Anthony J. Olszanski,1 Rene Gonzalez,2 Pippa Corrie,3 Anna Pavlick,4 Mark Middleton,5 Paul Lorigan,6 Ruth Plummer,7 Sunil Skaria,8 Christopher Herbert,9 Martin Gore,10 Sanjiv S. Agarwala,11 Adil Daud,12 Steven Zhang,13 Brittany Bahamon,13

Lakshmi Rangachari,13 Eric Hoberman,13 Michelle Kneissl,13 Drew Rasco14

1Fox Chase Cancer Center, Philadelphia, PA, USA; 2University of Colorado Denver, Denver, CO, USA; 3Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; 4New York University Cancer Center, New York, NY, USA; 5Oxford University Hospitals NHS Trust, Oxford, UK; 6University of Manchester, Institute of Cancer Sciences, and The Christie NHS Foundation Trust, Manchester, UK; 7Newcastle University, Newcastle-upon-Tyne, UK; 8Mid Essex Hospital, Chelmsford, UK; 9University Hospitals Bristol, Bristol, UK; 10The Royal Marsden Hospital, London, UK; 11St Luke’s Cancer Center, Bethlehem, PA, USA; 12University of California, San Francisco, CA, USA13Millennium Pharmaceuticals, Inc., Cambridge MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited; 14South Texas Accelerated Research Therapeutics, San Antonio, TX, USA

Phase 1 study of the investigational, oral pan-RAF kinase inhibitor TAK-580 (MLN2480) in patients with advanced solid tumors or melanoma: Final analysis

#410P

Results

Characteristic200 mg Q2D

(n=80)600 mg QW

(n=19)All patients

(n=99)Median age, years (range) 65 (31−94) 70 (41−83) 66 (31−94)Male, % 54 53 54ECOG PS 0 / 1, %* 50 / 49 58 / 42 52 / 47

Disease stage at entry III / IV / missing, % 0 / 75 / 8 5 / 63 / 0 1 / 73 / 6

Prior regimens 0 / 1 / 2 /3 / 4+, %

35 / 29 / 40 /12 / 19

21 / 20 / 33 /20 / 27

32 / 27 / 39 /13 / 21

Table 1. Patient demographics and baseline disease characteristics

Poster presented at the 2017 European Society for Medical Oncology (ESMO) Congress, September 8–12, 2017, Madrid, Spain

• The MAPK pathway plays a key role in regulating cell proliferation and survival by integrating signals from various cell surface receptors (Figure 1).1,2

• Signaling hyperactivation secondary to genetic aberrations affecting the MAPK pathway occur frequently in several human tumors, and results in increased cell proliferation and survival.3,4

– Genetic alterations in the MAPK pathway occur in approximately 50–60% and 20–25% of melanomas thought to harbor BRAF and NRASmutations, respectively.5

• Because of their central role in this hyperactivated MAPK signaling cascade, RAF kinases present as candidate therapeutic targets.1,6

Antitumor activity• Of 14 NRAS+ melanoma patients naïve to MAPK inhibitors who received TAK-580 200 mg Q2D,

one achieved a PR, which lasted 1.5 months.– In comparison, none of 17 response-evaluable NRAS+ melanoma patients who received

TAK-580 600 mg QW had an objective response.• Overall, eight of the 16 BRAF+ melanoma patients naïve to MAPK inhibitors receiving TAK-580

Q2D achieved a PR (one patient is ongoing with a PFS of 40.8 months).– Of seven BRAF+ melanoma patients previously treated with MAPK inhibitors receiving

TAK-580 200 mg Q2D, one patient achieved a PR lasting 2.9 months.• There were no other objective responses.

1. Avruch J. Biochim Biophys Acta 2007;1773:1150–60. 2. Frémin C, Meloche S. J Hematol Oncol 2010;3:8.3. Davies H, et al. Nature 2002;417:949–54.4. Vakiani E, Solit DB. J Pathol 2011;223:219–29.5. Shtivelman E, et al. Oncotarget 2014;5:1701–52.6. Beeram M, et al. J Clin Oncol 2005;23:6771–90.7. Galvin K. AACR Annual Meeting 2012 (Special Session: New Drugs on the Horizon 1).8. Elenbaas B, et al. Eur J Cancer Suppl 2010;8:40–1 (abstract 105).9. Chouitar J, et al. Pigment Cell Melanoma Res 2012;25:848–9 (abstract).10. Sun Y, et al. Neuro Oncol 2017;19:774–85.11. Rasco D, et al. The European Cancer Congress 2015 (abstract 300).12. Eisenhauer EA, et al. Eur J Cancer 2009;45:228–47.

