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M.J. Hochmair

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Poster Display Session (ID 63)

Event: ELCC 2017
Type: Poster Display Session
Track:
Presentations: 1

Moderators:
Coordinates: 5/07/2017, 12:30 - 13:00, Hall 1

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97P - Brigatinib in crizotinib-refractory ALK+ NSCLC: Updates from the pivotal randomized phase 2 Trial (ALTA) (ID 247)

12:30 - 13:00 | Author(s): M.J. Hochmair

Abstract

Background:
In a phase 1/2 trial (NCT01449461), the investigational next-generation anaplastic lymphoma kinase (ALK) inhibitor brigatinib (BRG) showed promising activity in crizotinib-treated ALK-positive non–small cell lung cancer (ALK+ NSCLC) patients (pts); because tumor responses and adverse events (AEs) varied with starting dose, two BRG regimens were evaluated in ALTA (NCT02094573).

Methods:
Pts with crizotinib-refractory advanced ALK+ NSCLC were stratified by presence of brain metastases and best response to prior crizotinib and randomized 1:1 to receive BRG at 90 mg qd in arm A or 180 mg qd with a 7-day lead-in at 90 mg in arm B. Investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1 was the primary endpoint.

Results:
222 pts were enrolled (112 in arm A, 110 in arm B); median age was 54 years, 57% were female, 74% had received chemotherapy, and 69% had brain metastases. As of 29 February 2016, 57%/69% of pts in arms A/B were receiving BRG, with 7.8/8.3-month median follow-up. Investigator-assessed efficacy by arm and subgroup is shown below. Per independent review committee, as of 16 May 2016, confirmed ORR was 48%/53% and median PFS was 9.2/15.6 months in arms A/B. Treatment-emergent AEs with ≥25% overall frequency (A/B, n = 109/n=110 treated) were nausea 33%/40%, diarrhea 19%/38%, headache 28%/27%, and cough 18%/34%; grade ≥3 events with ≥3% frequency were hypertension 6%/6%, increased blood creatine phosphokinase 3%/9%, pneumonia 3%/5%, and increased lipase 4%/3%. A subset of pulmonary AEs with early onset (median onset: Day 2) occurred in 14/219 (6%) treated pts (3%, grade ≥3); no such events occurred after escalation to 180 mg in arm B, and 7/14 pts were successfully retreated.

Conclusions:
BRG yielded substantial efficacy, with an acceptable safety profile, in both arms. 180 mg with 90 mg lead-in showed an improvement in efficacy endpoints, particularly PFS, with no increase in early pulmonary AEs, compared with 90 mg. Investigator-Assessed Efficacy by Subgroup.rnTable: 97PDrn

rnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrn rnrn

rn	Arm A n = 112	Arm B n = 110	Total N = 222
Confirmed ORR, n/N (%)	rn	rn	rn
All pts[a]	50/112 (45)	59/110 (54)	109/222 (49)
Race	rn	rn	rn
Asian	18/39 (46)	18/30 (60)	36/69 (52)
Non-Asian	32/73 (44)	41/80 (51)	73/153 (48)
Prior chemotherapy	rn	rn	rn
Yes	35/83 (42)	44/81 (54)	79/164 (48)
No	15/29 (52)	15/29 (52)	30/58 (52)
Best response to prior crizotinib	rn	rn	rn
CR or PR	36/71 (51)	47/73 (64)	83/144 (58)
Other	14/41 (34)	12/37 (32)	26/78 (33)
Baseline brain metastases	rn	rn	rn
Yes	31/80 (39)	43/74 (58)	74/154 (48)
No	19/32 (59)	16/36 (44)	35/68 (51)
Median PFS, months	rn	rn	rn
All pts	9.2	12.9	11.1
Race	rn	rn	rn
Asian	8.8	11.1	11.1
Non-Asian	9.2	12.9	11.8
Prior chemotherapy	rn	rn	rn
Yes	8.8	12.9	11.8
No	9.2	8.1	9.2
Best response to prior crizotinib	rn	rn	rn
CR or PR	11.1	15.6	15.6
Other	7.4	12.9	9.2
Baseline brain metastases	rn	rn	rn
Yes	9.2	11.8	11.1
No	7.4	15.6	15.6

rnCR = complete response, ORR = objective response rate, PFS = progression-free survival, PR = partial responsernaPrimary endpointrn

Clinical trial identification:
NCT02094573

Legal entity responsible for the study:
ARIAD Pharmaceuticals, Inc.

Funding:
ARIAD Pharmaceuticals, Inc.

Disclosure:
M. Tiseo: Consulting or advisory role (AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Novartis, Otsuka, Pierre Fabre), research funding (ARIAD). K.L. Reckamp: Consulting or advisory role (ARIAD), research funding (ARIAD). H.L. West: Consulting or advisory role (ARIAD, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Merck, Novartis, Pfizer, Roche/Genentech, Trovagene), speakers’ bureau (ARIAD, Eli Lilly, Roche/Genentech). H.J. Groen: Consulting or advisory role (Eli Lilly, MSD, Novartis, Pfizer, Roche). C.J. Langer: Honoraria (BMS, Lilly/ImClone, Roche/Genentech), consulting or advisory role (Abbott, ARIAD, AstraZeneca, Bayer/Onyx, BMS, Cancer Support Community, Celgene, Clarient, Clovis Oncology, Lilly/ImClone, Merck, Millennium, Roche/Genentech), research funding (Advantagene, ARIAD, Celgene, Clovis Oncology, GSK, Inovio, Merck, Roche/Genentech). W. Reichmann, D. Kerstein: Employment, stock and other ownership interests (ARIAD). D.R. Camidge: Honoraria (ARIAD), research funding (ARIAD). All other authors have declared no conflicts of interest.

