
| By 18 months | 23 (15–34) | 21 (13–32) |
| CIR of death prior to all disease progression (in CNS or at non-CNS site), % (95% CI) | ||
| By 6 months | 5 (2–12) | 3 (1–9) |
| By 12 months | 9 (4–17) | 6 (2–13) |
| By 18 months | 9 (4–17) | 7 (3–15) |
Pts with baseline brain metastases are shown; in these pts, CNS disease was tracked by MRI every 8 weeks Last scan date: 28 Feb 2017 ALK+ NSCLC, anaplastic lymphoma kinase–positive non–small cell lung cancer; BRG, brigatinib; CI, confidence interval; CIR, cumulative incidence rate; CNS, central nervous system; CRZ, crizotinib; iORR, intracranial objective response rate; iPFS, intracranial progression-free survival; IRC, independent review committee; MRI, magnetic resonance imaging; NR, not reached; pts, patients
a180 mg qd with 7-day lead-in at 90 mg
bUntreated, or treated and progressed c From Kaplan-Meier analysis.
Clinical trial identification
NCT02094573 First received by ClinicalTrials.gov: March 18, 2014
Legal entity responsible for the study
ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited
Funding
ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
Disclosure
S-H.I. Ou: Honoraria (ARIAD, AstraZeneca, Novartis, Pfizer, Roche), consulting or advisory role (ARIAD, AstraZeneca, Novartis, Pfizer, Roche), speakers bureau (AstraZeneca, Roche), research funding (ARIAD, AstraZeneca, Clovis Oncology, Daiichi Sankyo, Ignyta, Novartis, Pfizer, Roche). M. Tiseo: Consulting or advisory role (AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Novartis, Otsuka, Pierre Fabre), research funding (ARIAD). R. Camidge: Honoraria (ARIAD), research funding (ARIAD). M-J. Ahn: Honoraria (AstraZeneca, BMS, Boehringer Ingelheim, MSD, Novartis), consulting or advisory role (AstraZeneca, BMS, Boehringer Ingelheim, MSD, Novartis). R.M. Huber: Honoraria (ARIAD, AstraZeneca, BMS, Boehringer Ingelheim, Pfizer, Roche), consulting or advisory role (BMS, Boehringer Ingelheim, Celgene, Clovis Oncology, Eli Lilly, Novartis, Roche), research funding (Pierre Fabre). H.L. West: Consulting or advisory role (ARIAD, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Guardant Health, Merck, Novartis, Roche/Genentech), speakers bureau (ARIAD, Roche/Genentech). K.L. Reckamp: Consulting or advisory role (Amgen, ARIAD, Astellas, Boehringer Ingelheim, Euclises, Nektar), research funding (Adaptimmune, ARIAD, BMS, Clovis Oncology, Eisai, Gilead Sciences, GSK, Novartis, Pfizer, Roche/Genentech, Xcovery). G. Liu: Honoraria (Novartis, Pfizer), consulting or advisory role (AstraZeneca/MedImmune, Novartis, Pfizer, Roche Canada, Takeda), research funding (Roche). A. Delmonte: Consulting or advisory role (BMS, Boehringer Ingelheim, Novartis). S. Viteri: Consulting or advisory role (Boehringer Ingelheim, Clovis Oncology, Idea Pharma, Novartis, Promega Biotech Ibérica, Roche, Targovax), research funding (AbbVie, ARIAD, Astex, AstraZeneca/MedImmune, Boehringer Ingelheim, Clovis Oncology, CytRx, Daiichi Sankyo, GSK, Hanmi, Incyte, Merck KGaA, Novartis, Pfizer, Puma, Roche, Servier, Vaxon). A. Bearz: Consulting or advisory role (Boehringer Ingelheim, Eli Lilly, Novartis, Roche). Y. Summers: Consulting or advisory role (AstraZeneca, BMS, Boehringer Ingelheim, Clovis Oncology, Eli Lilly, MSD, Pfizer, Tesaro). W. Reichmann, D. Kerstein: Employment, stock and other ownership interests (ARIAD). S.N. Gettinger: Consulting or advisory role (ARIAD, BMS, Janssen), research funding (ARIAD, AstraZeneca/MedImmune, BMS, Boehringer Ingelheim, Incyte, Pfizer, Roche/Genentech). All other authors have declared no conflicts of interest.