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Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

2448 - Dose-determination results from a Phase Ib/II study of ceritinib (CER) + ribociclib (RIB) in ALK-positive (ALK+) non-small cell lung cancer (NSCLC)

Date

20 Oct 2018

Session

Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

Topics

Clinical Research;  Targeted Therapy

Tumour Site

Presenters

Armando Santoro

Citation

Annals of Oncology (2018) 29 (suppl_8): viii493-viii547. 10.1093/annonc/mdy292

Authors

A. Santoro1, W. Su2, A. Navarro3, M. Simonelli4, J.C. Yang5, A. Ardizzoni6, F. Barlesi7, J.H. Kang8, S. Didominick9, A. Abdelhady10, B. Goswami10, A. Crystal9, E. Felip11

Author affiliations

  • 1 Humanitas Research Hospital, Humanitas University and Humanitas Cancer Center, 20089 - Milan/IT
  • 2 National Cheng Kung University Hospital, National Cheng Kung University Hospital, Tainan/TW
  • 3 Vall D'hebron University Hospital, Vall d'Hebron University Hospital, Barcelona/ES
  • 4 Department Of Biomedical Sciences, Humanitas University and Humanitas Cancer Center, Milan/IT
  • 5 National Taiwan University Hospital, National Taiwan University Hospital, Taipei/TW
  • 6 University Hospital Bologna, University Hospital Bologna, Bologna/IT
  • 7 Aix-marseille University, Assistance Publique Hopitaux de Marseille, 13015 - Marseille/FR
  • 8 Catholic University Of Korea, Catholic University of Korea, Seoul/KP
  • 9 Oncology, Novartis Pharmaceutical Corporations, Cambridge/US
  • 10 Oncology, Novartis Pharmaceutical Corporations, Hyderabad/IN
  • 11 Vall D'hebron University Hospital, Vall d'Hebron University Hospital, 08035 - Barcelona/ES
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Resources

Abstract 2448

Background

Preclinical data suggest cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) may improve ALK inhibitor (ALKi) efficacy in ALK+ NSCLC. A Phase Ib/II study (NCT02292550) is assessing CER (ALKi) + RIB (CDK4/6i) in patients (pts) with ALK+ NSCLC; here we report data from the Phase Ib dose-escalation.

Methods

Pts with Stage IIIB/IV ALK+ NSCLC (≥1 prior therapy for advanced NSCLC; no prior CDK4/6i) received escalating doses of CER (starting dose 300 mg once daily [QD]; continuous [cont]) + RIB (starting dose 100 mg QD; 3 weeks [wks] on/1 wk off) under fed conditions. Primary objective: maximum tolerated dose/recommended Phase II dose (RP2D); secondary objectives: safety, pharmacokinetics, and efficacy.

Results

As of Jan 8, 2018, 27 pts were enrolled into 5 dose cohorts (Table); 8 were ALKi naive, 14 had prior crizotinib; 5 had prior 3rd-generation (gen) ALKi. Treatment was ongoing in n = 4; the most common reason for discontinuation was disease progression (n/n; 10/27). One dose-limiting toxicity occurred (CER 450 mg + RIB 100 mg; Grade [G] 2 increased blood creatinine for ≥7 consecutive days); RP2D was CER 300 mg QD (cont) + RIB 200 mg QD (3 wks on/1 wk off). At steady state, CER and RIB exposure (AUC0–24h) each increased by ∼1.5–2 fold compared with CER and RIB single-agent exposures under fasting conditions, with considerable variability in the setting of limited pt numbers. G3/4 treatment-related adverse events occurred in 15 pts; the most common (≥10% of pts) were decreased neutrophil count, increased ALT, and increased AST. Efficacy data are shown in the table. ORR (n/n; 90% CI) was 50% (4/8; 0.19–0.80) in ALKi-naive pts; 64% (9/14; 0.39–0.84) in pts with prior crizotinib; 0% (0/5; 0.00–0.45) in pts with prior 3rd-gen ALKi.Table: 1392P