ReferencesAST, aspartate aminotransferase; AUC168h, area under the concentration-time curve from time 0 to 48 or 168 hours; BRAF+, BRAF-mutation-positive; CPK, creatine phosphokinase; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; IHC, immunohistochemistry; MAPK, mitogen-activated protein kinase; MET, tyrosine-protein kinase Met; MTD, maximum tolerated dose; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; NRAS+, NRAS-mutation-positive; PD, pharmacodynamic; pERK, phosphorylated ERK; PFS, progression-free survival; PK, pharmacokinetic(s); POC, proof-of-concept; PR, partial response; Q2D, once every 2 days; QW, once weekly; RECIST, Response Evaluation Criteria in Solid Tumors; TEAE, treatment-emergent adverse event; VEGFR, vascular endothelial growth factor receptor; WT, wild type.

Abbreviations

The authors would like to thank the patients and their families, as well as staff at all investigational sites. The authors also acknowledge Yosef Mansour of FireKite, an Ashfield Company, part of UDG Healthcare plc, who provided medical writing assistance during the development of this poster, which was funded by Millennium Pharmaceuticals, Inc.

Acknowledgements

Background

• The safety and PK profiles of TAK-580 at the MTDs of 200 mg Q2D and 600 mg QW were acceptable. – PK profiles achieved comparable systemic exposures as measured by normalized AUC.– QW dosing was better tolerated than Q2D.

• The 50% response rate in BRAF+ melanoma with TAK-580 200 mg Q2D is similar to that achieved with approved BRAF inhibitors. – However the absence of a comparable cohort of BRAF+ melanoma patients receiving the

QW schedule makes an efficacy comparison difficult.– Response rates in patients with BRAF WT melanoma were disappointing (no objective

responses). – Response rates in patients with NRAS+ melanoma were limited to a single PR using the

Q2D schedule.• PD results were consistent with the proposed mechanism of action of TAK-580 and

demonstrated effective MAPK pathway inhibition.• Together these results suggest that the QW dosing has revealed only an improvement in safety

and no improvement in efficacy.• The improved safety profile of the QW dosing schedule is currently being assessed in rational

drug combinations to target tumor indications where dysregulation of the MAPK pathway is present (NCT02327169).

Conclusions

*Corresponding author contact information: anthony.olszanski@fccc.edu

This study was funded by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.Disclosures

Figure 5. Representative images of pERK and BIM staining in matched screening and post-dose tumor biopsy pairs

• TAK-580 is an orally administered, investigational pan-RAF kinase inhibitor7–9 that is being investigated for the treatment of solid tumors, both as a single agent and in combination.– Biochemically, TAK-580 demonstrates potent inhibition of BRAF and CRAF WT kinases in

addition to BRAFV600E-mutant. Further, TAK-580 is described as a type-II inhibitor targeting the ‘Asp-Phe-Gly (DFG)-out’ conformation of the kinase leading to activity in cells where the RAF kinase functions as a dimer.10 Together these features define TAK-580 as a pan-RAF inhibitor and support its differentiation from approved BRAF-specific RAF inhibitors indicated in metastatic melanoma.7,8

– As RAF is downstream from RAS, a pan-RAF inhibitor should also inhibit signaling emanating from cells with mutated RAS.

• We report updated data from the dose-expansion cohorts of a single-agent, first-in-human study of TAK-580 in patients with locally advanced metastatic melanoma (NCT01425008).– Previous findings from the dose-escalation cohorts indicated an acceptable safety profile that

is consistent with other therapies targeting the MAPK pathway, and early signs of antitumor activity.11

– The MTDs of TAK-580 identified during dose escalation, and used for the dose-expansion cohorts were 200 mg Q2D and 600 mg QW.11

Study design• This was a phase 1, multicenter, non-randomized, open-label, dose-escalation and

dose-expansion study (Figure 2).

Methods

Inclusion criteria• Age ≥18 years.• Dose-escalation and PK expansion cohort:

– Patients with advanced solid tumors (excluding lymphoma, including melanoma) who had failed or were not candidates for standard therapies, or for whom no approved therapy was available.

