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First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study

Ryan J. Sullivan, Jeffrey R. Infante, Filip Janku, Deborah Jean Lee Wong, Jeffrey A. Sosman, Vicki Keedy, Manish R. Patel, Geoffrey I. Shapiro, James W. Mier, Anthony W. Tolcher, Andrea Wang-Gillam, Mario Sznol, Keith Flaherty, Elizabeth Buchbinder, Richard D. Carvajal, Anna M. Varghese, Mario E. Lacouture, Antoni Ribas, Sapna P. Patel, Gary A. DeCrescenzo, Caroline M. Emery, Anna L. Groover, Saurabh Saha, Mary Varterasian, Dean J. Welsch, David M. Hyman and Bob T. Li
Ryan J. Sullivan
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
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  • For correspondence: rsullivan7@mgh.harvard.edu lib1@mskcc.org
Jeffrey R. Infante
2Sarah Cannon Research Institute, Tennessee Oncology, Nashville, Tennessee.
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Filip Janku
3The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Deborah Jean Lee Wong
4University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California.
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Jeffrey A. Sosman
5Vanderbilt University Medical Center, Nashville, Tennessee.
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Vicki Keedy
5Vanderbilt University Medical Center, Nashville, Tennessee.
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Manish R. Patel
6Sarah Cannon Research Institute, Florida Cancer Specialists, Sarasota, Florida.
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Geoffrey I. Shapiro
7Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
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James W. Mier
8Beth-Israel Deaconess Medical Center, Boston, Massachusetts.
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Anthony W. Tolcher
9South Texas Accelerated Research Therapeutics, San Antonio, Texas.
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Andrea Wang-Gillam
10Washington University in St. Louis, St. Louis, Missouri.
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Mario Sznol
11Yale University, New Haven, Connecticut.
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Keith Flaherty
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
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Elizabeth Buchbinder
7Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
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Richard D. Carvajal
12Memorial Sloan Kettering Cancer Center, New York, New York.
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Anna M. Varghese
12Memorial Sloan Kettering Cancer Center, New York, New York.
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Mario E. Lacouture
12Memorial Sloan Kettering Cancer Center, New York, New York.
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Antoni Ribas
4University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California.
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Sapna P. Patel
3The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Gary A. DeCrescenzo
13BioMed Valley Discoveries, Inc., Kansas City, Missouri.
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Caroline M. Emery
13BioMed Valley Discoveries, Inc., Kansas City, Missouri.
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Anna L. Groover
13BioMed Valley Discoveries, Inc., Kansas City, Missouri.
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Saurabh Saha
13BioMed Valley Discoveries, Inc., Kansas City, Missouri.
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Mary Varterasian
13BioMed Valley Discoveries, Inc., Kansas City, Missouri.
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Dean J. Welsch
13BioMed Valley Discoveries, Inc., Kansas City, Missouri.
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David M. Hyman
12Memorial Sloan Kettering Cancer Center, New York, New York.
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Bob T. Li
12Memorial Sloan Kettering Cancer Center, New York, New York.
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  • For correspondence: rsullivan7@mgh.harvard.edu lib1@mskcc.org
DOI: 10.1158/2159-8290.CD-17-1119 Published February 2018
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    Figure 1.

    Study schema. An accelerated dose-escalation study design was used to investigate doses from 10 to 900 mg, twice daily (b.i.d.), followed by expansion cohorts initially receiving the preliminary recommended phase II dose (RP2D) of 600 mg, twice daily.

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    Figure 2.

    Pharmacokinetics and pharmacodynamics of ulixertinib. Plasma concentrations of ulixertinib as a function of time and dose level following dosing on day 1 (A) and at steady state (B). AUC as a function of dose level following dosing on day 1 (C) and at steady state (D). The data for dose levels 10 to 150 mg twice daily (b.i.d.) represent a single patient at each dose level. Plasma levels and pharmacodynamic effects of ulixertinib are shown as a function of the dose level (E). Ulixertinib plasma levels from patients dosed with 600 mg/kg, twice daily, are shown at day 1 and steady state (F).