CER 300 mg + RIB 100 mgCER 450 mg + RIB 100 mgCER 300 mg + RIB 200 mgCER 450 mg + RIB 200 mgCER 450 mg + RIB 300 mgAll
Enrolled (n)4747527
Prior antineoplastic therapy, n (%)
ALKi naive3 (75.0)2 (28.6)1 (25.0)1 (14.3)1 (20.0)8 (29.6)
Prior crizotinib1 (25.0)4 (57.1)2 (50.0)5 (71.4)2 (40.0)14 (51.9)
Prior 3rd-gen ALKi§01 (14.3)1 (25.0)1 (14.3)2 (40.0)5 (18.5)
Treatment ongoing, n (%)2 (50.0)1 (14.3)1 (25.0)004 (14.8)
Discontinuation due to disease progression, n (%)2 (50.0)1 (14.3)1 (25.0)3 (42.9)3 (60.0)10 (37.0)
Most common Grade 3/4 treatment-related adverse events (≥10% of all pts), n (%)
All2 (50.0)5 (71.4)1 (25.0)4 (57.1)3 (60.0)15 (55.6)
Decreased neutrophil count01 (14.3)02 (28.6)3 (60.0)6 (22.2)
Increased ALT02 (28.6)02 (28.6)04 (14.8)
Increased AST02 (28.6)02 (28.6)04 (14.8)
Best overall response, n (%)
Complete response1 (25.0)00001 (3.7)
Partial response1 (25.0)4 (57.1)2 (50.0)3 (42.9)2 (40.0)12 (44.4)
Stable disease2 (50.0)2 (28.6)1 (25.0)2 (28.6)2 (40.0)9 (33.3)
Progressive disease00001 (20.0)1 (3.7)
Unknown*01 (14.3)1 (25.0)2 (28.6)04 (14.8)
ORR, n (%) [90% CI]2 (50.0) [0.10–0.90]4 (57.1) [0.22–0.87]2 (50.0) [0.10–0.90]3 (42.9) [0.13–0.77]2 (40.0) [0.08–0.81]13 (48.1) [0.31–0.65]
*

These 4 pts discontinued study treatment prior to completing their first tumor evaluation;

Pts received prior crizotinib only;

§

Pts received prior 3rd-gen ALKi only (n = 2) or prior 3rd-gen ALKi and crizotinib (n = 3); ORR = complete response + partial response.

Conclusions

RP2D was CER 300 mg QD (cont) + RIB 200 mg QD (3 wks on/1 wk off) in pts with Stage IIIB/IV ALK+ NSCLC. CER + RIB showed a manageable safety profile and preliminary efficacy, including in pts with prior ALKi exposure.

Clinical trial identification

NCT02292550 and November 17, 2014.

Legal entity responsible for the study

Novartis Pharmaceuticals Corporation.

Funding

Novartis Pharmaceuticals Corporation.

Editorial Acknowledgement

Editorial assistance was provided by Bhavika Modasia PhD of ArticulateScience Ltd.

Disclosure

A. Santoro: Advisory board member: Bayer, Takeda, Lilly, Amgen, Bristol-Myers Squibb, Celgene, Merck Sharp & Dohme, Novartis, Roche, Servier, Eisai; Consulting fees: ArQule. J.C-H. Yang: Personal fees: Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono Pharmaceuticals, Daiichi Sankyo, AstraZeneca, Hansoh Pharmaceuticals, outside the submitted work. A. Ardizzoni: Grants and personal fees: BMS; Personal fees: MSD, Eli Lilly, Boehringer Ingelheim, Pfizer; Grants: Celgene, outside the submitted work. F. Barlesi: Support for the trial: Novartis, during the conduct of the study; Personal fees: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer, Takeda, outside the submitted work. S. Didominick, A. Abdelhady, B. Goswami, A. Crystal: Employee: Novartis, during the conduct of the study. E. Felip: Consultancy/advisory board: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb Celgene, Eli Lilly, Guardant Health, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda, Merck, outside the submitted work. All other authors have declared no conflicts of interest.

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