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Targeted therapies and management of brain metastasis (ID 40)

Event: ELCC 2017
Type: Proffered Paper session
Track:
Presentations: 1

Moderators:D.P. Carbone, S. Ekman
Coordinates: 5/06/2017, 16:45 - 18:15, Room A

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87O - Brigatinib in ALK+ NSCLC pts with intracranial CNS metastases in 2 clinical trials (ID 241)

16:45 - 18:15 | Author(s): M.J. Hochmair

Abstract
Presentation
Slides

Background:
The investigational next-generation anaplastic lymphoma kinase (ALK) inhibitor brigatinib is being evaluated in patients (pts) with ALK-positive non–small cell lung cancer (ALK+ NSCLC) in a phase 1/2 trial (Ph1/2) and a pivotal phase 2 trial (ALTA); most of these pts had intracranial central nervous system (CNS) metastases at baseline.

Methods:
In Ph1/2 (NCT01449461), pts with advanced malignancies, including ALK+ NSCLC, received brigatinib (30–300 mg/d). In ALTA (NCT02094573), crizotinib-resistant pts with advanced ALK+ NSCLC received brigatinib at 90 mg qd in arm A or 180 mg qd with a 7-day lead-in at 90 mg in arm B. ALK+ NSCLC pts with baseline brain metastases were analyzed. CNS efficacy in both trials and safety in ALTA are shown.

Results:
In Ph1/2 and ALTA, 50/79 (63%) and 154/222 (69%) ALK+ NSCLC pts had baseline brain metastases based on independent review committee (IRC) and investigator assessment, respectively. Most pts had received chemotherapy (Table). In Ph1/2, 25/50 (50%) pts were receiving brigatinib as of 16 November 2015; in ALTA, 101/154 (66%) pts were receiving brigatinib as of 29 February 2016. In pts with measurable brain lesions, confirmed intracranial objective response rate was 53% in Ph1/2 and 42%/67% in ALTA A/B (Table). In pts with only nonmeasurable brain lesions, 35% (11/31) in Ph1/2 and 7% (4/54)/18% (10/55) in ALTA A/B had confirmed complete resolution of brain lesions. Further data are shown in the table. The most common treatment-emergent adverse events (TEAEs) in the 151 treated ALTA pts with baseline brain metastases were nausea (A/B, 32%/43%), headache (30%/30%), diarrhea (18%/36%), cough (21%/30%), and vomiting (25%/26%); the most common grade ≥3 TEAEs were increased blood creatine phosphokinase (1%/11%), hypertension (4%/7%), increased lipase (3%/3%), and pneumonia (1%/4%).

Conclusions:
Brigatinib yielded substantial clinical activity in ALK+ NSCLC pts with brain metastases in 2 trials.rnTable: 87OBaseline characteristics and IRC-assessed intracranial efficacy of brigatinib in ALK+ NSCLC Pts with brain metastases at baselinern

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rn	Ph1/2 n = 50	ALTA Arm A n = 80	ALTA Arm B n = 74
Median age, years	53	49	55
Received prior chemotherapy, %	76	74	76
Crizotinib-naive, %	8	0	0
Pts evaluable for intracranial efficacy by IRC, n[a]	46	80	73
Median iPFS, months	14.6	15.6	12.8
Pts with measurable brain lesions, n	15	26	18
iORR, n (%)	8 (53)	11 (42)	12 (67)
iDCR, n (%)	13 (87)	22 (85)	15 (83)
No rad/active[b] subset, n	9	19	15
iORR, n (%)	6 (67)	8 (42)	11 (73)
iDCR, n (%)	8 (89)	16 (84)	14 (93)

rniDCR = intracranial disease control rate, iORR = intracranial objective response rate (confirmed), iPFS = intracranial progression-free survivalrnaLast scan date: 8 October 2015 in Ph1/2; 14 April 2016 in ALTArnbNo prior brain radiotherapy in Ph1/2; active (untreated or treated and progressed) brain lesions in ALTArn

Clinical trial identification:
NCT01449461 and NCT02094573

Legal entity responsible for the study:
ARIAD Pharmaceuticals, Inc.

Funding:
ARIAD Pharmaceuticals, Inc.

Disclosure:
M. Tiseo: Consulting or advisory role (AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Novartis, Otsuka, Pierre Fabre), research funding (ARIAD). 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). L.A. Bazhenova: Stock and other ownership interests (Epic Sciences), honoraria (Novartis), consulting or advisory role (AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Clovis Oncology, Genoptix, Heat Biologics, Pfizer, Roche/Genentech, Seattle Genetics, Trovagene), speakers bureau (AstraZeneca, Novartis, Pfizer, Roche/Genentech), research funding (AbbVie, ARIAD, Astellas, Astex, AstraZeneca/MedImmune, Boehringer Ingelheim, Chugai, Clovis Oncology, Eisai, Eli Lilly, Heat Biologics, Johnson & Johnson, Merck, Mirati, NanoCarrier, Novartis, Pfizer, Roche/Genentech). S-H.I. Ou: Advisory board (ARIAD). W. Reichmann, J. Haney, D. Kerstein: Employment, stock and other ownership interests (ARIAD). D.R. Camidge: Honoraria (ARIAD), research funding (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.

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