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K.L. Reckamp
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Poster Display Session (ID 63)
- Event: ELCC 2017
- Type: Poster Display Session
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 5/07/2017, 12:30 - 13:00, Hall 1
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105P - Prognostic factors in crizotinib (CRZ)-resistant anaplastic lymphoma kinase (ALK+) non-small cell lung cancer (NSCLC) patients (Pts) (ID 469)
12:30 - 13:00 | Author(s): K.L. Reckamp
- Abstract
Background:
The aim of this analysis was to assess prognostic factors in patients with CRZ-resistant ALK+ NSCLC associated with progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) based on the Phase 2 ALTA Trial (NCT02094573) of brigatinib.
Methods:
Analyses used data from ALTA Arm B (180 mg qd with a 7-day lead-in at 90 mg, N = 110). Potential prognostic factors were evaluated using univariate and multivariate Cox proportional hazards models for PFS and OS, and logistic regression for ORR. Potential prognostic factors included age, sex, race, ECOG performance status, prior radiotherapy (RT), prior RT to brain, prior chemotherapy, prior platinum-based chemotherapy, smoking status, number of prior regimens, best response to prior CRIZ, number of metastatic sites, and active brain lesions. ALTA trial was not powered to detect differences in outcomes by these factors, thus a threshold of p < 0.5 was used to select variables into all models. Factors with hazard ratios >1.30 or < 0.77 were also included in the final models for PFS and OS.
Results:
As of February 29, 2016, median follow-up was 8.3 months, and independent review committee (IRC) assessed median PFS was 15.6 months [95% CI: 11.0, NR] (31 events). Median OS was not reached (17 deaths). IRC-assessed ORR was 52.7% [95% CI: 43.0%, 62.3%]. Prognostic factors are shown in the table.rnTable: 105PImportant prognostic factors in CRIZ-resistant ALK+ NSCLC treated with brigatinib 180 mg qd with a 7-day lead-in at 90 mg (N = 110)rnrn
rnAbbreviations: PFS = progression-free survival; OS = overall survival; ORR = objective response rate; HR = hazard ratio; OR = odds ratio; CI = confidence interval; CR = complete response; PR = partial response; ECOG = Eastern Cooperative Oncology Group;rn*HR < 1 indicates lower risk of progression or death vs reference group;rn**OR > 1 indicates higher odds of response vs reference grouprnrn rnrnPrognostic Factor rnPFS (HR [95% CI])* rnOS (HR [95% CI])* rnORR (OR [95% CI])** rnrn rnAge (per 1-year increase) rn– rn– rn0.98 [0.95, 1.01] rnrn rnSex Male vs female rn1.79 [0.84, 3.79] rn– rn– rnrn rnRace Asian vs non-Asian rn1.29 [0.55, 3.04] rn0.15 [0.02, 1.25] rn1.87 [0.73, 5.00] rnrn rnECOG performance status 1 vs 0 2 vs 0 rn0.72 [0.33, 1.58] 3.24 [0.99, 10.60] rn2.56 [0.72, 9.06] 4.02 [0.73, 22.14] rn0.64 [0.26, 1.53] 0.19 [0.02, 1.07] rnrn rnPrior chemotherapy Yes vs no rn0.42 [0.19, 0.95] rn0.34 [0.11, 1.04] rn1.90 [0.71, 5.24] rnrn rnBest response to prior CRIZ CR/PR vs any other status or unknown rn0.56 [0.25, 1.27] rn0.74 [0.24, 2.33] rn1.88 [0.77, 4.70] rnrn rnPrior radiotherapy to brain Yes vs no rn2.21 [1.02, 4.78] rn0.51 [0.17, 1.57] rn– rnrn rnActive brain lesions Yes vs no rn– rn0.45 [0.15, 1.39] rn– rnrn rnSmoking status Never vs current/former/unknown rn– rn0.49 [0.14, 1.67] rn2.45 [1.04, 5.97] rnrn rnrnNumber of metastatic sites 3 vs 1-2 4+ vs 1-2 rn– rn1.05 [0.20, 5.58] 2.66 [0.59, 12.03] rn0.34 [0.10, 1.08] 0.81 [0.27, 2.36] rn
Conclusions:
In this analysis of CRZ-resistant ALK+ NSCLC patients, a history of prior chemotherapy was associated with longer PFS, while prior radiotherapy was associated with shorter PFS, both likely due to unmeasured patient characteristics. Never smokers had more than double the odds of response, versus current or former smokers. ECOG status 2 was nominally associated with shorter PFS and OS and lower ORR, and presence of active brain lesions was associated with longer OS.