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    Figure 3.

    Dose-escalation patient response. Individual patient's target lesion response (A) and time on study (B) are shown as a function of initial dose level. C, A representative sustained partial tumor response in a melanoma patient that was refractory to prior BRAF inhibitor therapy. Horizontal red line in A depicts RECIST v1.1 partial response threshold. b.i.d., twice daily.

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    Figure 4.

    Cohort expansion patient response. Target lesion responses (A) and time on study (B), grouped by cohort, are shown for each evaluable patient initially dosed with 600 mg of ulixertinib twice daily in the expansion phase of the study. Specific genetic mutations are also indicated (A, B). C, Tumor response data for patients with atypical (non-V600) BRAF mutations, with specific mutations indicated. Data are further discriminated by color based on the literature-reported MAPK pathway activity, as indicated by pERK levels. CRC, colorectal cancer; NSCLC, non–small cell lung cancer.

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    Figure 5.

    Representative patient responses to ulixertinib. Longitudinal radiographic scans from a subset of patients who responded to ulixertinib are shown. A, A patient with gallbladder adenocarcinoma with a BRAF L485W mutation who experienced partial response in two lesions (green circles) over 12 weeks. B, A patient with glioblastoma multiforme with a BRAF V600E mutation who experienced a 64% reduction of their tumor (green circles) after 10 cycles of treatment with ulixertinib.

Tables

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  • Table 1.

    Clinical characteristics of patients at baseline, including cancer types, prior therapies, and enrollment

    Baseline characteristicAll patients (N = 135)
    Age
     Median (range), years62 (21–85)
     ≥65 year63 (47)
    Sex, n (%)
     Male83 (61)
     Female52 (39)
    ECOG performance status, n (%)
     045 (33)
     190 (67)
    Prior immune therapy, n (%)
     Yes69 (51)
     No66 (49)
    Prior BRAFi/MEKi therapy, n (%)
     Yes32 (24)
     No103 (76)
    Pretreatment LDH, n (%)
     Elevated43 (32)
     Not elevated50 (37)
     Not done42 (31)
    Body mass index
     Median (range), kg/m226.83 (14.6–148.2)
    Primary cancer type, n (%)
     Melanoma53 (39)
     Colorectal26 (19)
     Non–small cell lung19 (14)
     Papillary thyroid6 (4)
     Glioblastoma4 (3)
     Prostate3 (2)
     Small intestine3 (2)
     Othera21 (16)
    Enrollment, n (%)
     Dose escalation27 (20)
     BRAF colorectal cohort17 (13)
     BRAF non–small cell lung cohort16 (12)
     BRAF melanoma cohort21 (16)
     BRAF other cancer cohort24 (18)
     NRAS melanoma cohort22 (16)
     MEK cancer cohort8 (6)
    • NOTE. Data are presented as N (%) unless indicated otherwise.

    • aIncludes adenoid cystic, angiosarcoma, appendiceal, cecum, cholangiocarcinoma, gallbladder, gastrointestinal stromal tumor, mediastinal non-seminomatous germ cell tumor, mesothelioma, ovarian, pancreatic, salivary duct, small cell lung, squamous cell, thyroid, urachal, and vaginal.

  • Table 2.

    Patients with AEs that occurred in ≥10% (possibly related or related) including combined rash events and combined ocular events

