INVICTUS: A Phase 3, INterVentional, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of Ripretinib as _4th-Line Therapy In...

Date 30 September 2019
Event ESMO 2019 Congress
Session Proffered Paper - Sarcoma
Topics Anticancer Agents
Clinical Research
GIST
Rare Cancers
Presenter Margaret von Mehren
Citation Annals of Oncology (2019) 30 (suppl_5): v851-v934. 10.1093/annonc/mdz394
Authors M. von Mehren1, C. Serrano2, S. Bauer3, H. Gelderblom4, S. George5, M. Heinrich6, P. Schöffski7, J. Zalcberg8, P. Chi9, R.L. Jones10, P. Reichardt11, S. Attia12, G. D'Amato13, J. Meade14, K. Shi15, R. Ruiz-Soto14, J. Blay16
  • 1Department Of Hematology/oncology, Fox Chase Cancer Center, 19111-2497 - Philadelphia/US
  • 2Medical Oncology Dept., Vall d'Hebron University Hospital, 08035 - Barcelona/ES
  • 3Sarcoma Center, University Hospital Essen West German Cancer Center, 45122 - Essen/DE
  • 4Medical Oncology Dept, Leids Universitair Medisch Centrum (LUMC), 2300 RC - Leiden/NL
  • 5Medical Oncology, Dana-Farber Cancer Institute, 02215 - Boston/US
  • 6Hematology/medical Oncology, OHSU Knight Cancer Institute, 97239 - Portland/US
  • 7General Medical Oncology, University Hospitals Leuven, B-3000 - Leuven/BE
  • 8School Of Public Health And Preventative Medicine, Alfred Health, 3004 - Melbourne/AU
  • 9Human Oncology And Pathogenesis Program & Department Of Medicine, Memorial Sloan Kettering Cancer Center, 10065 - New York/US
  • 10Sarcoma Unit, Royal Marsden and Institute of Cancer Research, SW3 6JJ - London/GB
  • 11Interdisciplinary Oncology, Helios Klinikum Berlin-Buch, 13125 - Berlin/DE
  • 12Medical Oncology, Mayo Clinic in Florida, 32224 - Jacksonville/US
  • 13Medical Oncology, Sylvester Comprehensive Cancer Center/University of Miami, 33130 - Miami/US
  • 14Clinical Development, Deciphera Pharmaceuticals, LLC, 02451 - Waltham/US
  • 15Biostatistics, Deciphera Pharmaceuticals, LLC, 02451 - Waltham/US
  • 16Medicine, Centre Léon Bérard, 69008 - Lyon/FR

Abstract

Background

Ripretinib is a switch-control kinase inhibitor that broadly inhibits KIT- and PDGFRA-mutated kinases by regulating the kinase switch pocket and activation loop.

Methods

Patients (pts) with advanced GIST who received prior treatment with at least imatinib, sunitinib, and regorafenib were enrolled. Pts were randomized 2:1 to ripretinib 150 mg QD or placebo (P) and stratified by 3 v ≥ 4 prior therapies and ECOG 0 v 1-2. Patients with a PD on 150 mg QD were allowed to dose escalate and patients on P arm crossed over to ripretinib at PD. The primary end point was PFS per blinded independent central review. Secondary end points included objective response rate (ORR; key end point) and OS.

Results

129 pts were randomized as ITT. In the double-blind period, ripretinib improved median PFS over P (6.3 v 1 mo; HR = 0.15; 95%CI: 0.09,0.25; P < 0.0001). PFS rates at 6 mo were 51% (95%CI: 39.4,61.4) for ripretinib and 3.2% (95%CI: 0.2,13.8) for P. Analysis of PFS in pt subgroups assessed favored ripretinib. ORR was 9.4% for ripretinib and 0% for P (P = 0.0504; median duration not reached). Ripretinib demonstrated an improvement over P in median OS (15.1 v 6.6 mo; HR = 0.36; 95%CI: 0.20,0.62; nominal P = 0.0004). OS rates at 12 mo were 65.4% (95%CI: 51.6,76.1) for ripretinib and 25.9% (95%CI: 7.2,49.9) for P. Ripretinib was generally well tolerated. Any dose reductions were in 7 pts (8.2%) in ripretinib arm v 1 (2.3%) in P arm; interruptions were in 18 pts (21.2%) in ripretinib v 8 (18.6%) in P arm. TEAE-related dose modifications are in the table below.Table:

LBA87

ParameterPlacebo (n = 43)*Ripretinib 150 mg QD (n = 85)
Any TEAE, n (%)42 (97.7)84 (98.8)
TEAE leading to dose reduction, n (%)1 (2.3)6 (7.1)
TEAE leading to treatment discontinuation, n (%)5 (11.6)7 (8.2)
TEAE leading to study discontinuation, n (%)0 (0)0 (0)
Any grade 3/4 TEAE, n (%)19 (44.2)42 (49.4)
Most common (>5%) grade 3/4 TEAE, n (%)
—Abdominal pain2 (4.7)6 (7.1)
—Anemia6 (14.0)8 (9.4)
—Hypertension0 (0)6 (7.1)
TEAEs in > 10% of patients in ripretinib arm, n (%)
—Alopecia2 (4.7)44 (51.8)
—Fatigue10 (23.3)36 (42.4)
—Nausea5 (11.6)33 (38.8)
—Abdominal pain13 (30.2)31 (36.5)
—Constipation8 (18.6)29 (34.1)
—Myalgia5 (11.6)27 (31.8)
—Diarrhea6 (14.0)24 (28.2)
—Decreased appetite9 (20.9)23 (27.1)
—Palmar-plantar erythrodysaethesia syndrome0 (0)18 (21.2)
—Vomiting3 (7.0)18 (21.2)
—Headache2 (4.7)16 (18.8)
—Weight decreased5 (11.6)16 (18.8)
—Arthralgia2 (4.7)15 (17.6)
—Blood bilirubin increased0 (0)14 (16.5)
—Edema peripheral3 (7.0)14 (16.5)
—Muscle spams2 (4.7)13 (15.3)
—Anemia8 (18.6)12 (14.1)
—Hypertension2 (4.7)12 (14.1)
—Asthenia6 (14.0)11 (12.9)
—Dry skin3 (7.0)11 (12.9)
—Dyspnea0 (0)11 (12.9)
—Hypophosphatemia0 (0)9 (10.6)
—Lipase increased0 (0)9 (10.6)
—Pruritus2 (4.7)9 (10.6)
—Stomatitis0 (0)9 (10.6)
Any treatment-emergent serious AE, n (%)19 (44.2)26 (30.6)
Most common (>2%) serious AE in ripretinib arm, n (%)
—Abdominal pain2 (4.7)4 (4.7)
—Anemia1 (2.3)3 (3.5)
—Death4 (9.3)3 (3.5)
—Nausea0 (0)2 (2.4)
—Vomiting0 (0)2 (2.4)
*

44 pts were randomized to P, but 1 did not receive treatment.

Conclusions

Ripretinib improved PFS over P in advanced GIST patients after progression on standard treatments. Ripretinib was associated with a favorable tolerability profile. Ripretinib is a novel therapy in a population with no other approved therapy and may represent a new standard of care.

Clinical trial identification

NCT03353753.

Editorial acknowledgement

Medical writing assistance was provided by Laura Jung, PharmD, of ETHOS Health Communications in Yardley, Pennsylvania, and financially supported by Deciphera Pharmaceuticals, Inc.

Legal entity responsible for the study

Deciphera Pharmaceuticals, LLC.

Funding

Deciphera Pharmaceuticals, LLC.