Clinical trial identification:
The trial protocol number is NCT02094573.
Legal entity responsible for the study:
Evidera Inc.
Funding:
ARIAD Pharmaceuticals
Disclosure:
K.L. Reckamp: Consulting or advisory role (ARIAD), research funding (ARIAD). J. Lee, M. Krotneva: Employee of Evidera Inc., which provides consulting services to pharmaceutical organizations. Evidera Inc. received funding from ARIAD pharmaceuticals. J. Huang: Employment, consulting or advisory role (ARIAD). W. Reichmann, D. Kerstein, H. Huang: Employment, stock shareholder (ARIAD). All other authors have declared no conflicts of interest.
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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): K.L. Reckamp
- 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: 97PDrnrn
rnCR = complete response, ORR = objective response rate, PFS = progression-free survival, PR = partial responsernaPrimary endpointrnrn Arm A n = 112 rnArm B n = 110 rnTotal N = 222 rnrn rnConfirmed ORR, n/N (%) rnrn rn rn rn rnAll pts[a] rn50/112 (45) rn59/110 (54) rn109/222 (49) rnrn rnRace rnrn rn rn rn rnAsian rn18/39 (46) rn18/30 (60) rn36/69 (52) rnrn rnNon-Asian rn32/73 (44) rn41/80 (51) rn73/153 (48) rnrn rnPrior chemotherapy rnrn rn rn rn rnYes rn35/83 (42) rn44/81 (54) rn79/164 (48) rnrn rnNo rn15/29 (52) rn15/29 (52) rn30/58 (52) rnrn rnBest response to prior crizotinib rnrn rn rn rn rnCR or PR rn36/71 (51) rn47/73 (64) rn83/144 (58) rnrn rnOther rn14/41 (34) rn12/37 (32) rn26/78 (33) rnrn rnBaseline brain metastases rnrn rn rn rn rnYes rn31/80 (39) rn43/74 (58) rn74/154 (48) rnrn rnNo rn19/32 (59) rn16/36 (44) rn35/68 (51) rnrn rnMedian PFS, months rnrn rn rn rn rnAll pts rn9.2 rn12.9 rn11.1 rnrn rnRace rnrn rn rn rn rnAsian rn8.8 rn11.1 rn11.1 rnrn rnNon-Asian rn9.2 rn12.9 rn11.8 rnrn rnPrior chemotherapy rnrn rn rn rn rnYes rn8.8 rn12.9 rn11.8 rnrn rnNo rn9.2 rn8.1 rn9.2 rnrn rnBest response to prior crizotinib rnrn rn rn rn rnCR or PR rn11.1 rn15.6 rn15.6 rnrn rnOther rn7.4 rn12.9 rn9.2 rnrn rnBaseline brain metastases rnrn rn rn rn rnYes rn9.2 rn11.8 rn11.1 rnrn rnrnNo rn7.4 rn15.6 rn15.6 rn
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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88O - CNS activity of ensartinib in ALK+ non-small cell lung cancer (NSCLC) patients (pts) (ID 461)
16:45 - 18:15 | Author(s): K.L. Reckamp
- Abstract
- Presentation
Background:
Ensartinib (X-396) is a potent ALK small molecule TKI with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. In animal studies, CNS concentration of ensartinib in mice given at the therapeutic dose was 4 times higher than the IC50 for growth inhibition of ALK+ cells in vitro. Ensartinib was significantly more effective than crizotinib (C) at inhibiting the intracranial (IC) growth of the SH-SY5Y neuroblastoma model harboring the F1174L mutation. We subsequently evaluated the CNS activity of ensartinib in pts with ALK+ NSCLC.