• Dose-expansion phase:– Patients with locally advanced, metastatic, and/or unresectable melanoma meeting cohort-

specific criteria with regard to tumor genotype and treatment history (Figure 2).• A fresh tumor biopsy for genotyping was taken for all patients in the melanoma expansion

cohorts (Q2D and QW) at screening. • Local testing was accepted for the NRAS+ QW dose-expansion cohort.

• ECOG PS ≤1.• Prior chemotherapy or hormone therapy completed at least 4 weeks or four half-lives prior to

TAK-580 dosing; immunotherapy/monoclonal antibody therapy completed at least 4 weeks prior to TAK-580 dosing; radiation therapy completed at least 3 weeks prior to TAK-580 dosing.

• All prior therapy-associated toxicity resolved to grade ≤1.• Adequate hematologic, hepatic, renal, and thyroid function.Assessments• Toxicity was graded according to NCI-CTCAE v4.03.• Disease assessments were performed at baseline and every 2 cycles thereafter, using modified

RECIST criteria (v1.1).12

• Patients underwent regular dermatologic examination.PD analysis• Tumor biopsies were obtained on day 21, cycle 1 (post-dose) in the Q2D melanoma

dose-expansion cohorts, and on day 22, cycle 1 (post-dose) in the QW dose-expansion cohort.• The downstream PD markers pERK and BIM (Figure 3) were assessed using IHC assays.PK analysis• Intensive plasma PK were assessed

pre-dose and at specified timepointspost-dose days 1 and 21 (Q2D schedule) and days 1 and 22 (QW schedule) of cycle 1. Sparse plasma PK samples were collected in melanoma expansion and dose expansion cohorts.

• Intensive PK data were analyzed using non-compartmental analysis methods (Phoenix WinNonlin version 6.3 or above).

Statistical considerations• All comparisons are descriptive; no

formal statistical analysis was undertaken.

• Safety and PK were compared between the two MTD schedules(200 mg Q2D and 600 mg QW).

• Activity was assessed in all cohorts (excluding the PK expansion cohort).

Patients• Data are presented from the data cutoff of February 8, 2017 in patients treated at the MTDs in the

dose-expansion phase (Table 1):– TAK-580 200 mg Q2D; n=80

• 60 patients with melanoma (58 patients in six cohorts, Figure 2, plus two with unknown mutation status).

• 20 patients with solid tumors (PK expansion cohort).– TAK-580 600 mg QW; n=19 (Figure 2).

Safety• The median number of cycles received was 2 (range 1–46); 33% of patients received ≥4 cycles.• Sixty-eight percent of all patients experienced a grade ≥3 TEAE (Table 2). • The most common drug-related TEAEs overall were fatigue (32%), maculopapular rash (31%), and

anemia (24%) (Table 3).– The incidence of TEAEs appeared lower with QW versus Q2D dosing.

Incidence, n (%)200 mg

Q2D (n=80)600 mg

QW (n=19)All patients

(n=99)

Any TEAE 80 (100) 19 (100) 99 (100)Grade ≥3 TEAE 58 (73) 9 (47) 67 (68)Drug-related grade ≥3 TEAE 33 (41) 6 (32) 39 (39)Serious TEAE 40 (50) 8 (42) 48 (48)Drug-related serious TEAE 12 (15) 4 (21) 16 (16)TEAE resulting in discontinuation 15 (19) 2 (11) 17 (17)On-study deaths* 6 (8) 0 6 (6)

Table 2. Summary of TEAE following TAK-580 treatment

200 mgQ2D (n=80)

600 mgQW (n=19)

All patients (n=99)

Incidence, n (%) All Grade ≥3 All Grade ≥3 All Grade ≥3Fatigue 24 (30) 2 (3) 8 (42) 0 32 (32) 2 (2)Maculopapular rash 29 (36) 7 (9) 2 (11) 0 31 (31) 7 (7)Anemia 21 (26) 6 (8) 3 (16) 2 (11) 24 (24) 8 (8)Elevated CPK 20 (25) 2 (3) 1 (5) 0 21 (21) 2 (2)Nausea 16 (20) 0 3 (16) 0 19 (19) 0Myalgia 14 (18) 0 3 (16) 0 17 (17) 0Periorbital edema 14 (18) 1 (1) 2 (11) 0 16 (16) 1 (1)Pruritis 14 (18) 0 1 (5) 0 15 (15) 0Constipation 13 (16) 1 (1) 2 (11) 0 15 (15) 1 (1)Elevated AST 10 (13) 2 (3) 0 0 10 (10) 2 (2)