Disclosure

M. von Mehren: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Deciphera Pharmaceuticals, LLC; Advisory / Consultancy, Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Arog Pharmaceuticals; Research grant / Funding (institution): Gradalis; Advisory / Consultancy: Exelixis; Leadership role, Chair of the Soft Tissue Sarcoma Panel: NCCN; Research grant / Funding (institution): Genmab; Research grant / Funding (institution): Novartis. C. Serrano: Advisory / Consultancy, Research grant / Funding (self): Deciphera Pharmaceuticals, LLC; Advisory / Consultancy, Speaker Bureau / Expert testimony: Blueprint Medicines; Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Bayer Healthcare; Research grant / Funding (self), Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Pharmamar; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Eli Lilly and Company. S. Bauer: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Novartis; Honoraria (self): Pfizer; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Pharmamar; Advisory / Consultancy, Research grant / Funding (institution): Blueprint Medicines; Advisory / Consultancy: ADC Therapeutics; Honoraria (self), Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Plexxikon; Advisory / Consultancy: Nanobiotix; Advisory / Consultancy: Deciphera Pharmaceuticals, LLC; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Janssen-Cilag; Advisory / Consultancy: Roche; Research grant / Funding (institution): Incyte; Non-remunerated activity/ies, External advisory board member : Federal Ministry of Health (Bundesgesundheitsministerium). H. Gelderblom: Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Deciphera Pharmaceuticals, LLC; Research grant / Funding (institution): Eli Lilly and Company; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Eisai Co, Ltd; Research grant / Funding (institution): Debio; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Teva. S. George: Advisory / Consultancy, Research grant / Funding (institution): Blueprint Medicines; Advisory / Consultancy, Research grant / Funding (institution): Deciphera Pharmaceuticals, LLC; Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Exelixis; Leadership role: Alliance Foundation; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Novartis; Shareholder / Stockholder / Stock options: Abbott Laboratories; Shareholder / Stockholder / Stock options: Allergan; Licensing / Royalties, UpToDate: Wolters Kluwer Health. M. Heinrich: Advisory / Consultancy, Speaker Bureau / Expert testimony, Licensing / Royalties, Expert testimony: Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Deciphera Pharmaceuticals, LLC; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Blueprint Medicines; Advisory / Consultancy: MolecularMD. P. Schöffski: Advisory / Consultancy, Research grant / Funding (institution), Advisory/consultancy is institutional support: Plexxikon; Advisory / Consultancy, Research grant / Funding (institution), Advisory/consultancy is institutional support: Eisai Co, Ltd; Advisory / Consultancy, Advisory/consultancy is institutional support: Loxo Oncology, Inc; Advisory / Consultancy, Research grant / Funding (institution), Advisory/consultancy is institutional support: Blueprint Medicines; Advisory / Consultancy, Advisory/consultancy is institutional support: Ellipses Pharma; Advisory / Consultancy, Advisory/consultancy is institutional support: Deciphera Pharmaceuticals, LLC; Advisory / Consultancy, Advisory/consultancy is institutional support: Merck & Co.; Advisory / Consultancy, Advisory/consultancy is institutional support: Servier; Advisory / Consultancy, Advisory/consultancy is institutional support: Genmab; Advisory / Consultancy, Advisory/consultancy is institutional support: Adaptimmune; Advisory / Consultancy, Advisory/consultancy is institutional support: Intellisphere LLC; Advisory / Consultancy, Advisory/consultancy is institutional support: Transgene; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): CoBioRes NV; Advisory / Consultancy, Research grant / Funding (institution), Advisory/consultancy is institutional support: Eli Lilly and Company; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): G1 Therapeutics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pharmamar. J. Zalcberg: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Research grant / Funding (institution): Specialized Therapeutics; Honoraria (self), Advisory / Consultancy: Targovax; Honoraria (self), Advisory / Consultancy: Halozyme; Honoraria (self): Gilead Sciences; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Sirtex Medical; Advisory / Consultancy: Lipotek; Advisory / Consultancy: Novella; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (institution): Baxalta/Shire; Research