Methods:
In this multicenter phase I/II study, pts with ALK+ NSCLC were enrolled and given ensartinib orally on a continuous 28-day schedule. 225 mg QD was selected for further evaluation. Pts enrolled with asymptomatic CNS metastases (with or without systemic disease) who were ALK TKI naïve or had received prior C or a 2nd generation ALK TKI were allowed to enroll. Overall and systemic response was assessed using RECIST 1.1. CNS response was assessed using modified RANO criteria. Pts with only CNS disease had to have at least 1 measurable target lesion ≥ 3 mm in diameter.
Results:
26 pts with ALK+ NSCLC and baseline CNS metastases were treated at ≥ 200 mg. Of the 26 pts, 13 pts had baseline target lesions, and 13 pts had only non-target lesions. CNS responses were observed in ALK TKI naïve pts and pts that received prior C or a 2[nd] generation ALK TKI. In the 13 pts with baseline target CNS lesions, IC response rate (RR) was 69%, including 1 CR, and 31% had SD, a 100% disease control rate. In the 13 pts with only non-target baseline lesions, 1 CR was achieved and 8 pts had SD. The IC RR in the 3 ALK TKI naïve pts with baseline target lesions was 100%, and 62% in 8 pts that received prior C only. Of 2 pts with baseline target lesions who received a prior 2[nd] generation ALK TKI, 1 had a PR and 1 SD. Median duration of IC response in the 10 pts who responded (9 with target lesions, 1 with non-target lesions only) is 5.8+ months, with the longest duration being 24 months.
Conclusions:
Our clinical findings support the preclinical results that the use of ensartinib may result in favorable therapeutic outcomes in pts with ALK+ NSCLC with CNS metastases. The ongoing phase III eXalt3 study will assess CNS RR and time to CNS progression in pts receiving 1st-line ensartinib vs C.
Clinical trial identification:
NCT02767804 and NCT01625234
Legal entity responsible for the study:
Xcovery Holding Company
Funding:
Xcovery Holding Company
Disclosure:
K. L. Reckamp: Xcovery Holding Company research funds to institution Ariad consultant and research funds to institution. H. A. Wakelee: Peregrin: Consultant/Independent contractor and honorarium recipient. Novartis: Grants/research support, consultant, honorarium recipient. ACEA: Consultant and honorarium recipient. Pfizer: Grants/research support, consultant, honorarium recipient. BMS: Grants/research support. Xcovery: Grants/research support. Celgene: Grants/research support. Roche/Genentech: Grants/research support. Medimmune: Grants/research support. Lilly: Grants/research support. S. Patel: Research funding from: Bristol-Myers Squibb, Eli Lilly, MedImmune, Pfizer, Roche/Genentech, Xcovery. Speaking fees from: Boehringer Ingelheim, Merck. G. Blumenschein: Grants/Research Support Recipient, Consultant- BMS, Bayer, Merck, Celgene Consultant- Clovis, AbbVie Grants/Research Support Recipient- Novartis, Xcovery, Astrazeneca. J. W. Neal: Consulting or Advisory role: Clovis Oncology, CARET/Physicians Resource Management, Nektar, Boehringer Ingelheim Research Funding- Genentech/Roche, Merck, ArQule, Novartis, Exelixis, Boehringer Ingelheim, Nektar. B. Gitlitz: Speakers Bureau for Lilly Speakers Bureau for Genentech. F. Tan: Manager- Xcovery Holding Company Chief Medical Officer- Betta Pharmaceuticals. K. Harrow: Xcovery Holding Company- Full-time Employee. L. Horn: Consulting for Xcovery Holding Company, BMS, BI, abbvie, Genentech, Merck. All other authors have declared no conflicts of interest.
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