    <300 mg b.i.d. (n = 5)300 mg b.i.d. (n = 4)600 mg (n = 115)>600 mg b.i.d. (n = 11)
    Adverse event, n (%)Grade 1/2Grade 3Grade 1/2Grade 3Grade 1/2Grade 3Grade 1/2Grade 3Total (N = 135)
    Combined rasha3 (60)0 (0)3 (75)0 (0)65 (56)22 (19)8 (72)1 (9)102 (76)
    Diarrhea5 (100)0 (0)1 (25)0 (0)44 (38)7 (6)5 (45)3 (27)65 (48)
    Fatigue3 (60)0 (0)1 (25)0 (0)43 (37)3 (3)5 (45)2 (18)57 (42)
    Nausea3 (60)0 (0)2 (50)0 (0)44 (38)2 (2)6 (54)0 (0)57 (42)
    Decreased appetite0 (0)0 (0)0 (0)0 (0)28 (24)0 (0)6 (54)0 (0)34 (25)
    Pruritus0 (0)0 (0)1 (25)0 (0)27 (23)1 (<1)4 (36)0 (0)33 (24)
    Vomiting0 (0)0 (0)2 (50)0 (0)18 (16)1 (<1)4 (36)1 (9)26 (19)
    Combined ocular eventsb1 (20)0 (0)0 (0)0 (0)14 (12)1 (<1)2 (18)0 (0)18 (13)
    Edema peripheral1 (20)0 (0)0 (0)0 (0)12 (10)1 (<1)1 (9)0 (0)15 (11)
    Anemia0 (0)1 (20)0 (0)0 (0)6 (5)5 (4)0 (0)3 (27)15 (11)
    Dehydration0 (0)0 (0)0 (0)0 (0)9 (8)1 (<1)1 (9)2 (18)13 (10)
    Alopecia1 (20)0 (0)0 (0)0 (0)10 (9)0 (0)2 (18)0 (0)13 (10)
    • Abbreviation: b.i.d., twice daily.

    • ↵a“Combined rash” includes preferred terms of dermatitis acneiform (42), acne (1), skin exfoliation (2), and any term containing rash (81).

    • ↵b“Combined ocular events” includes preferred terms of halo vision (1), photophobia (2), retinal detachment (1), retinal vein occlusion (1), retinopathy (1), vision blurred (6), visual impairment (10), and vitreous floaters (1). Note that retinal vein occlusion event (grade 3) occurred after >10 months on study and resolved with drug cessation.

Additional Files

  • Figures
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  • Supplementary Data

    • Table S1 - Tumor types and molecular alterations of enrolled patients
    • Table S2 - Dose levels enrolled in dose escalation with number and description of dose limiting toxicities at each dose level.
    • Table S3 - Pharmacokinetic data expressed in Cmax at each dose level in the dose escalation portion of the study.
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Cancer Discovery: 8 (2)
February 2018
Volume 8, Issue 2
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First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study
Ryan J. Sullivan, Jeffrey R. Infante, Filip Janku, Deborah Jean Lee Wong, Jeffrey A. Sosman, Vicki Keedy, Manish R. Patel, Geoffrey I. Shapiro, James W. Mier, Anthony W. Tolcher, Andrea Wang-Gillam, Mario Sznol, Keith Flaherty, Elizabeth Buchbinder, Richard D. Carvajal, Anna M. Varghese, Mario E. Lacouture, Antoni Ribas, Sapna P. Patel, Gary A. DeCrescenzo, Caroline M. Emery, Anna L. Groover, Saurabh Saha, Mary Varterasian, Dean J. Welsch, David M. Hyman and Bob T. Li
Cancer Discov February 1 2018 (8) (2) 184-195; DOI: 10.1158/2159-8290.CD-17-1119

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First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study
Ryan J. Sullivan, Jeffrey R. Infante, Filip Janku, Deborah Jean Lee Wong, Jeffrey A. Sosman, Vicki Keedy, Manish R. Patel, Geoffrey I. Shapiro, James W. Mier, Anthony W. Tolcher, Andrea Wang-Gillam, Mario Sznol, Keith Flaherty, Elizabeth Buchbinder, Richard D. Carvajal, Anna M. Varghese, Mario E. Lacouture, Antoni Ribas, Sapna P. Patel, Gary A. DeCrescenzo, Caroline M. Emery, Anna L. Groover, Saurabh Saha, Mary Varterasian, Dean J. Welsch, David M. Hyman and Bob T. Li
Cancer Discov February 1 2018 (8) (2) 184-195; DOI: 10.1158/2159-8290.CD-17-1119
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