Table 3. All-grade drug-related TEAEs occurring in ≥15% of patients overall, and grade ≥3 TEAEs occurring in ≥2 patients following TAK-580 treatment

Figure 2. Study schema

BRAF+ Naïve to MAPK

inhibitors (n=16)

Q2D escalation: 20–280 mg

MTD = 200 mg

Dose-escalation phase

Dose-expansion phase

QW escalation: 400–800 mg

MTD = 600 mg

POC in melanoma Q2D expansion

NRAS+ Naïve to MAPK

inhibitors (n=16)

PK: Any solid tumor (excluding lymphoma, including melanoma)

(n=20)

BRAF+ Prior MAPK

inhibitors (n=8)

Additional melanoma Q2D expansion

NRAS+ Prior MAPK

inhibitors (n=1)

BRAF / NRAS WT Prior chemotherapy

(n=11)

BRAF / NRAS WT Naïve to

chemotherapy (n=6)

NRAS+Naïve to MAPK

inhibitors (n=19)

QW melanoma expansion

*On-study deaths were due to sepsis, pneumonia, malignant melanoma, small intestinal bowel obstruction (each n=1) and metastatic malignant melanoma (n=2). None were considered related to study treatment

Figure 4. Comparison of systemic exposure in terms of AUC following oral administration of TAK-580 200 mg Q2D on day 21, cycle 1 or TAK-580 600 mg QW on day 22, cycle 1

TAK

-580

AU

C

(ng*

h/m

L)

7 x 105

3 x 105

6 x 105

4 x 1055 x 105

1 x 1052 x 105

03 x AUC48h

200 mg (n=19)

AUC168h600 mg(n=9)

Box plots represent median and 25–75 percentiles, with bars representing 10–90 percentiles.Black dots indicate data points outside of the 10–90 percentiles

*ECOG PS data missing for one patient at 200 mg Q2D

PK• AUC168h after TAK-580 600 mg was comparable to 3-fold AUC48h after 200 mg (Figure 4). Figure 6. Target inhibition (pERK and BIM) in the 200 mg Q2D melanoma expansion cohort

for individual patients (n=18) before and after dosing (A) and by response (B)

Pre- and post-dose refer to screening and day 21, cycle 1 Each line represents one individual patient

• Patients were enrolled into seven separate cohorts in the Q2D dose-expansion phase:– Six cohorts of patients with melanoma, divided according to tumor genotype and treatment

history.– A PK expansion cohort, comprising patients with any advanced solid tumor.

• The QW dose-expansion phase included a cohort of NRAS+ melanoma patients who had not received prior treatment with RAF or MEK inhibitors.

Study drug administration• During the dose-expansion phase, TAK-580 was given continuously (no washout) in 28-day

cycles at either 200 mg Q2D or 600 mg QW (days 1, 8, 15, and 22).– Patients in the PK expansion cohort received TAK-580 200 mg Q2D on days 1–21 in cycle 1

(11 doses), with no drug given on days 22–28; dosing was continuous for the remaining cycles.• All patients fasted (with the exception of water) for at least 2 hours prior to and at least 2 hours

after taking TAK-580.• All patients received TAK-580 until disease progression, unacceptable toxicity, or patient

withdrawal.Objectives• Primary: Safety, MTD.• Secondary: Preliminary antitumor activity, PK and PD effects.

Figure 3. PD markers assessed: pERK and BIM

GTP P P

TAK-580

BIM

GDP

P

P

SHCGRB2

SOS RASRAF

MEK1/2

ERK1/2

RAF

ON OFF

PD• Eighteen tumor biopsy pairs (screening and post-dose) have been analyzed to date.• MAPK pathway inhibition was confirmed by inhibition of pERK and associated increases in BIM

expression, as shown by IHC analysis (Figures 5 and 6).

Post

Pre

BIMpERK

Figure 1. The RAS/RAF/MEK/ERK signaling pathway

GRB2SHC

BIM

AP-1 Cyclin D1 PROLIFERATION

MAPK(ERK)

MEK1MEK2

ARAFBRAFCRAF

TAK-580

RAS

Growth factorReceptor tyrosine kinases (e.g. EGFR, MET, VEGFR)

CytoplasmSOS

Nucleus

GTP

P P

P P

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