grant / Funding (institution): Eli Lilly and Company; Research grant / Funding (institution): Boehringer Ingelheim; Travel / Accommodation / Expenses: Deciphera Pharmaceuticals, LLC; Travel / Accommodation / Expenses: Sirtex; Shareholder / Stockholder / Stock options: GW Pharmaceuticals; Shareholder / Stockholder / Stock options: Aimmune; Shareholder / Stockholder / Stock options: Vertex; Shareholder / Stockholder / Stock options: Bluebird Bio; Shareholder / Stockholder / Stock options: Alnylam; Shareholder / Stockholder / Stock options: Biomarin; Shareholder / Stockholder / Stock options: Sage Therapeutics; Shareholder / Stockholder / Stock options: Dova Pharmaceuticals; Shareholder / Stockholder / Stock options: Therapeutics MD; Shareholder / Stockholder / Stock options: Juno Therapeutics; Shareholder / Stockholder / Stock options: Kite Pharma; Shareholder / Stockholder / Stock options: Kiadis Pharma; Shareholder / Stockholder / Stock options: CSL Limited; Shareholder / Stockholder / Stock options: Cochlear; Non-remunerated activity/ies, Chair: Australian Clinical Trials Alliance; Non-remunerated activity/ies, Co-Chair: National Oncology Alliance; Non-remunerated activity/ies, Co-Chair: All.Can Australia. P. Chi: Advisory / Consultancy, Research grant / Funding (institution), Clinical research support: Deciphera Pharmaceuticals, LLC; Advisory / Consultancy: Exelixis; Research grant / Funding (institution), Clinical research support: Novartis; Research grant / Funding (institution), Clinical research support: Array Biopharma. R.L. Jones: Honoraria (self), Advisory / Consultancy: Adaptimmune; Honoraria (self), Advisory / Consultancy: Blueprint Medicines; Honoraria (self), Advisory / Consultancy: Clinigen; Honoraria (self), Advisory / Consultancy: Eisai Co., Ltd; Honoraria (self), Advisory / Consultancy: Epizyme; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy: Deciphera Pharmaceuticals, LLC; Honoraria (self), Advisory / Consultancy: Immune Design Corp; Honoraria (self), Advisory / Consultancy: Eli Lilly and Company; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Pharmamar; Honoraria (self), Advisory / Consultancy: UpToDate; Advisory / Consultancy: TRACON Pharmaceuticals; Research grant / Funding (institution), Clinical trial: MSD Pharmaceuticals. P. Reichardt: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pharmamar; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly and Company; Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy: Clinigen; Advisory / Consultancy: Deciphera Pharmaceutcials, LLC; Advisory / Consultancy: Roche. S. Attia: Research grant / Funding (self): Desmoid Tumor Research Foundation; Research grant / Funding (institution): AB Science; Research grant / Funding (institution): TRACON Pharmaceuticals; Research grant / Funding (institution): CytRx Corp; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Eli Lilly and Company; Research grant / Funding (institution), Travel / Accommodation / Expenses: Immune Design; Research grant / Funding (institution): Karyopharm Therapeutics; Research grant / Funding (institution): Epizyme; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Genmab; Research grant / Funding (institution): CBA Pharma; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Philogen; Research grant / Funding (institution): Gradalis; Research grant / Funding (institution): Deciphera Pharmaceuticals, LLC; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Springworks; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution): Advenchen Laboratories; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (institution): BTG; Research grant / Funding (institution): PTC Therapeutics; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): FORMA Therapeutics. G. D’Amato: Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly and Company; Advisory / Consultancy: Blueprint Medicines; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Eisai Co., Ltd. J. Meade: Shareholder / Stockholder / Stock options, Full / Part-time employment: Deciphera Pharmaceuticals, LLC. K. Shi: Shareholder / Stockholder / Stock options: Alnylam; Shareholder / Stockholder / Stock options: Immunogen; Full / Part-time employment: Deciphera Pharmaceuticals, LLC. R. Ruiz-Soto: Shareholder / Stockholder / Stock options, Full / Part-time employment: Deciphera Pharmaceuticals, LLC. J. Blay: Honoraria (self), Honoraria (institution), Advisory / Consultancy: Novartis; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Bayer; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Pfizer; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Deciphera Pharmaceuticals, LLC; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Roche.